nanomaterials Review Platinum-Based Nanoformulations for Glioblastoma Treatment: The Resurgence of Platinum Drugs? Paula Alfonso-Triguero 1,2 , Julia Lorenzo 1,3 , Ana Paula Candiota 1,3,4 , Carles Arús 1,3,4 , Daniel Ruiz-Molina 2 and Fernando Novio 2,5, * 1 Institut de Biotecnologia i de Biomedicina, Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; paula.alfonso@icn2.cat (P.A.-T.); julia.lorenzo@uab.es (J.L.); anapaula.candiota@uab.cat (A.P.C.); carles.arus@uab.es (C.A.) 2 Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, 08193 Barcelona, Spain; dani.ruiz@icn2.cat 3 Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain 4 Centro de Investigación Biomédica en Red, Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 08193 Cerdanyola del Vallès, Spain 5 Departament de Química, Universitat Autònoma de Barcelona (UAB), Campus UAB, 08193 Cerdanyola del Vallès, Spain * Correspondence: fernando.novio@icn2.cat; Tel.: +34-935814699 Abstract: Current therapies for treating Glioblastoma (GB), and brain tumours in general, are in- efficient and represent numerous challenges. In addition to surgical resection, chemotherapy and radiotherapy are presently used as standards of care. However, treated patients still face a dismal prognosis with a median survival below 15–18 months. Temozolomide (TMZ) is the main chemother- apeutic agent administered; however, intrinsic or acquired resistance to TMZ contributes to the limited efficacy of this drug. To circumvent the current drawbacks in GB treatment, a large number of classical and non-classical platinum complexes have been prepared and tested for anticancer activity, especially platinum (IV)-based prodrugs. Platinum complexes, used as alkylating agents in the anti- cancer chemotherapy of some malignancies, are though often associated with severe systemic toxicity Citation: Alfonso-Triguero, P.; (i.e., neurotoxicity), especially after long-term treatments. The objective of the current developments Lorenzo, J.; Candiota, A.P.; Arús, C.; is to produce novel nanoformulations with improved lipophilicity and passive diffusion, promoting Ruiz-Molina, D.; Novio, F. intracellular accumulation, while reducing toxicity and optimizing the concomitant treatment of Platinum-Based Nanoformulations chemo-/radiotherapy. Moreover, the blood–brain barrier (BBB) prevents the access of the drugs to for Glioblastoma Treatment: The the brain and accumulation in tumour cells, so it represents a key challenge for GB management. The Resurgence of Platinum Drugs? development of novel nanomedicines with the ability to (i) encapsulate Pt-based drugs and pro-drugs, Nanomaterials 2023, 13, 1619. https:// (ii) cross the BBB, and (iii) specifically target cancer cells represents a promising approach to increase doi.org/10.3390/nano13101619 the therapeutic effect of the anticancer drugs and reduce undesired side effects. In this review, a Academic Editor: Mikhael Bechelany critical discussion is presented concerning different families of nanoparticles able to encapsulate platinum anticancer drugs and their application for GB treatment, emphasizing their potential for Received: 12 April 2023 increasing the effectiveness of platinum-based drugs. Revised: 6 May 2023 Accepted: 9 May 2023 Published: 12 May 2023 Keywords: glioblastoma; platinum drugs; nanoformulation; chemotherapy; brain tumours Copyright: © 2023 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. Glioma is a general term used to describe primary brain tumours with an imbalance This article is an open access article between high mortality and morbidity compared to their low incidence. These tumours are distributed under the terms and classified according to their originating cell (supportive glial cells) including astrocytomas, conditions of the Creative Commons oligodendrogliomas, ependymomas, and mixed gliomas. Glioblastomas (GB) are the most Attribution (CC BY) license (https:// malignant and frequent type of primary astrocytomas, accounting for about 33% of all creativecommons.org/licenses/by/ brain tumours and about 80% of the total malignant central nervous system (CNS) tumours 4.0/). Nanomaterials 2023, 13, 1619. https://doi.org/10.3390/nano13101619 https://www.mdpi.com/journal/nanomaterials Nanomaterials 2023, 13, 1619 2 of 32 in adults [1]. Despite several efforts to improve GB treatment, nowadays it is still a deadly disease with poor prognosis and a median survival of less than 2 years upon diagnosis and a 5-year survival rate of 5.1% [2]. Moreover, GB is characterized by a diffuse infiltration of the adjacent brain parenchyma and development of drug resistance to standard treatments [3]. In addition to GB tumour cells, it is important to consider the tumour microenvi- ronment (TME) factors in which neoplastic and non-neoplastic (e.g., tumour-associated macrophages, infiltrating lymphocytes) cell types interact, influencing GB growth, progres- sion, and therapy resistance [4,5]. Recent studies indicate that differentiated tumour cells may dedifferentiate, acquiring a stem-like phenotype, in response to microenvironment stressful conditions such as hypoxia, acidic extracellular pH, or presence of nitric oxide [6]. Moreover, patient habits such as smoking also can induce pharmacokinetic interactions, through prevention of proapoptotic events or downregulation of proapoptotic proteins, and have a great impact on the effectiveness and toxicity of anticancer drugs [7]. As a result, adjustments of drug dosages should be taken into account in specific cases. The standard of care for many years has consisted of surgical resection followed by radiotherapy (RT) and concomitant chemotherapy (CT), first described by Stupp et al. [8]. However, due to the location and infiltrative nature of GB, complete surgical resection of the tumour is often not feasible without a high risk of neurological damage for the patient [9]. The main anticancer drug used for GB treatment is temozolomide (TMZ), although acquired resistance of TMZ often contributes to the poor efficacy of the treatment, and patient survival is only slightly improved in few months. After almost two decades since the initial publication, and several efforts devoted in preclinical and clinical studies, the harsh truth is that the outcome of GB therapeutic approaches has not significantly improved. Thus, the failure in GB treatment by now is attributable to different challenges during therapy, and also to interactions among different cells within the tumour microenviron- ment (TME). Therefore, methods to monitor genomic heterogeneity and even immune evasion would be interesting to adequate the therapy, using non-invasive strategies, to improve delivery across the blood–brain barrier and facilitate the success of personalized therapies [10]. On top of that, the economic burden of GB treatment has been reviewed in terms of cost-of-illness and cost-effectiveness studies [11]. 2. Current Landscape for GB Treatment The most effective standard clinical protocol for GB used nowadays was established back in 2005 [8] and, as previously stated, involves maximum surgical resection without compromising neurological functions followed by a combination of CT (oral administration of TMZ) and RT, and a period of adjuvant TMZ. However, there are several challenges related to treatment effectiveness: the infiltrative GB nature hampers complete tumour removal, since tumour excessive resection can lead to brain dysfunction, while incomplete removal may lead to tumour regrowth from remaining tumour cells. Moreover, a key point to brain tumour treatment is the contribution of the biological barriers, blood–brain barrier (BBB) and blood–tumour barrier (BTB) to restrictions in local drug delivery. TMZ, approved by the FDA in 1999, is the most commonly used anticancer drug for GB treatment due to its lipophilic nature enabling it to easily cross the BBB [12]. Although TMZ demonstrated increasing patient survival and suppressing tumour growth in early stages of disease, ca. 50% of treated patients do not respond to this anticancer drug. Additionally, several GB cell lines such as U87, U251, U373, or T98G have been shown to develop TMZ resistance [13–15]. The combination of TMZ with radiotherapy does not significantly improve GB patient survival [16]. Then, even after aggressive therapy, overall survival is below 2 years and therapeutic alternatives are rather limited since surgery is not always feasible [17]. Approaches such as tumour-treating fields (TTFields), in which alternating electrical fields are delivered via cutaneous transducer arrays, inhibited GB cell proliferation by interfering with mitotic apparatus, although a recent review highlighted that other effects related to TTFields such as immunogenic signaling or anti-migratory effects can be an added value in GB treatment [18]. Nanomaterials 2023, 13, 1619 3 of 32 Alternative chemotherapeutic approaches offered as second-line treatment upon TMZ failure include nitrosoureas such as lomustine, carmustine, fotemustine [19], and antiangio- genic agents which are human monoclonal antibodies that inhibits vascular endothelial growth factor (VEGF), such as Bevacizumab [20]. Additionally, many research efforts have been described towards targeted therapies in GB: targeting epidermal growth factor recep- tor (EGFR) [21], inhibiting protein kinase C (PKC) [22], or inhibiting phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling pathways PI3K and mTor [23], respectively, among others. Considering the relevant immunosuppressive effects on the GB microenvironment and crosstalk with TME, immunotherapeutic approaches are also being currently exploited, alone or in combination with standard/novel GB therapies. These therapeutic actions have been basically focused on immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 or dendritic cell-based vaccine therapies, as well as adoptive T-cell therapies [24]. Interestingly, Liu et al. reported the co-encapsulation of TMZ and an immunity activator (OTX015), using ApoE decorated red blood cell membrane, to obtain a biomimetic nanomedicine. The resulting nanoformulation showed a brain- targeted drug co-delivery and synergistic chemoimmunotherapy in vivo, with marked tumour inhibition and enhanced anti-tumour immune responses [25]. However, the strong immunosuppressive environment in GB may require further additional strategies to sensi- tize GB cells to immunotherapy [26]. Altogether, these factors contribute to the lack of a cure for GB, requiring continuous research efforts towards novel treatment strategies. An additional key factor to take into account is the side effects implication of the chemotherapeutics, and the interaction with concurrent medications. Although TMZ is one of the main chemotherapeutics used for glioblastoma first-line treatment, the admin- istration of intense doses used in the clinical protocol provoke relevant side effects such as bone marrow problems (leading to the need of treatment halting due to anemia, throm- bocytopenia, etc.) [27]. On the other hand, side effects of nitrosoureas are related to bone marrow, as well as liver, kidney, and lung damage, and an increased risk of developing leukemia [28]. In addition, nitrosoureas can cross the blood–brain barrier and cause neu- rotoxicity. Platinum complexes, and more specifically cisplatin-related therapeutics, are usually associated with nephrotoxicity and neurotoxicity [29]. Any type of therapy directed towards fast-proliferating cells might affect cell populations such as digestive system, skin, and immune cells, among others. Some therapeutic combinations have demonstrated to be effective and act synergistically for GB treatment. Moreover, since combination drugs target multiple pathways, their administration can cause significant savings: smaller drug doses, lower treatment failure rate, and slower development of drug resistance. However, it is important to consider some limitations to the use combination therapy in GB since it can trigger cumulative side effects and modest clinical benefit [30]. In this scenario, it is important to build mathematical models of synergism/antagonism of drugs and pathways for the prediction of drug combinations for the treatment of heterogeneous tumours in GB. It is also important to identifying synergistic interactions between chemotherapy, radio- therapy, and immunotherapy in order to maximize the antitumour potential of individual treatment approaches. 3. Platinum and Glioblastoma: State-of-the-Art Platinum (Pt) complexes arise as an alternative option for treating brain tumours through chemotherapy. Platinum complexes are alkylating-like drugs that crosslink with the DNA, interfering with its repairing mechanism and inducing DNA damage and cell apoptosis [31]. Pt derivatives may also modulate anti-tumour immunity [32], impair tumour invasiveness through matrix metalloproteinase (MMP) downregulation, exhibit anti-angiogenic effects, and modulate MGMT DNA repair enzyme, among others. Pt-based drugs and prodrugs have demonstrated to be effective as anticancer agents in a variety of carcinomas (i.e., testicular, ovarian, lung, and head and neck cancer) [33]. The gold-standard Pt-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have been proved to exert clinical effects in brain tumour patients [29,34–36]. Three additional platinum complexes Nanomaterials 2023, 13, x FOR PEER REVIEW 4 of 31 based drugs and prodrugs have demonstrated to be effective as anticancer agents in a Nanomaterials 2023, 13, 1619 variety of carcinomas (i.e., testicular, ovarian, lung, and head and neck cancer) [33]. The 4 of 32 gold-standard Pt-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have been proved to exert clinical effects in brain tumour patients [29,34–36]. Three additional plati- num complexes (nedaplatin, lobaplatin, and heptaplatin) have been approved in specific (nedaplatin, countries. lobaplatin, Figure 1 depictsand heptaplatin) the chemical have been structures approved of these approvedin Pt specific drugs countries. [37]. This Figure 1 depictsmay section the be chemical dividedstructures of these by subheadings. approved It should Pt drugs provide [37]. and a concise Thisprecise section may be divided descrip- by subheadings. tion It should of the experimental provide results, a concise and their interpretation, as precise description well as the of the experimental experimental conclu- results, sions thattheir can beinterpretation, drawn. as well as the experimental conclusions that can be drawn. Figure Figure1.1.Structured of Clinically Structured Approved of Clinically Platinum Approved Anticancer Platinum Drugs. Reproduced Anticancer from Ref. [37] Drugs. Reproduced from Ref. [37] with permission of the copyright holder. with permission of the copyright holder. PtPtcomplexes complexes areare described describedas effective therapeutic as effective agents agents therapeutic against against gliomas [38–40] gliomas [38–40] showing the following: (I) anti-angiogenic effects [41], (II) enhanced adjuvant therapy ef- showing the following: (I) anti-angiogenic effects [41], (II) enhanced adjuvant therapy ficacy (TMZ and radiotherapy) [36,42,43], (III) successful combination with a tyrosine ki- efficacy (TMZ and radiotherapy) [36,42,43], (III) successful combination with a tyrosine nase inhibitor [44], and (IV) acceptable toxicity in chemotherapy-naïve patients with re- kinaseGB current inhibitor [44], and [45]. Moreover, the (IV) acceptable well know toxicity chemistry in chemotherapy-naïve of Pt allows designing and generating patients with an enormous variety of platinum-based complexes with stimuli-responsiveness proper-generating recurrent GB [45]. Moreover, the well know chemistry of Pt allows designing and an enormous ties in front of pHvariety of platinum-based variation, complexes changes, redox activity, temperature with stimuli-responsiveness light irradiation, or en-properties in front zyme of pH variation, overexpression redoxdevelopments [46]. These activity, temperature offer a good changes, light irradiation, opportunity for obtainingor enzyme overexpression site-specific prodrugs[46]. These developments to maximize the therapeuticoffer efficacy a good opportunity and minimize the sidefor obtaining effect of site- platinum specific metallodrugs prodrugs toinmaximize anticancerthetherapies. However, therapeutic reportsand efficacy in the literature the minimize describ- side effect of ing the usemetallodrugs platinum of Pt, either alone or in combination in anticancer therapies. in However, different approaches/scenarios, reports in the literaturehavedescribing controversial results. In vitro studies with human SNB19 and U87 the use of Pt, either alone or in combination in different approaches/scenarios, GB cells reported the have use of non-conventional Pt complexes (platinum-acridine hybrid agent) controversial results. In vitro studies with human SNB19 and U87 GB cells reported with excellent re- the sults and toxicity profiles superior to cisplatin [47]. Different therapeutic approaches have use of non-conventional Pt complexes (platinum-acridine hybrid agent) with excellent been tested—mostly results and toxicityinprofiles vitro—in combination superior with Pt[47]. to cisplatin suchDifferent as bee venom [48], β-elemene therapeutic approaches have extracted from curcuma wenyujin [49], nitrosoureas [50,51], bioconjugates combining been tested—mostly in vitro—in combination with Pt such as bee venom [48], β-elemene EGFR targeting [52], microRNAs (miRNAs) [53,54], protein kinases C [55], tumour necro- extracted from curcuma wenyujin [49], nitrosoureas [50,51], bioconjugates combining sis factor (TNF) [56], a histone deacetylase inhibitor (HDACi) [57], topoisomerase II [58], EGFR targeting [52], microRNAs (miRNAs) [53,54], protein kinases C [55], tumour necrosis PI3K inhibitors [59], and a BK (large conductance, Ca2+-activated K+) channel inhibitor [60]. factor In (TNF) addition, [56], a histone a combination deacetylase of p(65)+Be inhibitor neutrons (HDACi) irradiation plus [57], topoisomerase cisplatin was attempted II [58], PI3K inhibitors [59], and a BK (large conductance, Ca 2+ -activated K+ ) channel inhibitor [60]. In in U87 GB cells, resulting in a marked reinforcement of cytotoxic effect [61]. addition, a combination of p(65)+Be neutrons irradiation plus cisplatin was attempted in U87 GB cells, resulting in a marked reinforcement of cytotoxic effect [61]. Regarding in vivo approaches, both in preclinical and clinical settings, single-agent car- boplatin/cisplatin has been attempted as a ‘rescue’ treatment for high-grade glioma (HGG)- afflicted patients who did not respond after treatment with chemotherapy, nitrosoureas, or temozolomide, showing only discrete, non-significant improvement in outcome [62]. When coming to drug combination, a phase II trial combining TMZ and cisplatin was performed in pretreated and recurring HGG patients (GB and grade III gliomas treated with standard surgery + chemo-radiotherapy) [35]. This study reported a progression-free survival of 35% (at 6 months) and 13.8% (at 12 months), although grades 4 and 5 side effects were observed. Although results in this study were promising, the same authors recognized Nanomaterials 2023, 13, 1619 5 of 32 that they originated from a small, non-randomized cohort, and a more detailed studied would be needed to achieve confident conclusions in this regard. Pt complexes have also been explored in combination with other chemotherapy approaches, such as a dose-intense TMZ [63,64], both in preclinical models [65] and phase II trials [66]. Moreover, Rousseau et al. reported the combination of cisplatin (delivered via convection-enhanced delivery (CED)) with photon irradiation leading to enhanced survival of F98 glioma-bearing rats [67]. Thus, Pt drugs may have great therapeutic potential when effectively delivered to the tumour regions [68]. Despite the favorable results previously described, in practice, Pt therapy is con- sidered fourth-line chemotherapeutics, i.e., it will only be used when all standard therapeutic protocols fail. At this point, we are probably facing unfavorable scenarios, dealing with highly resistant tumours. The performance observed in clinical settings has limited incidence on the overall survival of patients with brain tumours [69], neither alone nor in combination with radiotherapy [70,71] or chemotherapeutics such as carmustine [71] and TMZ [72]. Despite initial benefits reported by some authors, the administration of such Pt(II) complexes is often associated with severe systemic toxicity resulting from long-term treat- ment [73]. Moreover, the BBB contributes to the scarce drug arrival to the brain when drugs are administered orally or intravenously (i.v.). This is a key factor to explain the poor activity of such complexes in brain tumours, since passive diffusion is uncommon, and it is only feasible for small lipophilic compounds or endogenous molecules that pass through specific transporters. In fact, the use of receptor-mediated transport methodologies has been studied for many years as the most efficient mechanism for drug delivery to the brain [74]. Different methods have been explored to minimize the BBB-related challenges and to overcome this limited uptake of drugs in brain tumour while minimizing side effects. These strategies include approaches to increase the BBB permeability [75,76], use of biodegradable implants directly in the tumour [77,78], or more aggressive approaches, such as the use of a catheter to deliver drugs directly into the brain through CED [79]. Despite successful results, the development of formulations that need local device placements for drug delivery are not attractive from a clinical point of view, so new approaches ensuring proper and efficient chemotherapeutic delivery still represent a major challenge nowadays [37]. The use of nanoparticles (NPs) to increase the i.v. local delivery of drugs into the brain is one of the most promising approaches [80,81]. Their small size and large surface area are suitable to increase the solubility and bioavailability of the anticancer drugs, facilitating BBB diffusion and concentrating higher CT doses in the brain parenchyma [82]. Although NPs can benefit from the enhanced permeability and retention (EPR) effect to access and be retained in tumour tissues, the possibility of their surface functionalization enables targeting receptors or specific (bio)molecules is an added value to increase specificity or to evade the mononuclear phagocyte system [83–85]. Additionally, NPs can transport different therapeutic agents at the same time, protecting them from premature metabolism/degradation and inducing a precise control of the drug release [86]. All these advantages convert nanoparticles into suitable systems to maximize therapeutic efficacy of anticancer drugs while reducing their undesirable toxic effects [87]. Specifically, for minimizing drug resistance and side effects of platinum-based anti- cancer drugs/prodrugs while increasing their efficacy, efficient delivery systems based on cancer-specific targeting can be used [88,89]. Thus, different drug delivery systems includ- ing liposomes [90], dendrimers [52,91], polymers [92], nanotubes [93], or inorganic [94,95] and hybrid [96] nanoparticles have been evaluated with these purposes. Among them, liposomes are one of the most developed and promising drug carriers for platinum-based drugs [97], showing excellent effects without toxicity in phase I clinical trials [98]. It has been demonstrated that the nanoformulation of platinum-based drugs can significantly reduce the drug toxicity [99], improving drug delivery to tumours with a concomitant re- duction in glioma growth, without neurotoxicity, and showing increased survival rate [100]. Moreover, the combination of drug administration using nanoformulations with other methodologies to improve brain delivery such as the disruption of the BBB by non-invasive transient focused ultrasound methods has been described [101,102]. Due to the complexity Nanomaterials 2023, 13, 1619 6 of 32 and heterogeneity of tumours [103], it is suggested that each patient might need personal- ized and combined treatments to increase the efficacy of platinum-based anticancer drugs against brain tumours. 4. Platinum-Based Drugs Limitations and Opportunities Many efforts have been made to improve brain tumour treatment efficacy. The clinical treatment using platinum-based anticancer drugs reveals a series of limitations related to their clinical application and to the signaling mechanisms that cause drug resistance [29]. However, different studies have demonstrated that the therapeutic efficacy of platinum- based anticancer drugs can be significantly higher than TMZ efficacy. Thus, some questions arise, namely (i) what are the specific limitations related to the use of cisplatin in the clinical/preclinical practice of brain cancer treatment, and (ii) can these limitations be minimized? Below we will comment on some of them. 4.1. Factors Related to Brain Uptake Less than 5% of drug plasma concentration is detected in the brain after i.v. delivery of platinum-based drugs to nonhuman primates, due to high selectivity of the BBB [36]. Even in the case of malignant brain tumours with compromised BBB integrity, only modest platinum compounds uptake was reported [104]. On the other hand, it has been demon- strated that chronic treatment with platinum-based drugs results in platinum accumulation in the brain. Different studies reveal that most of the adverse effects of chemotherapy are cumulative and occur after chronic exposure to the drug [105]. Along with cumulative chronic side effects, platinum drug treatment (i.e., oxaliplatin) also causes transient acute neuropathy, affecting sensory nerves in particular [106]. 4.2. Narrow Therapeutic Window Cisplatin is a potent chemotherapeutic agent with good results for standard medul- loblastoma treatment but not for GB therapeutic protocols [107,108]. However, there is no clear explanation for the differences observed in the clinical efficacy against medulloblas- tomas and GB, even though cisplatin is effective in vitro against the latter. Recent results demonstrate that treatment with intratumoural cisplatin may be an efficient approach for brain tumour treatment with an effective narrow therapeutic window [109]. 4.3. Inappropriate Dosing Schedule Frequency of administration may be a key issue when balancing effects against tumour cells and effects over host immune system. Platinum-based chemotherapy can enhance host antitumour immune responses in several ways, e.g., inducing immunogenic cell damage (ICD), increasing the activity of tumour-killing immune cells, enhancing the sensitivity of tumour cells to immune checkpoint inhibitors [110], and increasing calreticulin and major histocompatibility complex (MHC I) expression in vivo [111]. With this in mind, unsuitable administration schedules, in addition to tumour killing, may also adversely affect the host immune system, leading to opposed effects. It has been shown that the immune-related effects of these chemotherapeutics can be dependent on the drug specificity, distribution, dosing, tumour model, and type of immunotherapy in case of drug combination [109]. 4.4. Extensive Off-Target Toxicity The use of platinum drugs for the treatment of GB has shown minimal success, in part due to the extensive off-target toxicities such as nephrotoxicity or neurotoxicity [112–114]. This is not an isolated event, considering that all large molecules and most of the small ones fail to reach the brain within the required therapeutic levels [115], even in GB showing disrupted BBB. Thus, achieving suitable therapeutic doses within brain tumours sometimes requires the use of adjuvants [116,117], which may also contribute to severe adverse ef- fects. Strategies considered for increasing BBB permeability [118] include cisplatin delivery within biodegradable polymer implants into the tumour bed of patients [119] or bypassing Nanomaterials 2023, 13, 1619 7 of 32 the BBB via injection under CED [120]. However, since some of the aforementioned ap- proaches are not feasible in clinical practice, the real improvement of half-life and toxicity is rather limited. Several studies indicate that free Pt-drugs at high doses induce lym- phodepletion and may hinder rather than stimulate antitumour immune responses [121]. However, new emerging information points to the broad and multi-faceted therapeutic potential of platinum-based agents, improving the therapeutic ratio. Recent recognized immunomodulatory properties of platinum compounds seem to be able to overcome many of the mechanisms related to GB immune evasion [122]. The main advantages of nanofor- mulations are the site-specific accumulation in the brain tumour, minimizing the systemic toxicity from therapeutic drugs and reducing the off-target effects [123]. 4.5. Sequestering/Deactivating Reactions One of the main objectives in platinum-based therapies is to minimize unwanted side reactions with biomolecules prior to DNA binding. For this purpose, the development of Pt(IV) prodrugs (most of them obtained by oxidation of the Pt(II)-related complex) afforded complexes with fine-tune desired biological properties such as lipophilicity, redox stability, cancer-cell targeting, improved cellular uptake, reduced off-target toxicity, and in some cases capability to modify the mechanism of action of the Pt(II) counterpart [37]. Reduction in the inner Pt(IV) center to anticancer-active Pt(II) due to the intracellular reductive envi- ronment, in concert with the loss of two ligands, is thought to be essential for the anticancer activity of these agents. Moreover, the possibility of attaching additional ligands to the octahedral coordinative sphere of the Pt(IV) metal center allows modifying its physicochem- ical properties and also facilitates attachment to nanoparticles and other carrier systems. The use of Pt(IV) complexes also offers solutions to different deactivation/sequestration pathways that can reduce the therapeutic actuation of platinum complexes, preventing Nanomaterials 2023, 13, x FOR PEER REVIEW cancer cells from triggering apoptosis and inducing the platinum complexes’ resistance 8 of 31 (see Figure 2) [124]. Figure 2. Deactivation and/or sequestration pathways of cisplatin. In extracellular environment, Figure 2. Deactivation and/or sequestration pathways of cisplatin. In extracellular environment, through through interaction interaction with with serum serum albumin; albumin; once once it isitinside is inside the the cell,cell, sequestration sequestration by coordination by coordination to to metal-thioneins (MT) or inactivation through reaction with glutathione (GSH). metal-thioneins (MT) or inactivation through reaction with glutathione (GSH). This inactivation This inactivation generates generates adducts adducts removed removed from from thethe cellcell through through specific specific pumpspumps suchsuch as ATP7B, as ATP7B, implicated implicated in cis-in cisplatin platin resistance. resistance. Reproduced Reproduced fromfrom Ref. Ref. [124][124] withwith permission permission of theofcopyright the copyright holder. holder. 5. Platinum-Based Drugs Limitations and Opportunities The studies published to date concerning the use of platinum-based nanoformula- tions for GB treatment were grouped into different categories according to the type of drug used, as follows. A summary of the principal examples is shown in Table 1. Nanomaterials 2023, 13, 1619 8 of 32 Apart from opportunities offered by the nanoformulations, the unique properties of drug delivery vehicles can additionally provide capabilities of in vivo tracking of encap- sulated drugs [125]. Nanoparticles have demonstrated potential as dual imaging contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT) in glioma diagnosis [126]. Considering the disappointing therapeutic landscape for GB patients, discovering novel and safe methods to encapsulate and enhance drug delivery overpassing the BBB while improving biodistribution/chemical stability and decreasing side effects, has overall become a medical priority. 5. Platinum-Based Drugs Limitations and Opportunities The studies published to date concerning the use of platinum-based nanoformulations for GB treatment were grouped into different categories according to the type of drug used, as follows. A summary of the principal examples is shown in Table 1. 