Journal of Drug Delivery Science and Technology 79 (2023) 104085 Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst Novel cannabinoid release system: Encapsulation of a cannabidiol precursor into γ-cyclodextrin metal-organic frameworks Jorge Rodríguez-Martínez 1, María-Jesús Sánchez-Martín *, 1, Oscar López-Patarroyo, Manuel Valiente GTS Research Group, Department of Chemistry, Faculty of Science, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain A R T I C L E I N F O A B S T R A C T Keywords: γ-Cyclodextrin-metal-organic frameworks (γ-CD-MOFs) are developed as a new promising and biocompatible γ-Cyclodextrin-metal-organic frameworks material, which shows a great potential for drug delivery system (DDS) applications. γ-CD-MOFs were suc­ (γ-CD-MOFs) cessfully synthesized using microwave-assisted technique from different potassium sources (KOH, KCl and Cannabidiol (CBD) KNO3). The encapsulation of olivetol (OLV) into these materials was investigated as an innovative model of DDS Cannabinoids Drug delivery systems (DDS) for cannabinoids. Loading of OLV in γ-CD-MOFs was performed by impregnation and co-crystallization methods. Olivetol (OLV) Scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD) were employed to study the structural properties of γ-CD-MOF samples, showing the typical cubic crystals in case of KOH and trigonal morphologies in case of KCl and KNO3. Olivetol content was determined using UV–Vis spectrophotometry and its interaction with γ-CD-MOFs was investigated by Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy analysis (ATR-FTIR). OLV content was significantly higher when KCl or KNO3 were employed in combination with a co- crystallization method, while the drug encapsulation using KOH and the impregnation method was really poor. For the first time, γ-CD-MOFs loaded with cannabinoids were developed and they could be considered a novel strategy as DDS of these compounds. 1. Introduction the MOFs. Within the uses of MOFs, the application of these materials in Metal-organic frameworks (MOFs) have emerged in several appli­ biomedical field has been growing over the last years since they could cations such as gas storage, catalysis, pollutant-removal agents and drug act as drug delivery systems in order to improve the characteristics of the delivery systems (DDS) [1,2]. These materials are made of metal ions encapsulated agent and to target its pharmaceutical effect [7]. Never­ and organic ligands linked in an infinite extended one-two-three theless, biocompatibility is a key aspect in these cases and the compo­ dimensional networks [3]. This packing confers crystallinity and nents that comprise the MOFs should show low toxicity [8,9]. In recent extraordinary properties to MOFs such as high surface areas, ultrahigh years, γ-cyclodextrin-metal-organic frameworks (γ-CD-MOFs) have porosity and thermal stability making them promising for plenty ap­ arisen as promising biocompatible candidates due to their relevance in plications as already mentioned above [4]. Moreover, the parameters pharmacy and biomedicine [10]. These types of MOFs are made of that define these properties could be modified by the selection of the γ-cyclodextrin as the organic ligand and the selected metal linker. γ-CD linkers and the control of the different steps during the synthesis pro­ presents a hydrophobic inner cavity where non-polar compounds could cedure [5]. Another aspect to take into account is the formation of the be encapsulated and a hydrophilic outer surface allowing its solubility in host-guest complexes. This encapsulation process depends on the drug to aqueous solutions [11]. Besides, the encapsulation capacity of encapsulate and on the medium. In fact, there are a lot of methodologies γ-CD-MOFs is higher than in the γ-CD alone and, according to reported for this purpose, like direct impregnation, vaporization, direct contact studies; these MOFs improve the physicochemical and biopharmaceu­ pressure or co-crystallization techniques [6]. Furthermore, the proced­ tical characteristics of the encapsulated drug and control its release ure should be selected properly in order not to affect the properties of process [12,13]. In order to perform the synthesis of these materials, the * Corresponding author. E-mail address: mariajesus.sanchez@uab.cat (M.-J. Sánchez-Martín). 