5.1. Cisplatin Duan et al. summarized several cisplatin-based nanoformulations with potential for clinic translation [127]. Reports related to the use of NPs for brain tumour treatment date back at least 10 years, with the encapsulation of cisplatin in polymeric NPs [128–131], polymeric mi- celles [132–134], polymeric conjugates [135,136], dendrimers [137,138], liposomes [139–141], nanocapsules [142,143], or its integration into metallic nanoparticles [144–147], silica nanoparticles [148–150], or hybrid nanoparticles (i.e., carbon nanotubes, nanoscale co- ordination polymers) [96,151–158]. Most of the published examples showed improved antitumoural effects, enhanced BBB crossing, and decreased side effects in comparison with free drugs. These benefits are related to the intrinsic properties of the NPs that can avoid the drug systemic toxicity, modulate the release of the therapeutic agent, and increase its accumulation into the tumour area by passive or active targeting processes. Different metal-based NPs containing cisplatin drugs designed for GB treatment were reported. Makharza et al. described a nanocarrier combining γ-Fe2 O3 NPs with nanographene oxide (NGO) for the selective vectorization of cisplatin. While NGO con- ferred high loading capabilities for cisplatin, the magnetic properties of the nanoparticles provided their magnetic guidance for targeting and delivery of therapeutics. The combina- tion resulted in a sustained in vitro drug release with therapeutic potential against human U87 GB cells with negligible toxicity, together with the possibility to spatially control the drug delivery in the site of action [159]. A couple of publications were reported in 2018 using gold nanoparticles (Au-NPs) for GB combined with radiation treatment. Coluccia et al. described that cisplatin conjugated Au-NPs chemotherapy was synergistic with radiation and MR-guided Focused Ultrasound (MRgFUS). Namely, viability assays with GB cell lines in vitro (U87, U251, T98G, U138) demonstrated cell growth inhibition compared to free cisplatin and showed marked syn- ergy with radiation therapy, while in vivo studies showed increased BBB permeability and brain drug delivery through MRgFUS [160]. In another example, Gotov et al. also presented cisplatin conjugated Au-NPs coated with hyaluronic acid [161]. Similarly, NPs showed enhanced cytotoxicity activity in comparison with free cisplatin in human breast adenocarcinoma MCF-7 cells, human primary U87 GB cells, or murine fibroblast NIH/3T3 (control) cell lines (see Figure 3). In vivo antitumour efficacy was demonstrated in tumour models upon i.v. administration and subsequent exposure to a near infra-red laser in the tumour site. These drug-loaded NPs showed marked in vivo activity due to their (i) long time of circulation in blood stream and (ii) selective accumulation in the tumour. This formulation demonstrated an enhanced therapeutic effect and reduced toxicity of cisplatin combining chemotherapy and laser treatment. adenocarcinoma MCF-7 cells, human primary U87 GB cells, or murine fibroblast NIH/3T3 (control) cell lines (see Figure 3). In vivo antitumour efficacy was demonstrated in tumour models upon i.v. administration and subsequent exposure to a near infra-red laser in the tumour site. These drug-loaded NPs showed marked in vivo activity due to their (i) long time of circulation in blood stream and (ii) selective accumulation in the tumour. This Nanomaterials 2023, 13, 1619 9 of 32 formulation demonstrated an enhanced therapeutic effect and reduced toxicity of cispla- tin combining chemotherapy and laser treatment. Preparation Figure3.3.Preparation Figure scheme scheme of HA-CisPt-AuNp. of HA-CisPt-AuNp. AuNp:AuNp: gold nanoparticle; gold nanoparticle; CisPt: cisplatin CisPt: cisplatin or cis- or diamminedichloroplatinum(II); DPA:DPA: cis-diamminedichloroplatinum(II); 3,30-dithiodipropionic acid; HA: 3,30-dithiodipropionic acid;hyaluronic acid; and HA: hyaluronic acid;PEG: and PEG: polyethylene polyethyleneglycol. glycol.Reproduced from Reproduced Ref. from [161] Ref. with [161] permission with of the permission of copyright holder. the copyright holder. In Invivo vivoexperiments experiments reported reported back in 2010 back with in 2010 the the with commercial commercialagent Lipoplatin™, agent Lipoplatin™, which whichhad hadalready alreadyreached reachedphasephase II/III clinical II/III studies clinical studiesfor for non-small-cell non-small-celllung lung cancercancer (NSCLC) (NSCLC)[162], [162],HER2/neu HER2/neu negative negativemetastatic metastaticbreast tumour breast tumour[163], and and [163], advanced gastric advanced gastric tumour, tumour,werewerenotnotsuccessful successful [164]. Unexpectedly, [164]. Unexpectedly, its administration its administration using CEDCED using showedshowed marked neurotoxicity resulting in death within a few days, while the i.v. marked neurotoxicity resulting in death within a few days, while the i.v. administration administration was waswell welltolerated. tolerated.The Thesame same authors authors have havealsoalso tested a home-made tested a home-made nanoformulation nanoformulation combining combining cisplatin with lipid cholesteryl hemisuccinate (CHEMS),a with cisplatin with lipid cholesteryl hemisuccinate (CHEMS), with Pt loading ef- a Pt loading ficiency of 25%. After 24 h treatment, CHEMS showed higher in vitro cytotoxicity efficiency of 25%. After 24 h treatment, CHEMS showed higher in vitro cytotoxicity against against F98 F98glioma gliomacells cellsinincomparison comparisonwith withfree freecisplatin cisplatin and andananexcellent excellentintracerebral intracerebralretention retention in in F98 glioma-bearing rats. Unfortunately, 10–14 days after administration, F98 glioma-bearing rats. Unfortunately, 10–14 days after administration, CHEMS unveiled CHEMS un- veiled dose-dependent neuropathologic findings [165]. Nowadays, there is an intense ef- dose-dependent neuropathologic findings [165]. Nowadays, there is an intense effort fort to promote targeting upon NP surface functionalization with peptides, antibodies, or to promote targeting upon NP surface functionalization with peptides, antibodies, or small molecules recognizing transporters, antigens, or receptors characteristic of tumoural cells [166]. Shein et al. described liposomes with sustained release of cisplatin reaching relevant intracellular concentration in U87 GB cells. This promising result was achieved thanks to the conjugation of liposomes with antibodies against the vascular endothelial growth factor (VEGF) and its receptor type II (VEGFR2), which account for resistance and rapid progression of brain tumours [167]. Later on, Ashrafzadeh et al. described pegylated liposomal formulations encapsulating cisplatin and decorated with thiolated OX26 monoclonal antibodies to target transferrin receptors (TR). These liposomes caused an increase in the cellular uptake by 1.4-fold in comparison to non-targeted analogous and an increase by 1.7-fold in the mean survival of the C6 glioma-bearing rats compared to non-targeted ones with notable reduction in toxicity effects [168]. Together with liposomes, polymeric NPs have been one of the most developed nanofor- mulations for cisplatin delivery in GB treatment. One of the first developments reported consisted in Pt-bearing Poly(Lactide-Co-Glycolide) (PLGA) NPs coated with protamine. These nanosystems were reported to cross the BBB using an in vitro model of bovine brain microvessel endothelial cell assay performed in 2014 [169]. In addition, the same study re- ported therapeutic activity against U87 human GB cells with these NPs. Similar poly(lactic- co-glycolic acid)-block-polyethyleneglycol NPs were used to target mitochondrial DNA Nanomaterials 2023, 13, 1619 10 of 32 in cisplatin-resistant cells. This was achieved due to their high encapsulation payloads and mitochondria-targeting abilities upon surface functionalization with a triphenylphos- phonium cation [170]. More successful experiments were performed with biodegradable PLGA NPs in 2014, which provided cisplatin-controlled release, with brain penetration and subsequent tumour targeting observed in ex vivo human and murine brain samples [171]. Experiments reported by Shahmabadi et al. using cisplatin-loaded (25% encapsulation effi- ciency) polybutylcyanoacrylate (PBCA) nanoparticles layered with polysorbate 80 failed to cross the BBB, most likely due its diameter average—larger than 400 nm [172]. PEGylated- Poly(aspartic acid) NPs encapsulating cisplatin with deep tumour penetration after local administration by CED were described by Zhang et al. [173]. With these brain-penetrating NPs, cisplatin reached concentrations feasible to kill tumour cells without healthy brain toxicity. This was demonstrated in in vivo experiments with rats bearing F98 orthotopic gliomas whose median survival was significantly increased in comparison to animals treated with free cisplatin. Later on, in 2018, poly(ethylene oxide)-triblock polymers were combined with Gd3+ /cisplatin to obtain micelles which can act as contrast agents in MRI acquisitions while increasing the therapeutic effect of free cisplatin. In fact, the formulated prodrug exhibited up to 50-fold increased accumulation in human GB cell lines and up to 32-fold enhanced subsequent Pt-DNA adduct formation in comparison with free cis- platin [174]. Moreover, in vivo MRI monitoring of Gd-bearing nanoparticles within the brain after CED determined their promising potential as multifunctional drug delivery systems for both therapy and MRI tracking. Other developments include nanogels, which are able to encapsulate cisplatin. Such approaches showed reduced toxicity in comparison with the free drug, inhibited tumour growth, and promoted extended survival of C6 glioma- bearing rats when the nanogel was functionalized with a monoclonal antibody targeted to connexin 43, a protein highly expressed in the tumour periphery of C6 gliomas [175]. Since GB usually relapses after eventual transient response, and there is no validated second-line treatment, the co-encapsulation of synergistic drugs was proposed as a thera- peutic alternative. It has been shown that cisplatin and fisetin encapsulated into liposomes have a synergistic effect, due to the combination of the anti-angiogenic effect of fisetin with the cytotoxic effect of cisplatin. The formulation showed an additive effect of cisplatin and fisetin against GB cells, demonstrating antitumoural effect [176]. Although combinatorial therapy based on TMZ plus cisplatin showed promising potential for GB therapy in clinical trials, the limited BBB crossing, poor targeting of GB tissues/cells, and systemic toxicity al- together hindered its efficacy in GB therapy. More recently, camouflaged GB cell membrane and pH-sensitive biomimetic nanoparticles demonstrated efficiently co-loading TMZ and cisplatin, providing transport across the BBB, and specifically targeting GB [177]. With this nanoformulation, a controlled release of drug cargos was obtained. A potent anti-GB effect in vivo was observed after treatment of mice bearing orthotopic U87 or the drug-resistant U251R GB tumours. The average survival was increased in mice receiving the combined drug administration compared to the survival time for mice receiving single-drug loaded nanoparticles, without noticeable side effects. Apart from the development of novel nanoformulations, the understanding of drug transport across the BBB remains limited and represents a significant challenge for HGG treatment. There is an urgent need for predictive in vitro models with realistic and dynamic blood–brain barrier vasculature features. Thus, different models have been attempted to simulate the brain tumour vasculature such as microfluidic devices emulating BBB using self-assembled endothelial cells, astrocytes, and pericytes using modular layer-by- layer assembly [178]. The objective of such approaches is to investigate the transport of targeted nanotherapeutics across the BBB and into GB cells. In the reported study, cisplatin-loaded nanoparticles decorated with GB-targeting motifs to improve tumour trafficking were evaluated in this in vitro platform. The obtained results were compared with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to properly model the in vivo BBB transport. These models represent Nanomaterials 2023, 13, 1619 11 of 32 a significant advance, enabling in-depth investigation of brain tumour vasculature and accelerating the development of targeted nanotherapeutics. The nanoformulation of cisplatin has demonstrated to remarkably improve its phar- macokinetics, which is especially unfavorable in case of glioblastomas, mainly due to challenges posed by biological barriers such as the BBB. However, the pharmacokinetic profile greatly depends on the type of nanostructure being used. In general, the integration of platinum complexes into nanoparticles allows for larger blood circulation time, more efficient arrival to the tumour zone while decreasing the amount of dosage needed, as well as protecting drugs from degradation, which increases stability. An example is a work published by Yu et al. that describes the pharmacokinetics of cisplatin-loaded polymeric nanoparticles [179]. The studies in vivo demonstrated that the selected nanoparticles had a long blood circulation time, the platinum concentration remained up to 46-fold higher than that of mice receiving equivalent doses of cisplatin, and the platinum concentration ratio of NPs to free cisplatin in tumours (lung tumour) reached as high as 9.4. Moreover, NPs im- prove the safety and tolerance in vivo, and improves the anticancer efficacy in comparison to cisplatin. Facts certainly change when talking about glioblastomas with the associated challenges for tumour delivery across the BBB: in this case, still, improvements can be obtained as shown by Ashrafzadeh et al., who reported a targeted pegylated liposomal cisplatin able to cause an increase in the cellular uptake and in brain tumour by 1.43 and 1.7-fold, respectively [168]. The administration of the NPs showed enhanced efficacy and reduced toxicity for the treatment of brain tumour. In fact, the blood–drug concentration was increased in comparison to cisplatin and then maintained in the effective range in a sustained mode. In general, the nanoformulations increase drug efficacy and low toxicity, and provide various pharmacokinetic benefits such as lowered drug accumulation with chronic drug dosing, and minimal fluctuation of drug concentration in blood. 5.2. Carboplatin Carboplatin has a lower nephrotoxicity and ototoxicity incidence than cisplatin, al- though it is less active mainly due to its lower cellular uptake [180], thus repeated adminis- tration cycles with a large number of doses are required to inhibit tumour growth [181]. Amongst the platinum complexes (carboplatin, cisplatin and oxaliplatin), carboplatin ex- hibited the lowest toxicity while providing the best survival benefits. In addition, studies inducing DNA damage by low-energy secondary electrons produced by radiation suggest that carboplatin is better than cisplatin as a radiosensitizer [182]. These studies indicate that carboplatin is the best candidate among the approved platinum drugs for treatment of human brain tumours. In an earlier study was described the covalent coupling of carboplatin to N-(2-Hydroxy- propyl)methacrylamide (HPMA) and the tetrapeptide glycyl-phenylalanyl-leucyl-glycine (GFLG), whose proteolytic cleavage allows for its intracellular drug delivery [183,184]. The resulting nanoparticles revealed a higher therapeutic effect in preclinical models (compared to free carboplatin) and were accepted in a Phase I clinical trial [185]. On the other hand, the encapsulation of carboplatin with poly (ε-caprolactone) NPs was able to minimize hemolysis and increase the cytotoxicity effect against U87 human GB cells, which was more remarkable than the free drug [186]. Recently, it has been reported that the use of carboplatin-loaded poly (butyl cyanoacrylate) (PBCA) NPs conjugated with monoclonal antibodies against epidermal growth factor receptors (EGFR) for GB treatment. In this study, both therapeutic efficacy and side effects of the resulting NPs were evaluated in vivo in a rat model of GB (see Figure 4) [187]. The findings showed a 40% augmented cytotoxicity compared to the free form of carboplatin. Moreover, in vivo studies demonstrated an increased survival and appearance of less side effects in brain, kidney, or liver, compared to rats treated with free carboplatin. In another study, authors have described biodegradable PLGA NPs with controlled carboplatin release in rat brain by CED [188]. The treatment involved recurrent infusions due to the rapid clearance of carboplatin from the brain, ment. In this study, both therapeutic efficacy and side effects of the resulting NPs were evaluated in vivo in a rat model of GB (see Figure 4) [187]. The findings showed a 40% augmented cytotoxicity compared to the free form of carboplatin. Moreover, in vivo stud- ies demonstrated an increased survival and appearance of less side effects in brain, kidney, or liver, compared to rats treated with free carboplatin. In another study, authors have Nanomaterials 2023, 13, 1619 12 of 32 described biodegradable PLGA NPs with controlled carboplatin release in rat brain by CED [188]. The treatment involved recurrent infusions due to the rapid clearance of car- boplatin from the brain, and improved outcome was observed in GB patients, essentially dueand improved to an increase inoutcome was cytotoxicity observed against in GB tumours, patients, lower essentially neuronal due toxicity, and to an increase in prolonged half-life. cytotoxicity against tumours, lower neuronal toxicity, and prolonged half-life. Figure Figure 4. Schematic 4. Schematic representation representation of targeted of targeted PBCA PBCA NPs NPs conjugated conjugated with monoclonal with monoclonal antibodies antibodies against epidermal against growth epidermal factorfactor growth receptors (EGFR)(EGFR) receptors and theand platinum-based complexescomplexes the platinum-based drug delivery drug delivery process. Reproduced process. fromfrom Reproduced Ref. [187] Ref. with [187]permission of the copyright with permission holder. holder. of the copyright Although liposomes Although are are liposomes the the principal nanosystems principal studied nanosystems for drug studied delivery, for drug the the most delivery, most appropriate liposomal formulation for CED brain tumour injection remains be appropriate liposomal formulation for CED brain tumour injection remains to to be deter- mined. Different liposomal carboplatin formulations were prepared and tested in vitro in F98 glioma cells and in Fischer rats carrying orthotopic F98 tumours. The results indicated that the therapeutic efficacy in vitro and in vivo may vary drastically depending on surface charge [189]. Cationic liposomes bind more efficiently to tumour cells, increasing their therapeutic efficacy in vitro although the median survival time did not significantly im- prove. Interestingly, anionic and pegylated liposomes diffuse better towards the tumoural area, increasing its concentration in the tumour, reducing its clearance rate, and reducing neurotoxicity relative to free carboplatin. Thus, intratumour injection of liposomal carbo- platin nanoformulations is considered a promising alternative to the administration of pure carboplatin in the chemotherapeutic treatment of GB. A comparative study tested cisplatin, oxaliplatin, carboplatin, Lipoplatin (liposomal formulation of cisplatin), and LipoxalTM (liposomal formulation of oxaliplatin) adminis- tered by intracarotid infusion to F98 gliomas orthotopically growing in Fischer rats. The nanoformulation of platinum compounds demonstrated reduced toxicity, improved cancer cell uptake, and increased survival rates either when combined or not with radiotherapy, in comparison with liposome-free drugs. Moreover, among the platinum compounds tested, liposomal carboplatin showed the largest survival increase when combined with radiation in vivo [97]. Interestingly, in the search of new routes of administration, Alex et al. encapsulated carboplatin into polycaprolactone NPs to target GB via the nasal route [190]. The NPs showed improved in vitro anti-tumour activity in comparison with the free drug against the human GB cell line LN229. Ex vivo permeation studies through sheep nasal mucosa Nanomaterials 2023, 13, 1619 13 of 32 showed a similar release pattern as for in vitro release studies. Moreover, in situ nasal perfusion administration in Wistar rats demonstrated that NPs show better nasal absorption than carboplatin solution while no severe damage to the integrity of nasal mucosa was detected. These results suggest that these nanoformulations are suitable to improve the nasal absorption of carboplatin and consequently to improve brain delivery. 