1 Shared co-first authorship. https://doi.org/10.1016/j.jddst.2022.104085 Received 27 May 2022; Received in revised form 7 December 2022; Accepted 12 December 2022 Available online 14 December 2022 1773-2247/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 vapor diffusion technique is the most conventional and well-known the followed synthesis method. The characterization of the drug delivery method but it requires at least several days to obtain γ-CD-MOFs [14]. systems is performed and the encapsulation efficiency of OLV into γ-CD- Therefore, new methodologies are being developed in order to solve this MOFs is determined. For the first time, γ-CD-MOFs are used for olivetol difficulty, such as the analytical microwave-assisted technique, obtain­ encapsulation, and it could be useful in the development of CD-MOFs as ing homogeneous crystal structures with editable size and a suitable promising drug delivery systems with analgesic effect in pharmacy and reaction yield [15,16]. Moreover, the synthesis time has been reduced biomedical field. from days to hours using this technique instead of the vapor diffusion method. Thus, microwave technique emerges as a fast and efficient 2. Materials and methods methodology in the synthesis of these frameworks. CD-MOFs based on α-CD, β-CD or γ-CD using potassium nitrate were developed for menthol 2.1. Reagents encapsulation [17]. The obtained crystals presented uniform size, or­ dered structures and regular shape, showing a better thermal stability Olivetol (95%) and γ-cyclodextrin (98%) were purchased from Car­ than alone CDs. This study could be useful in the design of efficient bosynth Ltd (Compton, United Kingdom). Potassium hydroxide (85.5%) materials in the food industry. Moreover, other study has made an and potassium nitrate (99.2%) were purchased from VWR BDH Chem­ attempt to improve the encapsulation of the insoluble drug, honokiol, icals (Oud-Heverlee, Belgium). Dichloromethane (99.5%) and ethanol into the pores of γ-CD-MOFs using supercritical carbon dioxide for its (96%) were purchased from Scharlau (Sentmenat, Spain). Potassium activation [18]. The resulting DDS improved the solubility and chloride (99.0%) was purchased from Sigma-Aldrich (St. Louis, MO, bioavailability of the drug and the activation of the MOFs maximized its USA). Polyethylene glycol 20,000 was purchased from Merk (Darm­ potential encapsulation capability. stadt, Germany). Methanol (99.8%) and acetic acid (99.9%) were pur­ Cannabidiol (CBD) is the main non-psychotropic cannabinoid of the chased from Fisher Scientific (Madrid, Spain). MilliQ water was purified Cannabis sativa plant. This compound is the main component responsible through a Millipore purification system from Millipore (Milford, MA, of the medical benefits of cannabis. Cannabidiol and other natural USA). cannabinoids act on the endocannabinoid system [19]. This system regulates several physiological processes in the body related to cognition 2.2. Preparation of the samples and brain function, pain pathways in the brain, immune and hemato­ poietic systems. Therefore, CBD presents interesting properties such as A fast synthesis of γ-CD-MOFs with microwave irradiation was per­ its analgesic, anti-inflammatory and immunomodulatory effects [20]. formed using a modified method [1]. This reported method offers the Because of that, this compound has been employed in several studies advantages of simple, rapid, inexpensive, relatively green, and efficient over the last few years for the treatment of diseases such as Alzheimer or non-conventional heating and high yield [13]. Briefly, γ-CD (324 mg) cancer [21,22]. These promising effects in a lot of different diseases are and KOH (112 mg) were mixed in milliQ water (10 mL). The molar ratio due to the capacity of CBD to interact not only with the corresponding of KOH to γ-CD was 1:8. Then, 6 mL of methanol were added. This initial endocannabinoid receptors but also with a wide spectrum of others re­ solution was treated at 50 ◦ C in the analytical microwave (CEM Cor­ ceptors [23]. However, CBD also presents some limitations that poration Matthews, North Carolina, USA) for 10 min and a power of 600 compromise its plenty applications. This compound is insoluble in w. After that process, 256 mg of PEG 20000 were added for 1 h to trigger water, it presents low chemical stability and it gets oxidized in alkali the precipitation of the crystals at room