5.3. Oxaliplatin Oxaliplatin was demonstrated to induce multi-faceted anti-tumour effects, more effec- tively than cisplatin and carboplatin at drug concentrations/doses below those required to induce apoptosis, which fostered specific research in the GB area. However,14inofvivo Nanomaterials 2023, 13, x FOR PEER REVIEW 31 preclinical studies were unsatisfactory since i.v. administration did not increase the me- dian survival time of F98 glioma-bearing rats [104]. This may be most likely due to the BBBApart preventing from thedrug accumulation gold-standard in braincomplexes, platinum tumours, even there when compromised are some such as additional devel- in HGGof opments [191]. novelToplatinum-based overcome thesenanoformulations limitations, the drug was with bound toresults interesting PEG-glutamic acid concerning (Glu) micelles functionalized with cyclic Arg-Gly-Asp (cRGD) in order to cross GB treatment. This is the case of a reported platinum-based polyethylenimine (PEI) poly-the BBB, target GBconjugate mer–drug cells, andwith penetrate intoanti-GB potential GB via stem cRGD-mediated transvascular cells. The cationic polymertransport presented(see a Figure 5) [192]. Their antitumour effect against GB was compared to the effect of control potent and specific toxicity in vitro. The results obtained from cytotoxicity studies with NPs functionalized with the nontargeted peptide. These nanoformulations exhibited signif- NCH421K and NCH644 GN cells indicated a necrotic cell death mechanism with an ab- icant growth inhibition effects against GB compared to the non-targeted micelles, as well sence of apoptotic markers. Several markers also indicated that this cell death mechanism as tumour accumulation, indicating the active transport of cRGD-mediated drug delivery could induce an anti-cancer immune response [195]. across vascular and tumour barriers. Figure 5. (a) Schematic showing the design strategy for the oxaliplatin encapsulation on the PEGl- Figure 5. (a) Schematic showing the design strategy for the oxaliplatin encapsulation on the PEGl- glutamic acid (Glu) micelles functionalized with cyclic Arg-Gly-Asp (cRGD), and proposed transvas- glutamic acid (Glu) micelles functionalized with cyclic Arg-Gly-Asp (cRGD), and proposed trans- cular transport vascular transportfor forthe theNPs; NPs; (b) (b) In In vitro vitro cytotoxicity, cytotoxicity, in U87 cells, in U87 cells, of offree freeoxaliplatin oxaliplatinororresulting resulting micelles with different percentages of targeting molecules (the data were analyzed micelles with different percentages of targeting molecules (the data were analyzed using Student’s using Student’s t-test,and t-test, and* *p p< <0.001 0.001was wasconsidered consideredsignificant; significant;NS: NS:not notsignificant); significant);(c) (c) Representative Representative in vivo bio- biolu- luminescence minescence imagesimagesofofmicemicetreated treatedwith with 20% 20% non-targeted non-targeted andand 20%20% of targeted of targeted micelles. micelles. Repro- Reproduced duced from from Ref. [192] Ref. [192] with permission with permission of theofcopyright the copyright holder. holder. 5.4. Pt(IV) Prodrugs Pt(IV) prodrugs have been used mainly to counteract cisplatin resistance and ne- phrotoxicity effects; while in its Pt(IV) oxidation state, side effects are considerably mini- mized, though inside the cells it is further reduced to the antitumoural active Pt(II) form [196]. Thanasupawat et al. reported self-assembled coiled nanotubes linked with a Pt(IV) Nanomaterials 2023, 13, 1619 14 of 32 Later, the liposomal formulation containing oxaliplatin (Lipoxal™) was administered via CED, which successfully improved tumour accumulation and subsequent survival time in F98 glioma-bearing rats when combined with radiotherapy. Moreover, the maximum tolerated dose (MTD) of Lipoxal™ was 3-fold superior to that of free oxaliplatin [193]. More recently, You et al. reported multiwalled carbon nanotubes (MWCNTs) containing oxali- platin functionalized with cell penetrating peptides (TAT) and the cancer targeting molecule biotin. This nanosystem enhanced oxaliplatin cytotoxicity towards glioma cells as a result of reactive oxygen species (ROS) overproduction while in vivo studies demonstrated its BBB penetration and outstanding antitumour efficacy against orthotopic glioma [194]. Apart from the gold-standard platinum complexes, there are some additional develop- ments of novel platinum-based nanoformulations with interesting results concerning GB treatment. This is the case of a reported platinum-based polyethylenimine (PEI) polymer– drug conjugate with potential anti-GB stem cells. The cationic polymer presented a potent and specific toxicity in vitro. The results obtained from cytotoxicity studies with NCH421K and NCH644 GN cells indicated a necrotic cell death mechanism with an absence of apop- totic markers. Several markers also indicated that this cell death mechanism could induce an anti-cancer immune response [195]. 5.4. Pt(IV) Prodrugs Pt(IV) prodrugs have been used mainly to counteract cisplatin resistance and nephro- toxicity effects; while in its Pt(IV) oxidation state, side effects are considerably minimized, though inside the cells it is further reduced to the antitumoural active Pt(II) form [196]. Thanasupawat et al. reported self-assembled coiled nanotubes linked with a Pt(IV) com- plex that exhibit better in vitro and in vivo toxicity against human U87 GB cells (and cells obtained from human GB samples) than free Pt(IV), mostly due to the activation of multiple death pathways. Moreover, the nanosystems were active in subcutaneous/orthotopic U87 xenografts using intratumoural administration [93]. A more complete study from Dhar and coworkers in 2015 reported a lipophilic poly- meric NP carrying a Pt(IV)-prodrug (see Figure 6) with capabilities of mitochondria tar- geting [128]. The platinum prodrug of cisplatin (Platin-M) was encapsulated in targeted polymeric nanoparticles carrying the drug across the BBB and specifically towards mito- chondria. NP-mediated controlled release of Platin-M and its subsequent reduction to cisplatin provoked the cross-linking with the mitochondrial DNA, thus forcing overactive cancer cells to undergo apoptosis. In vitro effects of the NPs in canine glioma and GB cell lines demonstrated to be much more effective than free cisplatin or carboplatin. In vivo biodistribution studies in healthy adult beagles after single i.v. injection showed high levels of Pt accumulation into the brain, with negligible amounts found in other organs. Moreover, no signs of neurotoxicity were observed, demonstrating the translational potential of these nanoformulation for applications in brain tumour treatment. A recent study showed that NPs encapsulating an oxaliplatin prodrug and a cationic DNA intercalator, administered through CED, were able to inhibit the growth of TMZ- resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human GB tumours in mice, without causing any noticeable toxicity [197]. Such polymeric nanoformulations contain disulfide bonds which are cleaved in the reductive tumour environment, which affords a selective release of anticancer drugs. The reported research findings suggest that the administration of drugs with different mechanisms of action, combined with CED, may represent a translational strategy for the treatment of TMZ- resistant gliomas. Another example includes polyethylene glycol (PEG)-stabilized solid lipid nanoparticles (SLNs) containing different Pt(IV) prodrugs derived from kiteplatin. An in vitro BBB model of immortalized human cerebral microvascular endothelial cells (hCMEC/D3) was used for evaluating the ability of the SLNs to cross the BBB, while U87 human GB was used for cell internalization and antitumour efficacy studies. These nanoformulations demonstrated potent ability to permeate the in vitro BBB model with chondria. NP-mediated controlled release of Platin-M and its subsequent reduction to cis- platin provoked the cross-linking with the mitochondrial DNA, thus forcing overactive cancer cells to undergo apoptosis. In vitro effects of the NPs in canine glioma and GB cell lines demonstrated to be much more effective than free cisplatin or carboplatin. In vivo Nanomaterials 2023, 13, 1619 15 of 32 biodistribution studies in healthy adult beagles after single i.v. injection showed high lev- els of Pt accumulation into the brain, with negligible amounts found in other organs. Moreover, no signs of neurotoxicity improved wereand cellular uptake observed, demonstrating higher reduction the intranslational in cell viability po-their comparison with tential of these nanoformulation for free counterparts applications in brain tumour treatment. [198]. Figure 6. In vitro efficacy of 6.T-Platin-M-NPs Figure In vitro efficacy of and comparison T-Platin-M-NPs and with cisplatin, comparison carboplatin, with cisplatin, Platin-M, carboplatin, Platin-M, and NT-Platin-M-NPs and in two canine brain NT-Platin-M-NPs tumour in two caninecell lines, brain J3TBG tumour andJ3TBG cell lines, SDT3G. Cell viability and SDT3G. was was Cell viability assessed by MTT assay after treatment for either 24 h followed by 48 h incubation or treatment for for assessed by MTT assay after treatment for either 24 h followed by 48 h incubation or treatment 72 h, depending on the72drug h, depending on the drug concentration. Theconcentration. The data data are mean ± SD from±three are mean SD from threeindependent to five to five independent *** p < 0.001; ** p experiments. *** p < 0.001; ** p < 0.001–0.01. Reproduced from Ref. [128] with permissionpermission experiments. < 0.001–0.01. Reproduced from Ref. [128] with of the cop- of the copyright holder. yright holder. A novel type of nanoparticles containing Pt(IV) prodrugs as building block of nanos- A recent study showed that NPs encapsulating tructured coordination polymers (NCPs)an wasoxaliplatin prodrug recently described, withand a cationic enormous potential for treating different cancers [157]. The versatility of DNA intercalator, administered through CED, were able to inhibit the growth of TMZ-coordination chemistry allows obtain- ing nanoparticles by reaction of a novel platinum (IV) prodrug and metal ions (i.e., iron or resistant cells from zinc) patient-derived xenografts, producing theranostic and [199]. nanosystems hinder the progression Ruiz-Molina of TMZ-re- et al. designed a nanoparticle sistant human GB tumours based on aincoordination mice, withoutpolymer causing any noticeable with building toxicity blocks containing [197]. Pt(IV) Such ob- complexes polymeric nanoformulations contain disulfide bonds which are cleaved in the reductivedual tained from cisplatin and iron ions as metallic nodes. This nanoformulation presents pH and redox sensitivity in vitro, showing controlled release and comparable cytotoxicity tumour environment, which affords a selective release of anticancer drugs. The reported to cisplatin against HeLa and GL261 GB cells. Interestingly, in vivo intranasal administra- research findings suggest that the preclinical tion in orthotopic administration of drugsmice GL261 GB-bearing with different increased demonstrated mechanisms of accumulation action, combined with CED, may of platinum represent in tumours, leading a translational in certain casesstrategy forprolonged to cure and the treatment survival of of the TMZ-resistant gliomas. Another example includes polyethylene glycol (PEG)-stabilizedions tested cohort (Figure 7) [96]. Additionally, the presence of magnetically active iron(III) allows these NPs to be proposed as potential nanoprobes to be tracked in vivo by MRI, solid lipid nanoparticles (SLNs) containing different Pt(IV) prodrugs derived from kitep- thus opening new opportunities for the design of intranasal glioblastoma therapies while latin. An in vitro BBB model of minimizing sideimmortalized effects. human cerebral microvascular endothelial cells (hCMEC/D3) was used for evaluating the ability of the SLNs to cross the BBB, while U87 human GB was used for cell internalization and antitumour efficacy studies. These nanoformulations demonstrated potent ability to permeate the in vitro BBB model with improved cellular uptake and higher reduction in cell viability in comparison with their free counterparts [198]. A novel type of nanoparticles containing Pt(IV) prodrugs as building block of nanostructured coordination polymers (NCPs) was recently described, with enormous potential for treating different cancers [157]. The versatility of coordination chemistry al- lows obtaining nanoparticles by reaction of a novel platinum (IV) prodrug and metal ions Gram-negative multi-drug re- Metal NPs sistant bacteria. Selective and dose- Pt(0) Ag-Pt NPs U87 cell line [201] (42 nm) dependent anticancer activity over U87 GB cells without being harm- Nanomaterials 2023, 13, 1619 ful to healthy human fibroblasts. 16 of 32 Figure 7. (a) Scheme of the Pt-Fe NCPs synthesis upon polymerization of a Pt(IV) prodrug with iron ions as metal nodes; Cumulative release profiles of Pt from Pt-Fe NCPs at 37 ◦ C at (b) pH 7.4 and (c) pH 5.5 in PBS using the dialysis method in the absence or in the presence of glutathione (GSH); (d) Biodistribution of Pt-Fe NCPs in mice organs 1 h after administration (dosage of 1.5 mg/kg, n = 3); (e) Tumour volume evolution in the period 0–20 days post-implantation (p.i.) [blue: control; red: therapy starting point at day 10 p.i.; pink: therapy starting point at day 6 p.i.; *: case of cured mice with therapy starting point at day 6 p.i. Reproduced from Ref. [96] with permission of the copyright holder. Table 1. Preclinical studies on the effect of nanoformulated anticancer Pt-complexes for GB treatment. Cells/Animal Nanocarrier Models Pt Agent Form Effect/Mechanism of Action Ref. & Size (Administration Mode) Iron oxide NPs in γ-Fe2 O3 NPs coated by NGO Superparamagnetic-like nanographene oxide Cisplatin (lateral width of U87 cell line behavior but showed little [159] (NGO) containing 80–100 nm and cytotoxicity at 10 µM. cisplatin thickness of 6.3 nm) Inhibited GB cells growth and U251/U87 cell showed marked synergy with lines, U251 Au-NPs Cisplatin conjugated to MR-guided Focused Ultrasound Cisplatin xenografts [160] (7 nm) gold NPs (MRgFUS) therapy. In vivo (intravenous assays demonstrated increased injection) BBB permeability. Nanomaterials 2023, 13, 1619 17 of 32 Table 1. Cont. Cells/Animal Nanocarrier Models Pt Agent Form Effect/Mechanism of Action Ref. & Size (Administration Mode) U87 cell line Cisplatinum attached to MCF-7 NPs inhibited GB cells growth hyaluronic Au-NPs tumour-bearing and showed marked synergy Cisplatin acid-functionalized gold [161] (145 nm) mice with the thermal effect of NPs and coated with (intravenous applying NIR laser radiation. PEG injection) F98 glioma cell line Potent in vitro cytotoxicity. High LipoplatinTM and novel F98 glioma-bearing intracerebral retention after CED. cisplatin bound to Liposomes rats CHEMS liposomes were better Cisplatin coordination complexes [165] (50–60 nm) (convection- tolerated than LipoplatinTM and with lipid cholesteryl enhanced showed increased survival data hemisuccinate (CHEMS) delivery) in vivo. Prolonged blood circulation time in C6 glioma-bearing rats. Cisplatin analogue and In vitro data confirmed that Liposomes antibodies against VEGF conjugation with specific Cisplatin C6, U87 cell lines [167] (130–160 nm) or VEGFR2 conjugated antibodies increases the on liposome surface intracellular concentration of the liposomes and improves cytotoxicity. C6 cell line Increased cellular uptake and Liposomes decorated C6 glioma-bearing Liposomes increased mean survival time Cisplatin with OX26 monoclonal rats [168] (160 nm) in vivo with notable reduction in antibodies (stereotactic toxicity effects. injection) Increased cellular uptake and Protamine- Polymeric NPs cytotoxicity in vitro and ability Cisplatin functionalized PLGA U87 cell line [169] (105 nm) to cross in vitro BBB model, NPs improving therapeutic index. PLGA-PEG copolymer C6 cell line NPs functionalized with C6 glioma-bearing Nanoparticles below 100 nm Polymeric NPs Cisplatin a rats diffused within mice brain if [170] (50–145 nm) triphenylphosphonium (intravenous densely coated with PEG. cation injection) Significantly higher cytotoxicity Polymeric NPs Cisplatin PLGA NPs U87 cell line than cisplatin, enhanced cellular [171] (114 nm) uptake. C6 cell line Similar cytotoxicity in C6 glioma-bearing Polymeric NPs comparison to cisplatin. Slightly Cisplatin PBCA NPs rats [172] (490 nm) longer mean survival time and (intraperitoneal reduced side effects. injection) 9L gliosarcoma and F98 glioma PEGylated- lines, orthotopic Reduction in toxicity associated Polymeric NPs Cisplatin Poly(aspartic acid) F98 brain tumour with cisplatin and increased [173] (70 nm) NPs model (convection- average survival in vivo. enhanced delivery) Nanomaterials 2023, 13, 1619 18 of 32 Table 1. Cont. Cells/Animal Nanocarrier Models Pt Agent Form Effect/Mechanism of Action Ref. & Size (Administration Mode) U87/U251 cell Hyperintense signal on lines, T2-weighted MRI, 50-fold Polymeric NPs U87 orthotopic Cisplatin Gd-grafted PEO micelles increased cellular accumulation, [174] (9 nm) xenografts and 32-fold Pt-DNA adduct (stereotactic compared to free cisplatin. injection) C6 cells PEG-b-PMAA nanogels Targeted delivery to C6 glioma. C6 glioma-bearing Nanogel functionalized with Prolonged the mean Cisplatin rats [175] (110 nm) monoclonal antibody to survival time of glioma-bearing (intravenous Cx43 rats. injection) U87 cell line, primary Cisplatin and small glioblastoma cell interfering RNA Potent ROS and ferroptosis, Cisplatin + line (P3#GB), (siRNA) targeting synergistically improved Glu- Iron NPs normal human glutathione peroxidase therapeutic efficacy, low [86] tathione (80–125 nm) astrocytes (NHAs) attached to IONPs and systemic toxicity achieved both Peroxidase U87orthotopic functionalized with folic in vitro and in vivo. xenografts acid (stereotactic injection) Both drugs incorporated to a liposomal Additive effect of cisplatin and Cisplatin + Liposomes formulation composed U87 cell line fisetin. Effective antitumoural [176] Fisetin (173 nm) by action against GB cells. DOPC/cholesterol/DODA- GLY-PEG2000 U87 or pH degradable acetal Improvement in BBB penetration drug-resistant grated dextran and targeting of GB tissue/cells. Cisplatin + Biomimetic NPs U251R GB inner core coated with Potent anti-GB activity in mice [177] TMZ (171 nm) tumours GB cancer cell bearing orthotopic U87 or TMZ (intravenous membrane resistant U251 (U251R) tumours. injection) Increase uptake and cytotoxicity Polymer poly in U87 human GB cell line. No Carboplatin Polymeric NPs U87 MG [186] (ε-caprolactone) NPs haemolytic activity in rat erythrocytes. Improved in vitro anti-tumour activity in comparison to free Polymeric NPs Polymer poly LN229 human GB Carboplatin. Better nasal Carboplatin [190] (20–100 nm) (ε-caprolactone) NPs cell line absorption compared to pure carboplatin solution and no severe damage of nasal mucosa. Augmented cytotoxicity Carboplatin-loaded poly C6 glioma cell lines compared to free carboplatin. (butyl cyanoacrylate) C6 glioma-bearing In vivo studies demonstrated an Polymeric NPs Carboplatin (PBCA) NPs conjugated rats increased survival time and less [187] (365 nm) with monoclonal (intraperitoneal side effects in the brain, kidney, antibody injection) or liver, compared to free carboplatin. Nanomaterials 2023, 13, 1619 19 of 32 Table 1. Cont. Cells/Animal Nanocarrier Models Pt Agent Form Effect/Mechanism of Action Ref. & Size (Administration Mode) Primary rat hippocampal cell Improved cytotoxicity in vitro. cultures. Negligible neurotoxic effects and Polymeric NPs Adult male Wistar Carboplatin PLGA NPs prolonged tissue half-life in vivo [188] (200 nm) rats and white pigs after infusion by CED in small (convection- and big animal models. enhanced delivery) PEG-P(Glu) NPs Target GB cells and ability to Polymeric NPs functionalized with Oxaliplatin U87MG cell line cross BBB. Tumour growth [192] (20–30 nm) cyclic Arg-Gly-Asp inhibition in orthotopic model. (cRGD) F98 cell line Administered by CED, increased Liposomes Liposomal formulation (convection- tumoural accumulation, and Oxaliplatin [193] (57–86 nm) (LipoxalTM ) enhanced median survival time in F98 delivery) glioma-bearing rats. Improved cytotoxicity of C6 and CHEM-5 oxaliplatin toward glioma cells. Multi-walled carbon cell lines, C6 Enhanced BBB penetration, CNTs Oxaliplatin nanotube functionalized orthotopic glioma improved brain-targeting [194] (20 nm–several µm) with TAT/Biotin (intravenous selectivity, and excellent injection) anti-tumour activity against orthotopic glioma. Canine J3TBG Overall 17 times more effective glioma and SDT3G than cisplatin in vitro. Pt(IV) Polymeric NPs Cisplatin Pt(IV) prodrug glioblastoma cell Capable of crossing the canine [128] prodrug (50–145 nm) in PLGA–PEG NPs lines BBB and accumulating in the (intravenous brain. injection) Enhanced in vitro and in vivo U87, U251, and tumour cell killing in patient GB cells, comparison with free prodrug, Pt(IV) CNTs human astrocytes, activating multiple cell death Coil nanotubes [93] prodrug (20 kDa~4 nm) U87 xenografts pathways in GB cells without (subcutaneous affecting astrocytes in vitro or injection) causing damage to healthy mouse brain. U87, TMZ-resistant Improved cell uptake and LN229 cell lines cytotoxicity in comparison to Oxaliplatin-derived and cells from a TMZ. Pt(IV) complexes patient-derived Lack of toxicity, favorable attached to a Pt(IV) Polymeric NPs xenograft. distribution of drugs into the reduction-responsive [197] prodrug (105 nm) In vivo LN229-TR region of interest, substantial polymer, xenografts tumour growth inhibition, and (poly(CHTA-co-HD)- (convection- increased by 3 the survival time PEG) enhanced in mice bearing tumours after delivery) CED administration in vivo. Solid lipid NPs U87 human GB cell Enhanced permeability, Pt(IV) Pt(IV) prodrugs derived (SLNs) line, hCMEC/D3 improved cell uptake compared [198] prodrugs from kiteplatin in (SLNs) (30–80 nm) endothelial cells to free drug. Nanomaterials 2023, 13, 1619 20 of 32 Table 1. Cont. Cells/Animal Nanocarrier Models Pt Agent Form Effect/Mechanism of Action Ref. & Size (Administration Mode) HeLa and GL261 In vitro dual pH and cell lines. redox-mediated control release. Orthotopic Nanostructured Pt(IV) prodrugs Comparable cytotoxicity to preclinical GL261 Pt(IV) Coordination obtained from cisplatin cisplatin. GB [199] prodrugs Polymers (NCPs) as building block in In vivo intranasal administration tumour-bearing (70 nm) NCPs demonstrated increased tumour mice accumulation of platinum and (intranasal effective anticancer action. administration) Marked cytotoxicity observed in Metal NPs U251, U87, and H4 lipophilic coated FePt NPs and Pt0 NPs FePt NPs [200] (2–20 nm) cell lines low cytotoxicity in the case of hydrophilic FePt NPs. Inhibition of Gram-positive and Gram-negative multi-drug resistant bacteria. Selective and Metal NPs Pt(0) Ag-Pt NPs U87 cell line dose-dependent anticancer [201] (42 nm) activity over U87 GB cells without being harmful to healthy human fibroblasts. Some references concerning use of metal-based Pt nanoparticles for GB treatment can also be found in literature. Thus, Kutwin et al. reported a comparative study between Pt-NPs and cisplatin against U87 GB cells or GB tumours growing on chorioallantoic mem- branes, observing that NPs showed antiproliferative activity although it was significantly lower than cisplatin [200]. Additionally, Lopez Ruiz et al. reported AgPt NPs with a selec- tive and dose-dependent anticancer activity on human U87 GB and A375 melanoma cell lines (10–250 µg/mL concentration range) without compromising the activity of healthy human fibroblasts [201]. Concerning the best route of administration for nanoformulations containing platinum- based drugs, Paquette et al. published a series of papers combining Pt-based complexes and radiotherapy while assessing different administration routes, being the best results achieved with intra-arterial administration [104]. The same authors had already reported in 2012 cisplatin (lipoplatin) or oxaliplatin (lipoxal) liposomes administered by intracarotid infusion in orthotopic F98 glioma-bearing rats, obtaining notable results related to reduced toxicity, improved cell uptake, and increased survival of animals when combined with radiotherapy [97]. Afterwards, they also reported the combination of Pt drugs (adminis- tered via CED) and radiation treatment in the same murine model, increasing tumour drug retention, reducing side effects, and achieving a larger median survival time [202]. The com- bination of cisplatin-bearing AuNPs with radiotherapy was also used in in vitro resistant conditions to enhance DNA double-strand rupture and therefore apoptosis rate [203]. 6. Why Repurpose Platinum Drugs and Use Nanotechnology? Treatment of GB has remained almost unchanged for more than 20 years despite of continuous research efforts towards improvement. In the search of new treatment, platinum-based drugs have resurfaced as suitable alternatives for GB therapy. Although the developed anticancer platinum drugs are being used successfully to treat a variety of cancer types, most clinical assays with GB patients fail, in general due to dose-limiting toxicities when delivered systemically or in the tumour region, the low amount of drug doses that crosses the BBB, and/or systemic toxicities occurring before effective drug Nanomaterials 2023, 13, 1619 21 of 32 concentrations can reach tumours. However, the relative success of platinum drugs for treatment of non-CNS cancers suggests that there is hope regarding their therapeutic potential, provided they are properly delivered to the tumour region. Moreover, additional effects of platinum drugs such as immunomodulatory effects, and the use of specific delivery strategies that can maximize these multimodal effects and minimize toxicities, may help to foster their re-purposing. Early clinical trials with these agents offered great promise by using cisplatin [204], carboplatin [205], or oxaliplatin [206,207]. However, in most of the clinical trials, the combination of platinum drugs with radiation therapy and/or other chemotherapeutic agents showed no significant survival advantage. In addition, systemic and dose-limiting toxicity remains a key challenge related to the administration of platinum chemotherapeutics, including nanoformulations such as LipoplatinTM which is currently in a Phase III clinical trial for treatment of non-small cell lung cancer. The DNA damaging effect of platinum-based drugs affects pathways related to cell invasion, angiogenesis, chemo- and radio-sensitization, and immunomodulation. A lower sustained platinum drug dose over longer times permits extended cell viability and reor- ganization of complex cellular pathways and the tumour microenvironment. Platinum compounds can considerably reduce the ability of GB cells to invade the surrounding tissue by downregulating matrix metalloproteinase (MMP) expression [208]; this is one of the key advantages of repurposing platinum drugs for GB therapy. Moreover, platinum com- pounds may have anti-angiogenic effects [41] and can enhance the efficacy of the current adjuvant therapies for GB (i.e., TMZ and radiotherapy) [42,43]. Additionally, it has been demonstrated that platinum drug-related immunomodula- tion can have an incidence in reversing GB-mediated immune evasion [209]. Moreover, platinum drugs are capable of modulating immunosuppressive features associated with numerous cancers including GB [210,211] and could even alter the profile of circulating immune cells or tumour-infiltrating immune cells [212]. Specifically, it has been demon- strated that oxaliplatin can induce immunogenic cell death, enhancing antitumour adaptive immune responses against antigens expressed by the dead cells [213]. However, cisplatin does not seem to induce immunogenic cell death [211]. Thus, future studies would be needed in order to investigate which platinum drugs are capable of modulating the glioma microenvironment, and to which extent, to improve the outcome of cancer treatments. Apart from the intrinsic effect of the platinum complexes, the use of nanoformulated systems may also foster improvement of the therapeutic outcomes. As it has been shown through different examples along this review, the integration of platinum drugs and prodrugs in a nanocarrier permits to protect the active compound and increase its delivery to the desired sites. Moreover, it can improve platinum-based therapies by (i) increasing the solubility of the complexes and their blood half-life, (ii) reducing side effects through targeted delivery and broader tissue distribution, (iii) providing a sustained drug release, and (iv) allowing simultaneous incorporation and delivery of other anticancer drugs for combination therapy [214]. 7. Summary and Future Perspectives The scarce advancements in GB therapy and lack of efficient therapeutic alternatives makes this disease a relevant field for pushing forward cutting-edge research. In this regard, nanoencapsulation can offer a new dimension for the assessment of both novel drugs and classic compounds with poor BBB penetration and/or previous failure in clinical trials. Among the already known drugs with demonstrated anticancer activity, but not included as usual therapeutic option at GB relapsing, platinum complexes have properties that make them especially suitable for the development of novel nanotechnology-based therapeutics. Cisplatin is usually chosen as frontline treatment [35,173], while carboplatin is rather used at tumour recurrence [215]. Recent studies using platinum drugs or prodrugs, alone or combining cisplatin with other adjuvants, have proven promising improvement in survival rates. Overall, these factors might place the platinum complexes back in the spotlight to test the new pharmacokinetic advantage paradigms provided by the nanoparticle technology. Nanomaterials 2023, 13, 1619 22 of 32 However, even though successful preclinical studies have already been reported, no clinical phases have been reached, preventing products to reach the market. The previously unrecognized or underestimated potential of platinum-based treat- ments can now offer another opportunity for platinum complexes. By using the principles of nanomedicine and chemistry formulation, new approaches for GB treatment can be developed, and hopefully reach clinical phases in the future. NPs can overcome some of the drug delivery limitations posed by the BBB, providing a controlled and sustained drug release in the site of action, targeting tumour cells, and reducing toxicity. Worth to mention, immunomodulation might be included in the newly recognized therapeutic effects, which may have broad application in future combination therapies for GB. In recent years, immunotherapy strategies have revolutionized the treatment of many cancer types, also increasing the hope for GB therapy. However, mostly due to the multifactorial immunosuppression occurring in the GB microenvironment, the poor knowledge of the neuroimmune system, and the presence of the BBB, the efficacy of immunotherapy in GB is still limited. New and recent strategies for GB treatment have employed immunotherapy combinations and have provided encouraging results in both preclinical and clinical stud- ies. The lessons learned from clinical trials highlight the importance of tackling different arms of immunity. Another interesting aspect lies in the investigation of novel non-invasive adminis- tration routes such as intranasal delivery, as alternatives to classical routes (i.e., CED or intravenous administration). Non-invasive brain targeting through the intranasal route arises as an attractive modality to circumvent the BBB along the trigeminal/olfactory neuronal pathways, thereby enhancing the therapeutic ratio with minimal systemic expo- sure [216,217]. The main goal of such novel administration routes is to provide effective drug concentration in brain tumours using reduced doses, overcoming the BBB while avoiding most of the systemic side effects. In other words, it is not a matter of how much Pt reaches the tumour site, but ensuring that enough Pt reaches the tumour milieu in order to trigger immunogenic cell damage and elicit host immune system. Last, but not least, it is also relevant to avoid systemic effects that are a limiting factor for single and combined Pt treatments for GB. Additionally, besides the therapeutic use of Pt complexes as single drugs, the combina- tion of Pt-based nanoparticles with other approaches such as chemotherapy, radiotherapy, immunotherapy, gene therapy, or functional inhibitors seems to be attractive and raise interesting possibilities. In this sense, it is important to highlight the preclinical evidence regarding combination immunotherapy in terms of both immune and survival benefits for GB management. Recent studies assessing the combination of different classes of im- munotherapeutic agents (e.g., immune checkpoint blockade and vaccines) offer interesting perspectives that may be an inspiring starting point to develop future strategies facilitating the clinical translation to address the unmet medical needs of GB treatment. Author Contributions: F.N., J.L., A.P.C. and D.R.-M. contributed to the conceptualization, method- ology, validation, literature search, writing original, draft preparation, writing review and editing. C.A. and P.A.