temperature. In order to remove media [24]. Consequently, numerous materials for CBD encapsulation the unreacted material, the crystals were washed first with 10 mL of have been developed to minimize these weaknesses, including inclusion methanol and then with 10 mL more of ethanol in a centrifuge at 3000 complexes of cyclodextrins, lipid carriers and microparticles, among rpm for 5 min. Next, γ-CD-MOFs were left under vacuum and dried others [25]. Poly (lactic-co-glycolic acid) spherical microparticles were overnight at 50 ◦ C. Herein, preliminary alkaline γ-CD-MOFs (pH = 12) used for CBD encapsulation improving the administration of the drug were obtained. Since cannabinoids get oxidized in alkali media, a and showing a useful formulation to be combined with conventional neutralization of the γ-CD-MOFs was needed. For this step, the crystals chemotherapy against ovarian cancer [26]. In other study, the prepa­ were treated with a mixture of 5.2 mL of ethanol and 0.8 mL of acetic ration of stable inclusion complex of CBD with three native cyclodex­ acid. The suspension was then shaken at 290 rpm for 2 h and the pre­ trins increased significantly the water solubility and in vitro anticancer cipitates were collected by centrifugation (3000 rpm for 5 min). Once activity of cannabidiol compared with free drug thanks to the encap­ again, the powder was left to dry overnight under vacuum at 50 ◦ C. sulation of the CBD into the inner cavity of cyclodextrins [27]. Similarly, Afterwards, an activation of the γ-CD-MOFs was performed using a nanostructured lipid carriers formulations loaded with CBD were solvent exchange method with dichloromethane in order to remove developed and characterized as a promising delivery system to enhance guest molecules from chemicals used in the synthetic procedure. the bioavailability of cannabidiol for the treatment of neuropathic pain γ-CD-MOFs were mixed with 10 mL of dichloromethane at 290 rpm for 3 [28]. Even though there are several studies on the encapsulation of days. Every 24 h the solvent was replaced by centrifugation (3000 rpm cannabidiol into different carriers, investigations on CBD being loaded for 5 min). Finally, the samples were dried overnight under vacuum at into γ-CD-MOFs have not been reported. Nevertheless, cannabidiol is not 50 ◦ C. γ-CD-MOFs were kept under vacuum at room temperature until its a very affordable product, therefore analogues or precursors of this use and the reaction yields were also calculated. compound could be used instead of CBD for multiple experimental ap­ Impregnation and co-crystallization methods were performed to load proaches. Olivetol (OLV), also known as 5-pentylresorcinol, is a natural olivetol into γ-CD-MOFs. In case of impregnation, 30.8 mg of MOF organic compound found in certain species of plants [29] and itis an samples were added to 20 mL of OLV 360 mg/mL solution in ethanol in intermediate involved in the cannabinoid biosynthesis in C. sativa. This order to obtain a 1:2 M ratio of γ-CD-MOFs:OLV respectively. The sus­ compound leads to the different cannabinoids, including CBD becoming pensions were incubated for 24 h at 37 ◦ C under stirring conditions (290 an important metabolite in cannabinoid biosynthesis [30]. In fact, it is rpm). After the incubation time, the crystals were washed with 10 mL of used in various methods to produce synthetic analogues of cannabinoids ethanol in a centrifuge at 3000 rpm for 5 min in order to remove the drug [31]. Chemically, OLV structure is found in cannabinoids, so OLV could that did not interact with the γ-CD-MOFs. Finally, the samples were be used as an analogue of CBD as it could mimic its interactions with the dried and kept under vacuum at room temperature until its use. drug delivery systems. The co-crystallization method is similar to that described before. In The aim of this study is to develop CD-MOFs for olivetol encapsu­ this case, the potassium sources were KCl or KNO3 instead of KOH, lation as a model of cannabinoid drug delivery system. CD-MOFs are adding 149 mg or 202 mg respectively, to maintain the 1:2 M ratio. The prepared using γ-CD and three different potassium sources depending on change in the potassium source is because of in the co-crystallization the 2 J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 drug is loaded on the initial solution where the synthesis takes place, and and a lineal X’Celerator detector for the diffracted beam. The samples the pH of the medium must be neutral from the beginning to avoid were irradiated with a ceramic X-ray tube with Cu Kα anode (l = 1.5406 olivetol oxidation. Additionally, 30 mg of OLV were also diluted in the Å), tube voltage of 45 kV, tube current of 40 mA in a step size scan mode initial solution. This amount of drug was selected in order to keep the (0.03◦ min− 1) and analysed over a 2θ angle range of 2.5–35◦ . same molar ratio between MOF and olivetol as in the impregnation method. In this method, the incubation time with PEG 20000 was 24 h 2.6. Attenuated total reflection-fourier transform Infrared Spectroscopy instead of 1 h in order to maintain the same incubation time with OLV analysis for its encapsulation as in the impregnation method, thus making them comparable but the neutralization and activation steps were not needed. Infrared Spectroscopy spectra of samples were obtained using an Finally, the washes were the same as before and the resultant samples Infrared Spectrophotometer Tensor 27 equipped with an Attenuated were left overnight under vacuum at 50 ◦ C and kept under vacuum at Total Reflectance module Specac Golden Gate (ATR-FTIR, Bruker, room temperature until its use. It should be noted that MOFs were not Ettlingen, Germany). The ATR accessory allows direct recording of obtained when KCl or KNO3 were employed following the same syn­ samples thus facilitating the recording of IR spectra on liquid or solid thesis procedure as for KOH. samples regardless of their physical nature. To measure the powder The γ-CD-MOFs loaded by impregnation method was named as γ-CD- samples 64 scans were carried out in wavenumber from 4000 cm− 1 to MOF-1, loaded or not with OLV. In the case of co-crystallization tech­ 600 cm− 1 at a resolution of 4 cm− 1 and at room temperature. For the nique, MOFs were named as γ-CD-MOF-2 and γ-CD-MOF-3, for KCl and background the own diamond window of the equipment was used. KNO3 as potassium sources respectively. 3. Results and discussion 2.3. Drug release and quantification 3.1. Structural properties of γ-CD-MOFs The quantification of the drug encapsulation into the MOFs was determined as follows: 15 mg of MOF sample were added to 5 mL of a The crystal morphology and element distribution of different γ-CD- mixture of milliQ water and ethanol (1:1, v/v). The mixture was incu­ MOFs compared with native γ-CD were determined by SEM and EDX bated at room temperature under stirring conditions (290 rpm) for 24 h analysis. In case of γ-CD-MOF-1, the final morphology of the crystals to promote the degradation of the crystals and release the encapsulated matched very well with the previously reported morphology of the same OLV. To determine the amount of olivetol, the solution was measured by material (Fig. 1A) [10]. The SEM images of γ-CD-MOF-1 showed that UV–Vis spectrophotometry (Thermo Fisher Scientific, Massachusetts, they presented cubic-shaped with a size average of 2 μm, while the USA) [32]. The UV detection was performed at 275 nm that is the morphology of the raw γ-CD alone was completely amorphous when the characteristic peak of OLV and the reference was a mixture of milliQ same technique was performed (Fig. A.2). Moreover, the EDX detector in water and ethanol (1:1, v/v). A calibration curve of different known the SEM equipment was used to the elemental qualitative analysis of concentrations of olivetol in milliQ water and ethanol solutions (1:1, γ-CD-MOF-1 and it confirmed the presence of potassium in the cubic v/v) was also performed from 0 to 100 mg/L of the drug (Fig. A.1) to structures (Table A.1). Thus, the cubic crystals were the material of in­ determine the concentration of olivetol in the samples. terest. Furthermore, the size average of the structures was reduced in The drug loading for each MOF was calculated following equation comparison with the γ-CD-MOFs obtained with conventional method­ (1): ologies, such as vapor diffusion method (Fig. A.3). This fact demon­ strated the high capabilities of the microwave technique to achieve Encapsulated OLV into CD − MOFs (mg) Drug loading (%) = ⋅100 [1] narrow size distributions and control of the morphology in the MOFs Total Weight of coplexation powder (mg) synthesis. Indeed, this is a key point when the final application of the All determinations of the