-T. contributed to the draft preparation, study design, literature search, data collection, data analysis, and data interpretation. All authors have read and agreed to the published version of the manuscript. Funding: This research was supported by grant PID2021-127983OB-C21, PID2021-127983OB-C22, and PID2020-113058GB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe and by PI21/00181 from the Instituto Carlos III. The ICN2 is funded by the CERCA programme/Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, Grant CEX2021-001214-S, funded by MCIN/AEI/10.13039.501100011033. This work was also supported by the Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN [http://www.ciber-bbn.es/en, accessed on 10 April 2023], CB06/01/0010), an initiative of the Instituto de Salud Carlos III (Spain). Nanomaterials 2023, 13, 1619 23 of 32 Data Availability Statement: No new data were created. Acknowledgments: This work was also supported by “Metalfármacos multifuncionales para el di- agnóstico y la terapia” network, through grant RED2018-102471-T, funded by MCIN/AEI/10.13039/5 01100011033. COST is kindly acknowledged for stimulating scientific discussion via the Cost Action CA 17140 “Cancer nanomedicine from the bench to the bedside”. Conflicts of Interest: The authors declare no conflict of interest. References 1. Hanif, F.; Muzaffar, K.; Perveen, K.; Malhi, S.M.; Simjee, S.U. Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pac. J. Cancer Prev. 2017, 18, 3–9. 2. Ostrom, Q.T.; Cote, D.J.; Ascha, M.; Kruchko, C.; Barnholtz-Sloan, J.S. Adult Glioma Incidence and Survival by Race or Ethnicity in the United States from 2000 to 2014. JAMA Oncol. 2018, 4, 1254–1262. [CrossRef] 3. Chen, X.; Zhang, M.; Gan, H.; Wang, H.; Lee, J.-H.; Fang, D.; Kitange, G.J.; He, L.; Hu, Z.; Parney, I.F.; et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat. Commun. 2018, 9, 2949. [CrossRef] 4. Broekman, M.L.; Maas, S.L.N.; Abels, E.R.; Mempel, T.R.; Krichevsky, A.M.; Breakefield, X.O. Multidimensional communication in the microenvirons of glioblastoma. Nat. Rev. Neurol. 2018, 14, 482–495. [CrossRef] 5. Brown, N.F.; Carter, T.J.; Ottaviani, D.; Mulholland, P. Harnessing the immune system in glioblastoma. Br. J. Cancer. 2018, 119, 1171–1181. [CrossRef] 6. Chen, D.S.; Mellman, I. Oncology meets immunology: The cancer-immunity cycle. Immunity 2013, 9, 1–10. [CrossRef] 7. Condoluci, A.; Mazzara, C.; Zoccoli, A.; Pezzuto, A.; Tonini, G. Impact of smoking on lung cancer treatment effectiveness: A review. Future Oncol. 2016, 12, 2149–2161. [CrossRef] 8. Stupp, R.; Warren, P.; Mason, P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.B.; Belanger, K.; Brandes, A.A.; Marosi, C.; et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 2005, 352, 987–996. [CrossRef] 9. Goldbrunner, R.; Ruge, M.; Kocher, M.; Lucas, C.W.; Galldiks, N.; Grau, S. The Treatment of Gliomas in Adulthood. Dtsch. Arztebl. Int. 2018, 115, 356–364. [CrossRef] 10. Mowforth, O.D.; Brannigan, J.; El Khoury, M.; Sarathi, C.I.P.; Bestwick, H.; Bhatti, F.; Mair, R. Personalised therapeutic approaches to glioblastoma: A systematic review. Front. Med. 2023, 10, 1166104. [CrossRef] 11. Messali, A.; Villacorta, R.; Hay, J.W. A Review of the Economic Burden of Glioblastoma and the Cost Effectiveness of Pharmaco- logic Treatments. PharmacoEconomics 2014, 32, 1201–1212. [CrossRef] 12. Reid, J.M.; Stevens, D.C.; Rubin, J.; Ames, M.M. Pharmacokinetics of 3-methyl-(triazen-1-yl) imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. Clin. Cancer Res. 1997, 3, 2393–2398. 13. Lee, S.Y. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016, 3, 198–210. [CrossRef] 14. Alonso, M.M.; Gomez-Manzano, C.; Bekele, B.N.; Yung, W.A.; Fueyo, J. Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res. 2007, 67, 11499–11504. [CrossRef] 15. Montaldi, A.P.; Godoy, P.R.; Sakamoto-Hojo, E.T. APE1/REF-1 down-regulation enhances the cytotoxic effects of temozolomide in a resistant glioblastoma cell line. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2015, 793, 19–29. [CrossRef] 16. Ramirez, Y.P.; Weatherbee, J.L.; Wheelhouse, R.T.; Ross, A.H. Glioblastoma multiforme therapy and mechanisms of resistance. Pharmaceuticals 2013, 6, 1475–1506. [CrossRef] 17. Alphandéry, E. Glioblastoma Treatments: An Account of Recent Industrial Developments. Front. Pharmacol. 2018, 9, 879. [CrossRef] 18. Rominiyi, O.; Vanderlinden, A.; Clenton, S.J.; Bridgewater, C.; Al-Tamimi, Y.; Collis, S.J. Tumour treating fields therapy for glioblastoma: Current advances and future directions. Br. J. Cancer. 2021, 124, 697–709. [CrossRef] 19. Nam, J.Y.; de Groot, J.F. Treatment of Glioblastoma. J. Oncol. 2017, 13, 629–638. [CrossRef] 20. Diaz, R.J.; Ali, S.; Qadir, M.G.; De La Fuente, M.I.; Ivan, M.E.; Komotar, R.J. The role of bevacizumab in the treatment of glioblastoma. J. Neurooncol. 2017, 133, 455–467. [CrossRef] 21. Taylor, T.E.; Furnari, F.B.; Cavenee, W.K. Targeting EGFR for Treatment of Glioblastoma: Molecular Basis to Overcome Resistance. Curr. Cancer Drug Targets 2012, 12, 197–209. [CrossRef] 22. Kreisl, T.N.; Kotliarova, S.; Butman, J.A.; Albert, P.S.; Kim, L.; Musib, L.; Thornton, D.; Fine, H.A. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol. 2010, 12, 181–189. [CrossRef] 23. Heffron, T.P.; Ndubaku, C.O.; Salphati, L.; Alicke, B.; Cheong, J.; Drobnick, J.; Edgar, K.; Gould, S.E.; Lee, L.B.; Lesnick, J.D.; et al. Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med. Chem. Lett. 2016, 7, 351–356. [CrossRef] 24. Medikonda, R.; Dunn, G.; Rahman, M.; Fecci, P.; Lim, M. A review of glioblastoma immunotherapy. J. Neuro-Oncol. 2021, 151, 41–53. [CrossRef] 25. Liu, Y.; Wang, W.; Zhang, D.; Sun, Y.; Li, F.; Zheng, M.; Lovejoy, D.B.; Zou, Y.; Shi, B. Brain co-delivery of first-line chemotherapy drug and epigenetic bromodomain inhibitor formultidimensional enhanced synergistic glioblastoma therapy. Exploration 2022, 2, 20210274. [CrossRef] Nanomaterials 2023, 13, 1619 24 of 32 26. Weenink, B.; French, P.J.; Sillevis Smitt, P.A.E.; Debets, R.; Geurts, M. Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives. Cancers 2020, 12, 751. [CrossRef] 27. Huang, B.; Yu, Z.; Liang, R. Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival. BMC Neurol. 2021, 21, 424. [CrossRef] 28. Aliyu, A.; Shaari, M.R.; Sayuti, N.S.A.; Reduan, M.F.H.; Sithambaram, S.; Noordin, M.M.; Shaari, K.; Hamzah, H. N-Ethyl-n- Nitrosourea Induced Leukaemia in a Mouse Model through Upregulation of Vascular Endothelial Growth Factor and Evading Apoptosis. Cancers 2020, 12, 678. [CrossRef] 29. Jeon, J.; Lee, S.; Kim, H.; Kang, H.; Youn, H.; Jo, S.; Youn, B.; Kim, H.Y. Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas. Int. J. Mol. Sci. 2021, 22, 5111. [CrossRef] 30. Ghosh, D.; Nandi, S.; Bhattacharjee, S. Combination therapy to checkmate Glioblastoma: Clinical challenges and advances. Clin. Trans. Med. 2018, 7, 33. [CrossRef] 31. Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 2007, 7, 573–584. [CrossRef] [PubMed] 32. de Biasi, A.R.; Villena-Vargas, J.; Adusumilli, P.S. Cisplatin-Induced Antitumor Immunomodulation: A Review of Preclinical and Clinical Evidence. Clin. Cancer Res. 2014, 20, 5384–5391. [CrossRef] [PubMed] 33. Ndagi, U.; Mhlongo, N.; Soliman, M.E. Metal complexes in cancer therapy—An update from drug design perspective. Drug. Des. Devel. Ther. 2017, 11, 599–616. [CrossRef] 34. Wang, J.L.; Barth, R.F.; Cavaliere, R.; Puduvalli, V.K.; Giglio, P.; Lonser, R.R.; Elder, J.B. Phase I trial of intracerebral convectio- nenhanced delivery of carboplatin for treatment of recurrent high-grade gliomas. PLoS ONE 2020, 15, e0244383. [CrossRef] [PubMed] 35. Silvani, A.; Eoli, M.; Salmaggi, A.; Lamperti, E.; Maccagnano, E.; Broggi, G.; Boiardi, A. Phase II trial of cisplatin plus temozolo- mide, in recurrent and progressive malignant glioma patients. J. Neuro-Oncol. 2004, 66, 203–208. [CrossRef] [PubMed] 36. Jacobs, S.; McCully, C.L.; Murphy, R.F.; Bacher, J.; Balis, F.M.; Fox, E. Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Cancer Chemother. Pharmacol. 2010, 65, 817–824. [CrossRef] 37. Johnstone, T.C.; Suntharalingam, K.; Lippard, S.J. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chem. Rev. 2016, 116, 3436–3486. [CrossRef] [PubMed] 38. Huncharek, M.; Muscat, J. Treatment of recurrent high grade astrocytoma; results of a systematic review of 1415 patients. Anticancer Res. 1998, 18, 1303–1311. 39. Yung, W.K.A.; Mechtler, L.; Gleason, M.J. Intravenous carboplatin for recurrent malignant glioma: A phase II study. J. Clin. Oncol. 1991, 9, 860–864. [CrossRef] 40. Posadas, I.; Alonso-Moreno, C.; Bravo, I.; Carrillo-Hermosilla, F.; Garzon, A.; Villaseca, N.; Lopez-Solera, I.; Albaladejo, J.; Cena, V. Synthesis, Characterization, DNA Interactions and Antiproliferative Activity on Glioblastoma of Iminopyridine Platinum(II) Chelate Complexes. J. Inorg. Biochem. 2017, 168, 46–54. [CrossRef] 41. Mishima, K.; Mazar, A.P.; Gown, A.; Skelly, M.; Ji, X.D.; Wang, X.D.; Jones, T.R.; Cavenee, W.K.; Huang, H.J. A peptide derived from the non-receptor binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin. Proc. Natl. Acad. Sci. USA 2000, 97, 8484–8489. [CrossRef] [PubMed] 42. Spiro, T.P.; Liu, L.; Majka, S.; Haaga, J.; Willson, J.K.V.; Gerson, S.L. Temozolomide: The effect of once- and twice-a-day dosing on tumor tissue levels of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase. Clin. Cancer Res. 2001, 7, 2309–2317. [PubMed] 43. Zheng, Y.; Hunting, D.J.; Ayotte, P.; Sanche, L. Role of secondary lowenergy electrons in the concomitant chemoradiation therapy of cancer. Phys. Rev. Lett. 2008, 100, 198101. [CrossRef] [PubMed] 44. Nagane, M.; Narita, Y.; Mishima, K.; Levitzki, A.; Burgess, A.W.; Cavenee, W.K.; Huang, H.J. Human Glioblastoma Xenografts Overexpressing a Tumor-Specific Mutant Epidermal Growth Factor Receptor Sensitized to Cisplatin by the Ag1478 Tyrosine Kinase Inhibitor. J. Neurosurg. 2001, 95, 472–479. [CrossRef] 45. Brandes, A.A.; Basso, U.; Reni, M.; Vastola, F.; Tosoni, A.; Cavallo, G.; Scopece, L.; Ferreri, A.J.; Panucci, M.G.; Monfardini, S.; et al. First-Line Chemotherapy with Cisplatin Plus Fractionated Temozolomide in Recurrent Glioblastoma Multiforme: A Phase Ii Study of the Gruppo Italiano Cooperativo Di Neuro-Oncologia. J. Clin. Oncol. 2004, 22, 1598–1604. [CrossRef] 46. Wang, X.; Wang, X.; Jin, S.; Muhammad, N.; Guo, Z. Stimuli-Responsive Therapeutic Metallodrugs. Chem. Rev. 2019, 119, 1138–1192. [CrossRef] 47. Hess, S.M.; Anderson, J.G.; Bierbach, U. A Non-Crosslinking Platinum-Acridine Hybrid Agent Shows Enhanced Cytotoxicity Compared to Clinical Bcnu and Cisplatin in Glioblastoma Cells. Bioorg. Med. Chem. Lett. 2005, 15, 443–446. [CrossRef] 48. Gajski, G.; Čimbora-Zovko, T.; Rak, S.; Osmak, M.; Garaj-Vrhovac, V. Antitumour Action on Human Glioblastoma A1235 Cells through Cooperation of Bee Venom and Cisplatin. Cytotechnology 2016, 68, 1197–1205. [CrossRef] 49. Zhu, T.; Xu, Y.; Dong, B.; Zhang, J.; Wei, Z.; Xu, Y.; Yao, Y. B-Elemene Inhibits Proliferation of Human Glioblastoma Cells through the Activation of Glia Maturation Factor B and Induces Sensitization to Cisplatin. Oncol. Rep. 2011, 26, 405–413. 50. Park, C.K.; Park, S.H.; Lee, S.H.; Kim, C.Y.; Kim, D.W.; Paek, S.H.; Kim, D.G.; Heo, D.S.; Kim, I.H.; Jung, H.W. Methylation Status of the Mgmt Gene Promoter Fails to Predict the Clinical Outcome of Glioblastoma Patients Treated with Acnu Plus Cisplatin. Neuropathology 2009, 29, 443–449. [CrossRef] Nanomaterials 2023, 13, 1619 25 of 32 51. Buckner, J.C.; Ballman, K.V.; Michalak, J.C.; Burton, G.V.; Cascino, T.L.; Schomberg, P.J.; Hawkins, R.B.; Scheithauer, B.W.; Sandler, H.M.; Marks, R.S.; et al. Phase Iii Trial of Carmustine and Cisplatin Compared with Carmustine Alone and Standard Radiation Therapy or Accelerated Radiation Therapy in Patients with Glioblastoma Multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials. J. Clin. Oncol. 2006, 24, 3871–3879. [PubMed] 52. Barth, R.F.; Wu, G.; Hans Meisen, W.; Nakkula, R.J.; Yang, W.; Huo, T.; Kellough, D.A.; Kaumaya, P.; Turro, C.; Agius, L.M.; et al. Design, synthesis, and evaluation of cisplatincontaining EGFR targeting bioconjugates as potential therapeutic agents for brain tumors. OncoTargets Ther. 2016, 9, 2769–2781. [CrossRef] [PubMed] 53. Wang, M.; Wu, Q.; Fang, M.; Huang, W.; Zhu, H. Mir-152-3p Sensitizes Glioblastoma Cells Towards Cisplatin Via Regulation of Sos1. OncoTargets Ther. 2019, 12, 9513–9525. [CrossRef] [PubMed] 54. Li, J.; Song, J.; Guo, F. Mir-186 Reverses Cisplatin Resistance and Inhibits The formation of the Glioblastoma-Initiating Cell phenotype by Degrading Yin Yang 1 in Glioblastoma. Int. J. Mol. Med. 2019, 43, 517–524. [CrossRef] [PubMed] 55. Baldwin, R.M.; Garratt-Lalonde, M.; Parolin, D.A.E.; Krzyzanowski, P.M.; Andrade, M.A.; Lorimer, I.A.J. Protection of Glioblas- toma Cells from Cisplatin Cytotoxicity Via Protein Kinase Cι-Mediated Attenuation of P38 Map Kinase Signaling. Oncogene 2006, 25, 2909–2919. [CrossRef] [PubMed] 56. Ding, L.; Yuan, C.; Wei, F.; Wang, G.; Zhang, J.; Bellail, A.C.; Zhang, Z.; Olson, J.J.; Hao, C. Cisplatin Restores Trail Apoptotic Pathway in Glioblastoma-Derived Stem Cells through up-Regulation of Dr5 and Down-Regulation of C-Flip. Cancer Investig. 2011, 29, 511–520. [CrossRef] 57. Ferrari, B.; Urselli, F.; Gilodi, M.; Camuso, S.; Priori, E.C.; Rangone, B.; Ravera, M.; Veneroni, P.; Zanellato, I.; Roda, E.; et al. New Platinum-Based Prodrug Pt(Iv)Ac-Poa: Antitumour Effects in Rat C6 Glioblastoma Cells. Neurotox. Res. 2020, 37, 183–197. [CrossRef] 58. Macieja, A.; Kopa, P.; Galita, G.; Pastwa, E.; Majsterek, I.; Poplawski, T. Comparison of the Effect of Three Different Topoisomerase Ii Inhibitors Combined with Cisplatin in Human Glioblastoma Cells Sensitized with Double Strand Break Repair Inhibitors. Mol. Biol. Rep. 2019, 46, 3625–3636. [CrossRef] 59. Gwak, H.-S.; Shingu, T.; Chumbalkar, V.; Hwang, Y.-H.; DeJournett, R.; Latha, K.; Koul, D.; Alfred Yung, W.K.; Powis, G.; Farrell, N.P.; et al. Combined Action of the Dinuclear Platinum Compound Bbr3610 with the Pi3-K Inhibitor Px-866 in Glioblastoma. Int. J. Cancer 2011, 128, 787–796. [CrossRef] 60. Rosa, P.; Catacuzzeno, L.; Sforna, L.; Mangino, G.; Carlomagno, S.; Mincione, G.; Petrozza, V.; Ragona, G.; Franciolini, F.; Calogero, A. Bk Channels Blockage Inhibits Hypoxia-Induced Migration and Chemoresistance to Cisplatin in Human Glioblastoma Cells. J. Cell. Physiol. 2018, 233, 6866–6877. [CrossRef] 61. Benzina, S.; Fischer, B.; Miternique-Grosse, A.; Dufour, P.; Denis, J.M.; Bergerat, J.P.; Gueulette, J.; Bischoff, P. Cell Death Induced in a Human Glioblastoma Cell Line by P(65)+Be Neutrons Combined with Cisplatin. Life Sci. 2006, 79, 513–518. [CrossRef] [PubMed] 62. Roci, E.; Cakani, B.; Brace, G.; Bushati, T.; Rroji, A.; Petrela, M.; Kaloshi, G. Platinum-based Chemotherapy in Recurrent High-grade Glioma Patients: Retrospective Study. Med. Arh. 2014, 68, 140–143. [CrossRef] [PubMed] 63. Wang, Y.; Kong, X.; Guo, Y.; Wang, R.; Ma, W. Continuous Dose-Intense Temozolomide and Cisplatin in Recurrent Glioblastoma Patients. Medicine 2017, 96, e6261. [CrossRef] [PubMed] 64. Wang, L.; Setlow, R.B. Inactivation of O-6-alkylguanine-DNA Alkyltransferase in HeLa cells by cisplatin. Carcinogenesis 1989, 10, 1681–1684. [CrossRef] 65. Piccioni, D.; D’atri, S.; Papa, G.; Caravita, T.; Franchi, A.; Bonmassar, E.; Graziani, G. Cisplatin increases sensitivity of human leukemic blasts to triazene compounds. J. Chemother. 1995, 7, 224–229. [CrossRef] 66. Britten, C.D.; Rowinsky, E.K.; Baker, S.D.; Agarwala, S.S.; Eckardt, J.R.; Barrington, R.; Diab, S.G.; Hammond, L.A.; Johnson, T.; Villalona-Calero, M.; et al. A phase I and pharmacokinetic study of Temozolomide and cisplatin in patients with advanced solid malignancies. Clin. Cancer Res. 1999, 5, 1629–1637. 67. Rousseau, J.; Barth, R.F.; Fernandez, M.; Adam, J.-F.; Balosso, J.; Estève, F.; Elleaume, H. Efficacy of Intracerebral Delivery of Cisplatin in Combination with Photon Irradiation for Treatment of Brain Tumors. J. Neurooncol. 2010, 98, 287–295. [CrossRef] 68. Billecke, C.; Finniss, S.; Tahash, L.; Miller, C.; Mikkelsen, T.; Farrell, N.P.; Bögler, O. Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma. Neuro Oncol. 2006, 8, 215–226. [CrossRef] 69. Newton, H.B.; Page, M.A.; Junck, L.; Greenberg, H.S. Intra-arterial cisplatin for the treatment of malignant gliomas. J Neurooncol. 1989, 7, 39–45. [CrossRef] 70. Feun, L.G.; Stewart, D.J.; Maor, M.; Leavens, M.; Savaraj, N.; Burgess, M.A.; Yung, W.K.A.; Benjamin, R.S. A pilot study of cis-diamminedichloroplatinum and radiation therapy in patients with high grade astrocytomas. J. Neurooncol. 1983, 1, 109–113. [CrossRef] 71. Silvani, A.; Gaviani, P.; Lamperti, E.A.; Eoli, M.; Falcone, C.; DiMeco, F.; Milanesi, I.M.; Erbetta, A.; Boiardi, A.; Fariselli, L.; et al. Cisplatinum and BCNU chemotherapy in primary glioblastoma patients. J. Neurooncol. 2009, 94, 57–62. [CrossRef] [PubMed] 72. Balaña, C.; López-Pousa, A.; Berrocal, A.; Yaya-Tur, R.; Herrero, A.; García, J.L.; Martín-Broto, J.; Benavides, M.; Cerdá-Nicolás, M.; Ballester, R.; et al. Phase II study of temozolomide and cisplatin as primary treatment prior to radiotherapy in newly diagnosed glioblastoma multiforme patients with measurable disease. A study of the Spanish Medical Neuro-Oncology Group (GENOM). J. Neurooncol. 2004, 70, 359–370. [CrossRef] [PubMed] Nanomaterials 2023, 13, 1619 26 of 32 73. Chovanec, M.; Abu Zaid, M.; Hanna, N.; El-Kouri, N.; Einhorn, L.H.; Albany, C. Long-term Toxicity of Cisplatin in Germ-Cell Tumor Survivors. Ann. Oncol. 2017, 28, 2670–2679. [CrossRef] [PubMed] 74. Wang, D.; Wang, C.; Wang, L.; Chen, Y. A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment. Drug Deliv. 2019, 26, 551–565. [CrossRef] [PubMed] 75. Kovacs, Z.I.; Burks, S.R.; Frank, J.A. Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions. Theranostics 2018, 8, 2245–2248. [CrossRef] 76. Sharabi, S.; Bresler, Y.; Ravid, O.; Shemesh, C.; Atrakchi, D.; Schnaider-Beeri, M.; Gosselet, F.; Dehouck, L.; Last, D.; Guez, D.; et al. Transient blood–brain barrier disruption is induced by low pulsed electrical fields in vitro: An analysis of permeability and trans-endothelial electric resistivity. Drug Deliv. 2019, 26, 459–469. [CrossRef] 77. Graham-Gurysh, E.; Moore, K.M.; Satterlee, A.B.; Sheets, K.T.; Lin, F.C.; Bachelder, E.M.; Miller, C.R.; Hingtgen, S.D.; Ainslie, K.M. Sustained Delivery of Doxorubicin Via Acetalated Dextran Scaffold Prevents Glioblastoma Recurrence after Surgical Resection. Mol. Pharm. 2018, 15, 1309–1318. [CrossRef] 78. Tabet, A.; Jensen, M.P.; Parkins, C.C.; Patil, P.G.; Watts, C.; Scherman, O.A. Designing Next-Generation Local Drug Delivery Vehicles for Glioblastoma Adjuvant Chemotherapy: Lessons from the Clinic. Adv. Healthc. Mater. 2019, 8, e1801391. [CrossRef] 79. Minghan, S.; Sanche, L. Convection-Enhanced Delivery in Malignant Gliomas: A Review of Toxicity and Efficacy. J. Oncol. 2019, 2019, 9342796. 80. Mathew, E.N.; Berry, B.C.; Yang, H.W.; Carroll, R.S.; Johnson, M.D. Delivering Therapeutics to Glioblastoma: Overcoming Biological Constraints. Int. J. Mol. Sci. 2022, 23, 1711. [CrossRef] 81. Ruiz-Molina, D.; Mao, X.; Alfonso-Triguero, P.; Lorenzo, J.; Bruna, J.; Yuste, V.J.; Candiota, A.P.; Novio, F. Advances in Preclinical/Clinical Glioblastoma Treatment: Can Nanoparticles Be of Help? Cancers 2022, 14, 4960. [CrossRef] [PubMed] 82. Harder, B.G.; Blomquist, M.R.; Wang, J.; Kim, A.J.; Woodworth, G.F.; Winkles, J.A.; Loftus, J.C.; Tran, N.L. Developments in Blood-Brain Barrier Penetrance and Drug Repurposing for Improved Treatment of Glioblastoma. Front. Oncol. 2018, 8, 462. [CrossRef] [PubMed] 83. Hersh, D.; Wadajkar, A.S.; Roberts, N.B.; Perez, J.G.; Connolly, N.P.; Frenkel, V.; Winkles, J.A.; Woodworth, G.F.; Kim, A.J. Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr. Pharm. Des. 2016, 22, 1177–1193. [CrossRef] [PubMed] 84. McCarthy, D.J.; Malhotra, M.A.; O’Mahony, M.; Cryan, J.F.; O’Driscoll, C.M. Nanoparticles and the Blood-Brain Barrier: Advancing from In-Vitro Models Towards Therapeutic Significance. Pharm. Res. 2015, 32, 1161–1185. [CrossRef] 85. Saraiva, C.; Praça, C.; Ferreira, R.; Santos, T.; Ferreira, L.; Bernardino, L. Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases. J. Control. Release 2016, 235, 34–47. [CrossRef] 86. Zhang, Y.; Fu, X.; Jia, J.; Wikerholmen, T.; Xi, K.; Kong, Y.; Wang, J.; Chen, H.; Ma, Y.; Li, Z.; et al. Glioblastoma therapy using codelivery of cisplatin and glutathione peroxidase targeting siRNA from iron oxide nanoparticles. ACS Appl. Mater. Interf. 2020, 12, 43408–43421. [CrossRef] 87. Wadajkar, A.S.; Dancy, J.G.; Hersha, D.S.; Anastasiadis, P.; Tran, N.L.; Woodworth, G.F.; Winkles, J.A.; Kim, A.J. Tumor-targeted Nanotherapeutics: Overcoming Treatment Barriers for Glioblastoma. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1439. [CrossRef] 88. Wang, X.; Guo, Z. Targeting and delivery of platinum-based anticancer drugs. Chem. Soc. Rev. 2013, 42, 202–224. [CrossRef] 89. Haxton, K.J.; Burt, H.M. Polymeric drug delivery of platinum-based anticancer agents. J. Pharm. Sci. 2009, 98, 2299–2316. [CrossRef] 90. Wu, H.; Cabral, H.; Toh, K.; Mi, P.; Chen, Y.-C.; Matsumoto, Y.; Yamada, N.; Liu, X.; Kinoh, H.; Miura, Y. Polymeric micelles loaded with platinum anticancer drugs target preangiogenic micrometastatic niches associated with inflammation. J. Control Release 2014, 189, 1–10. [CrossRef] 91. Kesavan, A.; Ilaiyaraja, P.; Beaula, W.S.; Kumari, V.V.; Lal, J.S.; Arunkumar, C.; Anjana, G.; Srinivas, S.; Ramesh, A.; Rayala, S.K.; et al. Tumor targeting using polyamidoamine dendrimer–cisplatin nanoparticles functionalized with diglycolamic acid and herceptin. Eur. J. Pharm. Biopharm. 2015, 96, 255–263. [CrossRef] [PubMed] 92. Timbie, K.F.; Afzal, U.; Date, A.; Zhang, C.; Song, J.; Miller, G.W.; Suk, J.S.; Hanes, J.; Price, R.J. MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound. J. Control. Release 2017, 263, 120–131. [CrossRef] 93. Thanasupawat, T.; Bergen, H.; Hombach-Klonisch, S.; Krcek, J.; Ghavami, S.; Del Bigio, M.R.; Krawitz, S.; Stelmack, G.; Halayko, A.; McDougall, M.; et al. Platinum (IV) coiled coil nanotubes selectively kill human glioblastoma cells. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 913–925. [CrossRef] [PubMed] 94. Ortiz-Islas, E.; Sosa-Arróniz, A.; Manríquez-Ramírez, M.E.; Rodríguez-Pérez, C.E.; Tzompantzi, F.; Padilla, J.M. Mesoporous silica nanoparticles functionalized with folic acid for targeted release Cis-Pt to glioblastoma cells. Rev. Adv. Mater. Sci. 2021, 60, 25–37. [CrossRef] 95. Depciuch, J.; Miszczyk, J.; Maximenko, A.; Zielinski, P.M.; Rawojc, K.; Panek, A.; Olko, P.; Parlinska-Wojtan, M. Gold Nanopeanuts as Prospective Support for Cisplatin in Glioblastoma Nano-Chemo-Radiotherapy. Int. J. Mol. Sci. 2020, 21, 9082. [CrossRef] [PubMed] Nanomaterials 2023, 13, 1619 27 of 32 96. Mao, X.; Calero-Pérez, P.; Montpeyó, D.; Bruna, J.; Yuste, V.J.; Candiota, A.P.; Lorenzo, J.; Novio, F.; Ruiz-Molina, D. Intranasal Administration of Catechol-Based Pt(IV) Coordination Polymer Nanoparticles for Glioblastoma Therapy. Nanomaterials 2022, 12, 1221. [CrossRef] [PubMed] 97. Charest, G.; Sanche, L.; Fortin, D.; Mathieu, D.; Paquette, B. Glioblastoma Treatment: Bypassing the Toxicity of Platinum Compounds by Using Liposomal Formulation and Increasing Treatment Efficiency with Concomitant, Radiotherapy. Int. J. Radiation Oncol. Biol. Phys. 2012, 84, 244–249. [CrossRef] 98. Zahednezhad, F.; Zakeri-Milani, P.; Shahbazi Mojarrad, J.; Valizadeh, H. The latest advances of cisplatin liposomal formulations: Essentials for preparation and analysis. Expert Opin. Drug Deliv. 2020, 17, 523–541. [CrossRef] 99. Liu, L.; Ye, Q.; Lu, M.; Lo, Y.-C.; Hsu, Y.-H.; Wei, M.-C.; Chen, Y.-H.; Lo, S.-C.; Wang, S.-J.; Bain, D.J. A new approach to reduce toxicities and to improve bioavailabilities of platinum-containing anti-cancer nanodrugs. Sci. Rep. 2015, 5, 10881. [CrossRef] 100. Hernández-Pedro, N.Y.; Rangel-López, E.; Magaña-Maldonado, R.; Pérez de la Cruz, V.; Santamaría del Angel, A.; Pineda, B.; Sotelo, J. Application of Nanoparticles on Diagnosis and Therapy in Gliomas. Biomed. Res. Int. 2013, 2013, 351031. [CrossRef] 101. Zhao, Y.Z.; Lin, Q.; Wong, H.L.; Shen, X.T.; Yang, W.; Xu, H.L.; Mao, K.L.; Tian, F.R.; Yang, J.J.; Xu, J.; et al. Glioma-targeted therapy using Cilengitide nanoparticles combined with UTMD enhanced delivery. J. Control. Release 2016, 224, 112–125. [CrossRef] [PubMed] 102. Nainwal, N. Recent advances in transcranial focused ultrasound (FUS) triggered brain delivery. Curr. Drug Targets 2017, 18, 1225–1232. [CrossRef] [PubMed] 103. Hoadley, K.A.; Yau, C.; Wolf, D.M.; Cherniack, A.D.; Tamborero, D.; Ng, S.; Leiserson, M.D.; Niu, B.; McLellan, M.D.; Uzunangelov, V. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 2014, 158, 929–944. [CrossRef] [PubMed] 104. Charest, G.; Sanche, L.; Fortin, D.; Mathieu, D.; Paquette, B. Optimization of the Route of Platinum Drugs Administration to Optimize the Concomitant Treatment with Radiotherapy for Glioblastoma Implanted in the Fischer Rat Brain. J. Neurooncol. 2013, 115, 365–373. [CrossRef] 105. Rahman, A.A.; Stojanovska, V.; Pilowsky, P.; Nurgali, K. Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats. Pflugers Arch—Eur. J. Physiol. 2021, 473, 107–120. [CrossRef] 106. Dermitzakis, E.V.; Kimiskidis, V.K.; Eleftheraki, A.; Lazaridis, G.; Konstantis, A.; Basdanis, G.; Tsiptsios, I.; Georgiadis, G.; Fountzilas, G. The impact of oxaliplatin-based chemotherapy for colorectal cancer on the autonomous nervous system. Eur. J. Neurol. 2014, 21, 1471–1477. [CrossRef] 107. Tajbakhsh, M.; Houghton, P.J.; Morton, C.L.; Kolb, E.A.; Gorlick, R.; Maris, J.M.; Keir, S.T.; Wu, J.; Reynolds, C.P.; Smith, M.A.; et al. Initial testing of cisplatin by the pediatric preclinical testing program. Pediatr. Blood Cancer 2008, 50, 992–1000. [CrossRef] 108. Rao, A.A.N.; Wallace, D.J.; Billups, C.; Boyett, J.M.; Gajjar, A.; Packer, R.J. Cumulative cisplatin dose is not associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma treated with cisplatin based adjuvant chemotherapy: Report from the Children’s Oncology Group. Pediatr. Blood Cancer 2014, 61, 102–106. [CrossRef] 109. Enríquez Pérez, J.; Fitzell, S.; Kopecky, J.; Visse, E.; Darabi, A.; Siesjö, P. The effect of locally delivered cisplatin is dependent on an intact immune function in an experimental glioma model. Sci. Rep. 2019, 9, 5632. [CrossRef] 110. Xue, Y.; Gao, S.; Gou, J.; Yin, T.; He, H.; Wang, Y.; Zhang, Y.; Tang, X.; Wu, R. Platinum-based chemotherapy in combination with PD-1/PD-L1 inhibitors: Preclinical and clinical studies and mechanism of action. Expert Opin. Drug Deliv. 2021, 18, 187–203. [CrossRef] 111. Park, S.J.; Ye, W.; Xiao, R.; Silvin, C.; Padget, M.; Hodge, J.W.; Van Waes, C.; Schmitt, N.C. Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer. Oral Oncol. 2019, 95, 127–135. [CrossRef] 112. Eiseman, J.L.; Beumer, J.H.; Rigatti, L.H.; Strychor, S.; Meyers, K.; Dienel, S.; Horn, C.C. Plasma Pharmacokinetics and Tissue and Brain Distribution of Cisplatin in Musk Shrews. Cancer Chemother. Pharmacol. 2015, 75, 143–152. [CrossRef] 113. McWhinney, S.R.; Goldberg, R.M.; McLeod, H.L. Platinum neurotoxicity pharmacogenetics. Mol. Cancer Ther. 2009, 8, 10–16. [CrossRef] [PubMed] 114. Rademaker-Lakhai, J.M.; Crul, M.; Zuur, L.; Baas, P.; Beijnen, J.H.; Simis, Y.J.; Van Zandwijk, N.; Schellens, J.H. Relationship between cisplatin administration and the development of ototoxicity. J. Clin. Oncol. 2006, 24, 918–924. [CrossRef] 115. Pardridge, W.M. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx 2005, 2, 3–14. [CrossRef] [PubMed] 116. Massimino, M.; Spreafico, F.; Riva, D.; Biassoni, V.; Poggi, G.; Solero, C.; Gandola, L.; Genitori, L.; Modena, P.; Simonetti, F.; et al. A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J. Neurooncol. 2010, 100, 65–71. [CrossRef] [PubMed] 117. Ferrari, B.; Roda, E.; Priori, E.C.; De Luca, F.; Facoetti, A.; Ravera, M.; Brandalise, F.; Locatelli, C.A.; Rossi, P.; Bottone, M.G. A New Platinum-Based Prodrug Candidate for Chemotherapy and Its Synergistic Effect with Hadrontherapy: Novel Strategy to Treat Glioblastoma. Front. Neurosci. 2021, 15, 589906. [CrossRef] 118. Prados, M.D.; Schold, S.C.; Fine, H.A.; Jaeckle, K.; Hochberg, F.; Mechtler, L.; Fetell, M.R.; Phuphanich, S.; Feun, L.; Janus, T.J.; et al. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro Oncol. 2003, 5, 96–103. [CrossRef] 119. Sheleg, S.; Korotkevich, E.; Zhavrid, E.; Muravskaya, G.; Smeyanovich, A.; Shanko, Y.; Yurkshtovich, T.; Bychkovsky, P.; Belyaev, S. Local chemotherapy with cisplatin-depot for glioblastoma multiforme. J. Neurooncol. 2002, 60, 53–59. [CrossRef] Nanomaterials 2023, 13, 1619 28 of 32 120. White, E.; Bienemann, A.; Taylor, H.; Hopkins, K.; Cameron, A.; Gill, S. A phase I trial of carboplatin administered by convection- enhanced delivery to patients with recurrent/progressive glioblastoma multiforme. Contemp. Clin. Trials 2012, 33, 320–331. [CrossRef] 121. Saida, Y.; Watanabe, S.; Tanaka, T.; Baba, J.; Sato, K.; Shoji, S.; Igarashi, N.; Kondo, R.; Okajima, M.; Koshio, J.; et al. Critical roles of chemoresistant effector and regulatory T cells in antitumor immunity after lymphodepleting chemotherapy. J. Immunol. 2015, 195, 726–735. [CrossRef] [PubMed] 122. Roberts, N.B.; Wadajkar, A.S.; Winkles, J.A.; Davila, E.; Kim, A.J.; Woodworth, G.F. Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma. Oncoimmunology 2016, 5, e1208876. [CrossRef] [PubMed] 123. Kreuter, J. Drug delivery to the central nervous system by polymeric nanoparticles: What do we know? Adv. Drug Deliv. Rev. 2014, 71, 2–14. [CrossRef] [PubMed] 124. Johnstone, T.C.; Wilson, J.J.; Lippard, S.J. Monofunctional and Higher-Valent Platinum Anticancer Agents. Inorg. Chem. 2013, 52, 12234–12249. [CrossRef] 125. Sun, H.; Chen, X.; Chen, D.; Dong, M.; Fu, X.; Li, Q.; Liu, X.; Wu, Q.; Qiu, T.; Wan, T.; et al. Influences of surface coatings and components of FePt nanoparticles on the suppression of glioma cell proliferation. Int. J. Nanomed. 2012, 7, 3295–3307. 126. Liang, S.; Zhou, Q.; Wang, M.; Zhu, Y.; Wu, Q.; Yang, X. Water-soluble l-cysteine-coated FePt nanoparticles as dual MRI/CT imaging contrast agent for glioma. Int. J. Nanomed. 2015, 10, 2325–2333. 127. Duan, X.; He, C.; Kron, S.J.; Lin, W. Nanoparticle formulations of cisplatin for cancer therapy. Wiley Interdiscip. Rev. Nanomed- Nanobiotechnol. 2016, 8, 776–791. [CrossRef] 128. Feldhaeusser, B.; Platt, S.R.; Marrache, S.; Kolishetti, N.; Pathak, R.K.; Montgomery, D.J.; Reno, L.R.; Howerth, E.; Dhar, S. Evaluation of nanoparticle delivered cisplatin in beagles. Nanoscale 2015, 7, 13822–13830. [CrossRef] 129. Kim, J.-H.; Kim, Y.-S.; Park, K.; Lee, S.; Nam, H.Y.; Min, K.H.; Jo, H.G.; Park, J.H.; Choi, K.; Jeong, S.Y.; et al. Antitumor efficacy of cisplatin-loaded glycol chitosan nanoparticles in tumor-bearing mice. J. Control Release 2008, 127, 41–49. [CrossRef] 130. Ding, D.; Zhu, Z.; Liu, Q.; Wang, J.; Hu, Y.; Jiang, X.; Liu, B. Cisplatin-loaded gelatin-poly(acrylic acid) nanoparticles: Synthesis, antitumor efficiency in vivo and penetration in tumors. Eur. J. Pharm. Biopharm. 2011, 79, 142–149. [CrossRef] 131. Mattheolabakis, G.; Taoufik, E.; Haralambous, S.; Roberts, M.L.; Avgoustakis, K. In vivo investigation of tolerance and antitumor activity of cisplatin-loaded PLGA-mPEG nanoparticles. Eur. J. Pharm. Biopharm. 2009, 71, 190–195. [CrossRef] [PubMed] 132. Song, W.; Li, M.; Tang, Z.; Li, Q.; Yang, Y.; Liu, H.; Duan, T.; Hong, H.; Chen, X. Methoxypoly(ethylene glycol)-block-poly(L- glutamic acid)-loaded cisplatin and a combination with iRGD for the treatment of non-small-cell lung cancers. Macromol. Biosci. 2012, 12, 1514–1523. [CrossRef] [PubMed] 133. Plummer, R.; Wilson, R.; Calvert, H.; Boddy, A.; Griffin, M.; Sludden, J.; Tilby, M.; Eatock, M.; Pearson, D.; Ottley, C. A Phase I clinical study of cisplatinincorporated polymeric micelles (NC-6004) in patients with solid tumours. Br. J. Cancer 2011, 104, 593–598. [CrossRef] [PubMed] 134. Nishiyama, N.; Yokoyama, M.; Aoyagi, T.; Okano, T.; Sakurai, Y.; Kataoka, K. Preparation and characterization of self-assembled polymer-metal complex micelle from cis-dichlorodiammineplatinum (II) and poly (ethylene glycol)-poly (α, β-aspartic acid) block copolymer in an aqueous medium. Langmuir 1999, 15, 377–383. [CrossRef] 135. Ye, H.; Jin, L.; Hu, R.; Yi, Z.; Li, J.; Wu, Y.; Xi, X.; Wu, Z. Poly (γ, l-glutamic acid)–cisplatin conjugate effectively inhibits human breast tumor xenografted in nude mice. Biomaterials 2006, 27, 5958–5965. [CrossRef] 136. Feng, Z.; Lai, Y.; Ye, H.; Huang, J.; Xi, X.G.; Wu, Z. Poly (γ, L-glutamic acid)-cisplatin bioconjugate exhibits potent antitumor activity with low toxicity: A comparative study with clinically used platinum derivatives. Cancer Sci. 2010, 101, 2476–2482. [CrossRef] 137. Kirkpatrick, G.J.; Plumb, J.A.; Sutcliffe, O.B.; Flint, D.J.; Wheate, N.J. Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin. J. Inorg. Biochem. 2011, 105, 1115–1122. [CrossRef] 138. Yellepeddi, V.K.; Kumar, A.; Maher, D.M.; Chauhan, S.C.; Vangara, K.K.; Palakurthi, S. Biotinylated PAMAM dendrimers for intracellular delivery of cisplatin to ovarian cancer: Role of SMVT. Anticancer Res. 2011, 31, 897–906. 139. Mallick, A.; More, P.; Ghosh, S.; Chippalkatti, R.; Chopade, B.A.; Lahiri, M.; Basu, S. Dual drug conjugated nanoparticle for simultaneous targeting of mitochondria and nucleus in cancer cells. ACS Appl. Mater. Interf. 2015, 7, 7584–7598. [CrossRef] 140. Iinuma, H.; Maruyama, K.; Okinaga, K.; Sasaki, K.; Sekine, T.; Ishida, O.; Ogiwara, N.; Johkura, K.; Yonemura, Y. Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposome on peritoneal dissemination of gastric cancer. Int. J. Cancer 2002, 99, 130–137. [CrossRef] 141. Krieger, M.L.; Eckstein, N.; Schneider, V.; Koch, M.; Royer, H.-D.; Jaehde, U.; Bendas, G. Overcoming cisplatin resistance of ovarian cancer cells by targeted liposomes in vitro. Int. J. Pharm. 2010, 389, 10–17. [CrossRef] [PubMed] 142. Burger, K.N.; Staffhorst, R.W.; de Vijlder, H.C.; Velinova, M.J.; Bomans, P.H.; Frederik, P.M.; de Kruijff, B. Nanocapsules: Lipid-coated aggregates of cisplatin with high cytotoxicity. Nat. Med. 2002, 8, 81–84. [CrossRef] [PubMed] 143. Hamelers, I.H.; De Kroon, A.I. Nanocapsules: A novel lipid formulation platform for platinum-based anticancer drugs. J. Liposome Res. 2007, 17, 183–189. [CrossRef] [PubMed] 144. Melanie, K.; Heike, Z.; Sibylle, B.S.; Hartmut, O.; Matthias, Z.; Christian, B.; Rudolf, H.; Karl-Jürgen, H.; Werner, A.K.; Ingrid, H. Characterization of iron oxide nanoparticles adsorbed with cisplatin for biomedical applications. Phys. Med. Biol. 2009, 54, 5109–5121. Nanomaterials 2023, 13, 1619 29 of 32 145. Comenge, J.; Romero, F.M.; Sotelo, C.; Domínguez, F.; Puntes, V. Exploring the binding of Pt drugs to gold nanoparticles for controlled passive release of cisplatin. J. Control. Release 2010, 148, e31–e32. [CrossRef] 146. Craig, G.E.; Brown, S.D.; Lamprou, D.A.; Graham, D.; Wheate, N.J. Cisplatin-tethered gold nanoparticles that exhibit enhanced reproducibility, drug loading, and stability: A step closer to pharmaceutical approval? Inorg. Chem. 2012, 51, 3490–3497. [CrossRef] 147. Min, Y.; Mao, C.-Q.; Chen, S.; Ma, G.; Wang, J.; Liu, Y. Combating the drug resistance of cisplatin using a platinum prodrug based delivery system. Angew. Chem. Int. Ed. 2012, 51, 6742–6747. [CrossRef] 148. Lin, C.-H.; Cheng, S.-H.; Liao, W.-N.; Wei, P.-R.; Sung, P.-J.; Weng, C.-F.; Lee, C.-H. Mesoporous silica nanoparticles for the improved anticancer efficacy of cisplatin. Int. J. Pharm. 2012, 429, 138–147. [CrossRef] 149. Gu, J.; Liu, J.; Li, Y.; Zhao, W.; Shi, J. One-pot synthesis of mesoporous silica nanocarriers with tunable particle sizes and pendent carboxylic groups for cisplatin delivery. Langmuir 2012, 29, 403–410. [CrossRef] 150. Tao, Z.; Toms, B.; Goodisman, J.; Asefa, T. Mesoporous silica microparticles enhance the cytotoxicity of anticancer platinum drugs. ACS Nano 2010, 4, 789–794. [CrossRef] 151. Vashist, S.K.; Zheng, D.; Pastorin, G.; Al-Rubeaan, K.; Luong, J.H.; Sheu, F.-S. Delivery of drugs and biomolecules using carbon nanotubes. Carbon 2011, 49, 4077–4097. [CrossRef] 152. Li, J.; Yap, S.Q.; Yoong, S.L.; Nayak, T.R.; Chandra, G.W.; Ang, W.H.; Panczyk, T.; Ramaprabhu, S.; Vashist, S.K.; Sheu, F.S.; et al. Carbon nanotube bottles for incorporation, release and enhanced cytotoxic effect of cisplatin. Carbon 2012, 50, 1625–1634. [CrossRef] 153. Guven, A.; Rusakova, I.A.; Lewis, M.T.; Wilson, L.J. Cisplatin@US-tube carbon nanocapsules for enhanced chemotherapeutic delivery. Biomaterials 2012, 33, 1455–1461. [CrossRef] 154. Dhar, S.; Liu, Z.; Thomale, J.; Dai, H.; Lippard, S.J. Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device. J. Am. Chem. Soc. 2008, 130, 11467–11476. [CrossRef] 155. Rieter, W.J.; Pott, K.M.; Taylor, K.M.L.; Lin, W. Nanoscale coordination polymers for platinum-based anticancer drug delivery. J. Am. Chem. Soc. 2008, 130, 11584–11585. [CrossRef] 156. He, C.; Liu, D.; Lin, W. Self-assembled nanoscale coordination polymers carrying siRNAs and cisplatin for effective treatment of resistant ovarian cancer. Biomaterials 2015, 36, 124–133. [CrossRef] 157. Adarsh, N.N.; Frias, C.; Ponnoth Lohidaksh, T.M.; Lorenzo, J.; Novio, F.; Garcia-Pardo, J.; Ruiz-Molina, D. Pt(IV)-based nanoscale coordination polymers: Antitumor activity, cellular uptake and interactions with nuclear DNA. Chem. Eng. J. 2018, 340, 94–102. [CrossRef] 158. He, C.; Liu, D.; Lin, W. Self-assembled core-shell nanoparticles for combined chemotherapy and photodynamic therapy of resistant head and neck cancers. ACS Nano 2015, 9, 991–1003. [CrossRef] 159. Makharza, S.A.; Cirillo, G.; Vittorio, O.; Valli, E.; Voli, F.; Farfalla, A.; Curcio, M.; Iemma, F.; Nicoletta, F.P.; El-Gendy, A.A.; et al. Magnetic Graphene Oxide Nanocarrier for Targeted Delivery of Cisplatin: A Perspective for Glioblastoma Treatment. Pharmaceuticals 2019, 12, 76. [CrossRef] 160. Coluccia, D.; Figueiredo, C.A.; YiJun Wu, M.; Riemenschneider, A.N.; Diaz, R.; Luck, A.; Smith, C.; Das, S.; Ackerley, C.; O’Reilly, M.; et al. Enhancing glioblastoma treatment using cisplatin-gold-nanoparticle conjugates and targeted delivery with magnetic resonance-guided focused ultrasound. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 1137–1148. [CrossRef] 161. Gotov, O.; Battogtokh, G.; Shin, D.; Ko, J.T. Hyaluronic acid-coated cisplatin conjugated gold nanoparticles for combined cancer treatment. J. Ind. Eng. Chem. 2018, 65, 236–243. [CrossRef] 162. Kosmas, C.; Angel, J.; Athanasiou, A.; Rapti, A.; Karanikas, C.; Lambaki, S.; Politis, N.; Mylonakis, N. 9088 Phase III study of Lipoplatin plus Gemcitabine versus Cisplatin plus Gemcitabine in advanced NSCLC; interim analysis. Eur. J. Cancer Suppl. 2009, 7, 531. [CrossRef] 163. Farhat, F.; Kattan, J.; Ibrahim, K.; Bitar, N.; Haddad, N.; Tamraz, S.; Hatoum, H.; Shamseddine, A. 457 Preliminary results of a phase II study of lipoplatin (liposomal cisplatin)–vinorelbine combination as first line treatment in HER2/neu negative metastatic breast cancer (MBC). Eur. J. Cancer Suppl. 2010, 8, 192. [CrossRef] 164. Koukourakis, M.I.; Giatromanolaki, A.; Pitiakoudis, M.; Kouklakis, G.; Tsoutsou, P.; Abatzoglou, I.; Panteliadou, M.; Sismanidou, K.; Sivridis, E.; Boulikas, T. Concurrent liposomal cisplatin (Lipoplatin), 5-fluorouracil and radiotherapy for the treatment of locally advanced gastric cancer: A phase I/II study. Int. J. Radiat. Oncol. Biol. Phys. 2010, 78, 150–155. [CrossRef] 165. Huo, T.; Barth, R.F.; Yang, W.; Nakkula, R.J.; Koynova, R.; Tenchov, B.; Chaudhury, A.R.; Agius, L.; Boulikas, T.; Elleaume, H.; et al. Preparation, Biodistribution and Neurotoxicity of Liposomal Cisplatin following Convection Enhanced Delivery in Normal and F98 Glioma Bearing Rats. PLoS ONE 2012, 7, e48752. [CrossRef] 166. Gonda, A.; Zhao, N.; Shah, J.V.; Calvelli, H.R.; Kantamneni, H.; Francis, N.L.; Ganapathy, V. Engineering Tumor-Targeting Nanoparticles as Vehicles for Precision Nanomedicine. Med. One 2019, 4, e190021. 167. Shein, S.A.; Kuznetsov, I.I.; Abakumova, T.O.; Chelushkin, P.S.; Melnikov, P.A.; Korchagina, A.A.; Bychkov, D.A.; Seregina, I.F.; Bolshov, M.A.; Kabanov, A.V.; et al. VEGF- and VEGFR2-Targeted Liposomes for Cisplatin Delivery to Glioma Cells. Mol. Pharm. 2016, 13, 3712–3723. [CrossRef] 168. Ashrafzadeh, M.S.; Akbarzadeh, A.; Heydarinasab, A.; Ardjmand, M. In vivo Glioblastoma Therapy Using Targeted Liposomal Cisplatin. Int. J. Nanomed. 2020, 15, 7035–7049. [CrossRef] Nanomaterials 2023, 13, 1619 30 of 32 169. Dhami, N.K.; Pandey, R.S.; Jain, U.K.; Chandra, R.; Madan, J. Non-Aggregated Protamine-Coated Poly(Lactide-Co-Glycolide) Nanoparticles of Cisplatin Crossed Blood-Brain Barrier, Enhanced Drug Delivery and Improved Therapeutic Index in Glioblas- toma Cells: In Vitro Studies. J. Microencapsul. 2014, 31, 685–693. [CrossRef] 170. Marrache, S.; Pathak, R.K.; Dhar, S. Detouring of cisplatin to access mitochondrial genome for overcoming resistance. Proc. Natl. Acad. Sci. USA 2014, 111, 10444–10449. [CrossRef] 171. Nance, E.A.; Woodworth, G.F.; Sailor, K.A.; Shih, T.Y.; Xu, Q.; Swaminathan, G.; Xiang, D.; Eberhart, C.; Hanes, J. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci. Transl. Med. 2012, 4, 149ra119. [CrossRef] 172. Ebrahimi Shahmabadi, H.; Movahedi, F.; Koohi Moftakhari Esfahani, M.; Alavi, S.E.; Eslamifar, A.; Mohammadi Anaraki, G.; Akbarzadeh, A. Efficacy of Cisplatin-Loaded Polybutyl Cyanoacrylate Nanoparticles on the Glioblastoma. Tumour Biol. 2014, 35, 4799–4806. [CrossRef] 173. Zhang, C.; Nance, E.A.; Mastorakos, P.; Chisholma, J.; Eberhart, S.B.C.; Tyler, B.; Brem, H.; Suk, J.S.; Hanes, J. Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats. J. Control. Release 2017, 263, 112–119. [CrossRef] 174. Lajous, H.; Riva, R.; Lelievre, B.; Tetaud, C.; Avril, S.; Hindre, F.; Boury, F.; Jerome, C.; Lecomte, P.; Garcion, E. Hybrid Gd3+/Cisplatin Cross-Linked Polymer Nanoparticles Enhance Platinum Accumulation and Formation of DNA Adducts in Glioblastoma Cell Lines. Biomater. Sci. 2018, 6, 2386–2409. [CrossRef] 175. Nukolova, N.V.; Baklaushev, V.P.; Abakumova, T.O.; Mel’nikov, P.A.; Abakumov, M.A.; Yusubalieva, G.M.; Bychkov, D.A.; Kabanov, A.V.; Chekhonin, V.P. Targeted delivery of cisplatin by connexin 43 vector nanogels to the focus of experimental glioma C6. Bull Exp. Biol. Med. 2014, 157, 524–529. [CrossRef] 176. Renault-Mahieux, M.; Vieillard, V.; Seguin, J.; Espeau, P.; Le, D.T.; Lai-Kuen, R.; Mignet, R.; Paul, M.; Andrieux, K. Co- Encapsulation of Fisetin and Cisplatin into Liposomes for Glioma Therapy: From Formulation to Cell Evaluation. Pharmaceutics 2021, 13, 970. [CrossRef] 177. Zou, Y.; Wang, Y.; Xu, S.; Liu, Y.; Yin, J.; Lovejoy, D.B.; Zheng, M.; Liang, X.-J.; Park, J.B.; Efremov, Y.M.; et al. Brain Co-Delivery of Temozolomide and Cisplatin for Combinatorial Glioblastoma Chemotherapy. Adv. Mater. 2022, 34, 2203958. [CrossRef] 178. Straehla, J.P.; Hajal, C.; Safford, H.C.; Offeddu, G.S.; Boehnke, N.; Dacoba, T.C.; Wyckoff, J.; Kamm, R.D.; Hammond, P.T. A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier penetrant nanoparticles. Proc. Natl. Acad. Sci. USA 2022, 119, e2118697119. [CrossRef] 179. Yu, H.; Tang, Z.; Zhang, D.; Song, W.; Zhang, Y.; Yang, Y.; Ahmad, Z.; Chen, X. Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy. J. Control Release 2015, 205, 89–97. [CrossRef] 180. Ho, G.Y.; Woodward, N.; Coward, J.I.G. Cisplatin versus carboplatin: Comparative review of therapeuticmanagement in solid malignancies. Crit. Rev. Oncol./Hematol. 2016, 102, 37–46. [CrossRef] 181. Colombo, N.; Guthrie, D.; Chiari, S.; Parmar, M.; Qian, W.; Swart, A.M.; Torri, V.; Williams, C.; Lissoni, A.; Bonazzi, C. International Collaborative Ovarian Neoplasm trial 1: A randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J. Natl. Cancer Inst. 2003, 95, 125–132. [PubMed] 182. Rezaee, M.; Hunting, D.J.; Sanche, L. New insights into the mechanism underlying the synergistic action of ionizing radiation with platinum chemotherapeutic drugs: The role of low-energy electrons. Int. J. Radiat. Oncol. Biol. Phys. 2013, 87, 847–853. [CrossRef] [PubMed] 183. Gianasi, E.; Buckley, R.G.; Latigo, J.; Wasil, M.; Duncan, R. HPMA copolymers platinates containing dicarboxylato ligands. Preparation, characterisation and in vitro and in vivo evaluation. J. Drug Target. 2002, 10, 549–556. [CrossRef] [PubMed] 184. Gianasi, E.; Wasil, M.; Evagorou, E.; Keddle, A.; Wilson, G.; Duncan, R. HPMA copolymer platinates as novel antitumour agents: In vitro properties, pharmacokinetics and antitumour activity in vivo. Eur. J. Cancer. 1999, 35, 994–1002. [CrossRef] 185. Rademaker-Lakhai, J.M.; Terret, C.; Howell, S.B.; Baud, C.M.; de Boer, R.F.; Pluim, D.; Beijnen, J.H.; Schellens, J.H.; Droz, J.-P. A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors. Clin. Cancer Res. 2004, 10, 3386–3395. [CrossRef] 186. Karanam, V.; Marslin, G.; Krishnamoorthy, B.; Chellan, V.; Siram, K.; Natarajan, T.; Bhaskar, B.; Franklin, G. Poly (ε -caprolactone) nanoparticles of carboplatin: Preparation, characterization and in vitro cytotoxicity evaluation in U-87 MG cell lines. Colloids Surf B Biointerfaces 2015, 130, 48–52. [CrossRef] 187. Hassanzadeganroudsari, M.; Soltani, M.; Heydarinasab, A.; Apostolopoulos, V.; Akbarzadehkhiyavi, A.; Nurgali, K. Targeted nano-drug delivery system for glioblastoma therapy: In vitro and in vivo study. J. Drug Deliv. Sci. Technol. 2020, 60, 102039. [CrossRef] 188. Arshad, A.; Yang, B.; Bienemann, A.S.; Barua, N.U.; Wyatt, M.J.; Woolley, M.; Johnson, D.E.; Edler, K.J.; Gill, S.S. Convection- enhanced delivery of carboplatin PLGA nanoparticles for the treatment of glioblastoma. PLoS ONE 2015, 10, e0132266. [CrossRef] 189. Shi, M.; Anantha, M.; Wehbe, M.; Bally, M.B.; Fortin, D.; Roy, L.-O.; Charest, G.; Richer, M.; Paquette, B.; Sanche, L. Liposomal formulations of carboplatin injected by convection-enhanced delivery increases the median survival time of F98 glioma bearing rats. J. Nanobiotechnol. 2018, 16, 77. [CrossRef] 190. Alex, A.T.; Joseph, A.; Shavi, G.; Rao, J.V.; Udupa, N. Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery. Drug Deliv. 2016, 23, 2144–2153. [CrossRef] Nanomaterials 2023, 13, 1619 31 of 32 191. Fortin, D.; Desjardins, A.; Benko, A.; Niyonsega, T.; Boudrias, M. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: The sherbrooke experience. Cancer 2005, 103, 2606–2615. [CrossRef] [PubMed] 192. Miura, Y.; Takenaka, T.; Toh, K.; Wu, S.; Nishihara, H.; Kano, M.R.; Ino, Y.; Nomoto, T.; Matsumoto, Y.; Koyama, H.; et al. Cyclic Rgd-Linked Polymeric Micelles for Targeted Delivery of Platinum Anticancer Drugs to Glioblastoma through the Blood-Brain Tumor Barrier. ACS Nano 2013, 7, 8583–8592. [CrossRef] 193. Shi, M.; Fortin, D.; Paquette, B.; Sanche, L. Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model. Investig. New Drugs. 2016, 34, 269–276. [CrossRef] 194. You, Y.; Wang, N.; He, l.; Shi, C.; Zhang, D.; Liu, Y.; Luo, L.; Che, T. Designing dual-functionalized carbon nanotubes with high blood–brain-barrier permeability for precise orthotopic glioma therapy. Dalton Trans. 2019, 48, 1569–1573. [CrossRef] [PubMed] 195. McCartin, C.; Dussouillez, C.; Bernhard, C.; Mathieu, E.; Blumberger, J.; Dontenwill, M.; Herold-Mende, C.; Idbaih, A.; Lavalle, P.; Bellemin-Laponnaz, S.; et al. Polyethylenimine, an Autophagy-Inducing Platinum-Carbene-Based Drug Carrier with Potent Toxicity towards Glioblastoma Cancer Stem Cells. Cancers 2022, 14, 5057. [CrossRef] [PubMed] 196. Wang, Z.; Denga, Z.; Zhu, G. Emerging platinum(IV) prodrugs to combat cisplatin resistance: From isolated cancer cells to tumor microenvironment. Dalton Trans. 2019, 48, 2536–2544. [CrossRef] 197. Wang, Y.; Jiang, Y.; Wei, D.; Singh, P.; Yu, Y.; Lee, T.; Zhang, L.; Mandl, H.K.; Piotrowski-Daspit, A.S.; Chen, X.; et al. Nanoparticle- mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance. Nat. Biomed. Eng. 2021, 5, 1048–1058. [CrossRef] 198. Arduino, I.; Depalo, N.; Re, F.; Dal Magro, R.; Panniello, A.; Margiotta, N.; Fanizza, E.; Lopalco, A.; Laquintana, V.; Cutrignelli, A.; et al. PEGylated solid lipid nanoparticles for brain delivery of lipophilic kiteplatin Pt(IV) prodrugs: An in vitro study. Int. J. Pharm. 2020, 583, 119351. [CrossRef] 199. Mao, X.; Wu, S.; Calero-Pérez, P.; Candiota, A.P.; Alfonso, P.; Bruna, J.; Yuste, V.J.; Lorenzo, J.; Novio, F.; Ruiz-Molina, D. Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment. Cancers 2022, 14, 410. [CrossRef] 200. Kutwin, M.; Sawosz, E.; Jaworski, S.; Hinzmann, M.; Wierzbicki, M.; Hotowy, A.; Grodzik, M.; Winnicka, A.; Chwalibog, A. Investigation of Platinum Nanoparticle Properties against U87 Glioblastoma Multiforme. Arch. Med. Sci. 2017, 13, 1322–1334. [CrossRef] 201. Lopez Ruiz, A.; Bartomeu Garcia, C.; Navarro Gallon, S.; Webster, T.J. Novel Silver-Platinum Nanoparticles for Anticancer and Antimicrobial Applications. Int. J. Nanomed. 2020, 15, 169–179. [CrossRef] 202. Shi, M.; Fortin, D.; Sanche, L.; Paquette, B. Convection-Enhancement Delivery of Platinum-Based Drugs and Lipoplatintm to Optimize the Concomitant Effect with Radiotherapy in F98 Glioma Rat Model. Investig. New Drugs 2015, 33, 555–563. [CrossRef] [PubMed] 203. Setua, S.; Ouberai, M.; Piccirillo, S.G.; Watts, C.; Welland, M. Cisplatin-Tethered Gold Nanospheres for Multimodal Chemo- Radiotherapy of Glioblastoma. Nanoscale 2014, 6, 10865–10873. [CrossRef] [PubMed] 204. Hall, P.E.; Lewis, R.; Syed, N.; Shaffer, R.; Evanson, J.; Ellis, S.; Williams, M.; Feng, X.; Johnston, A.; Thomson, J.A. A phase I study of Pegylated arginine deiminase (Pegargiminase), cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-deficient recurrent high-grade glioma. Clin. Cancer Res. 2019, 25, 2708–2716. [CrossRef] 205. Allen, J.; Siffert, J.; Donahue, B.; Nirenberg, A.; Jakacki, R.; Robertson, P.; DaRosso, R.; Thoron, L.; Rosovsky, M.; Pinto, R. A phase I/II study of carboplatin combined with hyperfractionated radiotherapy for brainstem gliomas. Cancer Interdiscip. Int. J. Am. Cancer Soc. 1999, 86, 1064–1069. [CrossRef] 206. Fouladi, M.; Blaney, S.M.; Poussaint, T.Y.; Freeman III, B.B.; McLendon, R.; Fuller, C.; Adesina, A.M.; Hancock, M.L.; Danks, M.K.; Stewart, C. Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: A pediatric brain tumor consortium study. Cancer Interdiscip. Int. J. Am. Cancer Soc. 2006, 107, 2291–2297. [CrossRef] 207. Macy, M.E.; Duncan, T.; Whitlock, J.; Hunger, S.P.; Boklan, J.; Narendran, A.; Herzog, C.; Arceci, R.J.; Bagatell, R.; Trippett, T. A multi-center phase Ib study of oxaliplatin (NSC# 266046) in combination with fluorouracil and leucovorin in pediatric patients with advanced solid tumors. Pediatr. Blood Cancer 2013, 60, 230–236. [PubMed] 208. Chintala, S.; Ali-Osman, F.; Mohanam, S.; Rayford, A.; Go, Y.; Gokaslan, Z.L.; Gagercas, E.; Vekaiah, B.; Sawaya, R.; Nicolson, G.; et al. Effect of cisplatin and BCNU on MMP-2 levels in human glioblastoma cell lines in vitro. Clin. Exp. Metastasis 1997, 14, 361–367. [CrossRef] [PubMed] 209. Rébé, C.; Demontoux, L.; Pilot, T.; Ghiringhelli, F. Platinum Derivatives Effects on Anticancer Immune Response. Biomolecules 2020, 10, 13. [CrossRef] 210. Nduom, E.K.; Weller, M.; Heimberger, A.B. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015, 17, vii9–vii14. [CrossRef] 211. Hato, S.V.; Khong, A.; de Vries, I.J.; Lesterhuis, W.J. Molecular pathways: The immunogenic effects of platinum-based chemother- apeutics. Clin. Cancer Res. 2014, 20, 2831–2837. [CrossRef] [PubMed] Nanomaterials 2023, 13, 1619 32 of 32 212. Lesterhuis, W.J.; Punt, C.J.; Hato, S.V.; Eleveld-Trancikova, D.; Jansen, B.J.; Nierkens, S.; Schreibelt, G.; de Boer, A.; Van Herpen, C.M.; Kaanders, J.H.; et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J. Clin. Investig. 2011, 121, 3100–3108. [CrossRef] 213. Bezu, L.; Gomes-de-Silva, L.C.; Dewitte, H.; Breckpot, K.; Fucikova, J.; Spisek, R.; Galluzzi, L.; Kepp, O.; Kroemer, G. Combinato- rial strategies for the induction of immunogenic cell death. Front. Immunol. 2015, 6, 187. [CrossRef] 214. Kang, L.; Gao, Z.; Huang, W.; Jin, M.; Wang, Q. Nanocarrier-mediated codelivery of chemotherapeutic drugs and gene agents for cancer treatment. Acta Pharm. Sin. B 2015, 5, 169–175. [CrossRef] [PubMed] 215. Field, K.M.; Simes, J.; Nowak, A.K.; Cher, L.; Wheeler, H.; Hovey, E.J.; Brown, C.S.; Barnes, E.H.; Sawkins, K.; Livingstone, A.; et al. Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma. Neuro Oncol. 2015, 17, 1504–1513. [CrossRef] [PubMed] 216. Bruinsmann, F.A.; Richter Vaz, G.; de Cristo Soares Alves, A.; Aguirre, T.; Raffin Pohlmann, A.; Stanisçuaski Guterres, S.; Sonvico, F. Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials. Molecules 2019, 24, 4312. [CrossRef] 217. Sandbhor, P.; Goda, J.; Mohanty, B.; Gera, P.; Yadav, S.; Chekuri, G.; Chaudhari, P.; Dutt, S.; Banerjee, R. Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model. Drug Deliv. Transl. 2023, 13, 608–626. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.