loaded drug in each MOF sample were structures is as drug delivery systems. In the case of olivetol loaded performed by triplicate. γ-CD-MOF-1, similar size and cubic shape were observed in comparison with the unloaded ones (Fig. 1B). Therefore, the morphology of the MOF 2.4. Scanning electron microscope and energy-dispersive X-ray structures was stable after the encapsulation with the drug. In case of spectroscopy γ-CD-MOF-2 and γ-CD-MOF-3, the resultant crystals presented a different morphology when they were compared with γ-CD-MOF-1 and The morphology and elemental composition of the MOF samples the reported ones. Co-crystallization of γ-CD-MOFs with OLV showed a were analysed by Scanning Electron Microscopy (SEM) and Energy rectangular shape as elongated prims and a bigger and less homoge­ Dispersive X-ray Spectroscopy (EDX) with a Zeiss Merlin FE-SEM neous size than in the synthesis with KOH. The differences in size and equipped with an EDX Oxford INCA X-Max Detector. The images were homogeneity may be due to the incubation time with PEG during the taken with the Secondary Electron Detector with a low voltage of 1–2 kV synthesis process [1]. Since in γ-CD-MOF-1 the incubation time was 1 h, and the EDX measurements were taken at 10 kV. This microscope has a in the co-crystallization it took 24 h to get the precipitation of the unique charge compensation system that allows the high-resolution crystals. It was reported that if enough amount of time is allowed for imaging of non-conductive samples, electrons which accumulate on crystallization, larger particles will obtain but also small ones because the sample surface are swept away by a fine jet of nitrogen. All the ex­ synthesis during a short time may be also possible. Therefore, the size periments were performed at room temperature. will not be homogeneous and bigger crystals will be obtained [15]. Differences observed in shape between MOFs obtained by 2.5. X-ray powder diffraction analysis co-crystallization (γ-CD-MOF-2 and γ-CD-MOF-3) and γ-CD-MOF-1 may be due to the use of the potassium salts instead of KOH as metal source. The crystallinity of the MOFs samples was characterized by X-ray The change of this reagent modifies an important solution parameter powder diffraction (XRPD) using a Malvern Panalytical X’Pert PRO MPD such as pH. For γ-CD-MOF-1, the pH of the initial solution was 12 and in (Material Powder Diffractometer). The MPD is suitable for the analysis the co-crystallization the pH was 7. It is reported that the pH control of of polycrystalline samples at room temperature. This diffractometer has the environment of the reaction medium in MOFs synthesis allows you a vertical theta-theta goniometer (240 mm radius). The XRD analysis to control the size and the morphology of the resulting crystals [33]. was carried in transmission mode using a capillary spinner and the Moreover, the totality of studies that synthetize γ-CD-MOF use alkali sample were filled inside borosilicate glass capillaries with outer media in order to get the classic cubic shapes regardless of metal source. diameter of 0.7 mm. A focusing mirror was used for the incident beam The fact that both KCl and KNO3 led the same elongated prisms 3 J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 Fig. 1. Scanning electron microscopy images of unloaded γ-CD-MOF-1 (A), olivetol loaded γ-CD-MOF-1 (B), γ-CD-MOF-2 (C) and γ-CD-MOF-3 (D) with a low voltage of 2 kV, 5000x of magnification and a working distance of 4.7 mm. morphologies supports this pH-dependent theory. Besides that, EDX analysis also showed the presence of potassium in the MOFs obtained by co-crystallization (Table A.1), confirming the interaction between the metal ion and the organic ligand to form this material. Further characterization was performed using X-ray diffraction. The crystallinity of γ-CD-MOF-1 before and after the encapsulation experi­ ments with the drug was measured by XRPD. According to reported studies about the synthesis of γ-CD-MOFs using KOH, the characteristic peaks in X-ray diffraction patterns of these materials are located in the next angles: 4◦ , 5.7◦ , 7◦ , 13.3◦ and 16.6◦ . These positions correspond to body-centered cubic crystals of space group I432 [34]. XRPD results showed that the diffractogram of the unloaded MOFs presented the same peaks in comparison with the standard reference of these crystals (Fig. 2 and fig. A.4). Therefore, the crystalline phase obtained for γ-CD-MOF-1 coincided with the typical cubic unit of these materials. Comparing the data before and after the encapsulation experiment with olivetol, the crystallinity of MOFs loaded with the drug changed with respect to the unloaded crystals. The intensity of the peaks of the γ-CD-MOF-1 with OLV was significantly reduced compared to those of the unloaded MOFs (Fig. 2). This partial loss of crystallinity of the MOFs may result from the filling of pores with olivetol, the high degree of disorder of the drug and the presence of a low percentage of water in the ethanol solution used in these experiments [32]. However, the peak positions in the diffracto­ grams were similar in both cases indicating that MOF crystals were stable after the encapsulation with olivetol [35]. Moreover, no new diffraction peaks appeared into the olivetol loaded MOFs, suggesting that the encapsulated drug is in an amorphous state. Taking into account SEM and XRPD results, we can conclude that the morphology of the γ-CD-MOF-1 was stable after the encapsulation with the drug, in spite of the partial loss of crystallinity. For γ-CD-MOF-2 and γ-CD-MOF-3, important changes were observed in the diffraction patterns (Fig. 2). The partial loss of crystallinity was observed again in the co-crystallization MOFs with a similar intensity in the diffraction peaks as in the previ­ ous case of OLV loaded γ-CD-MOF-1, probably due to the encapsulation of the drug. Furthermore, the characteristics positions peaks were Fig. 2. X-ray powder diffraction patterns of unloaded γ-CD-MOF-1 (pink), located in different angles: 5.3◦ , 7.4◦ , 10.5◦ , 11.5◦ , 12.1◦ , 14.2◦ , 14.9◦ , olivetol loaded γ-CD-MOF-1 (red), γ-CD-MOF-2 (blue) and γ-CD-MOF-3 (green). 15.8◦ and 16.7◦ . These peaks did not correspond with the diffraction (For interpretation of the references to colour in this figure legend, the reader is pattern described before for the conventional CD-MOFs synthetized with referred to the Web version of this article.) KOH, despite the metal linker has not changed. Moreover, they did not 4 J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 match with the peaks of raw γ-CD or any simulated references (Fig. A.4). A possible explanation for that is the pH of the initial solution during the MOF synthesis, as described before for SEM results. Since for γ-CD-MOF-1 the pH of the initial solution was around 12 due to the use of potassium hydroxide, for γ-CD-MOF-2 and γ-CD-MOF-3 the potassium salts led the initial solution to a neutral pH. It is reported that the body-centered cubic CD-MOFs were grown from solutions of basic salts, such as hydroxides and carbonates. Although this alkali media is not enough to deprotonate the hydroxyl groups of γ-CD, it seems to facilitate the growing of this type of crystals [36]. Moreover, previous studies about CD-MOFs have reported trigonal crystals with several spaces groups (R32, I4, P1 or P32) different from I432 [5,36]. In these CD-MOFs, the metal sources were not the typical potassium hydroxide. Therefore, the metal linker and the pH of the initial solution could be causes of the different morphology and diffraction pattern observed for the CD-MOFs. This fact would explain the new diffraction patterns in γ-CD-MOF-2 and γ-CD-MOF-3 that did not match with the cubic space group I432 correlating to the trigonal morphology observed in their respective SEM images. Fig. 3. Drug loading percentage of olivetol in γ-CD-MOF-1, γ-CD-MOF-2 and γ-CD-MOF-3 with their respective standard deviations. 3.2. Reaction synthesis yield and olivetol content in γ-CD-MOFs the encapsulation that is a relatively polar organic solvent. However, Reaction time, power and temperature were selected according to this hybrid polarity behaviour may cause that olivetol could interact bibliography [1]. Reaction time was critical in the fabrication of these with both hydrophobic and hydrophilic environments and the drug is MOFs crystals due to the crystallization kinetics such as nucleation. They not strongly attracted to the inner cavities of the MOFs, affecting its are time dependent factors and if the time is too short, the development encapsulation efficiency. In the case of the co-crystallization process, the of the crystallization process cannot occur, and the yield is too small. drug loading was higher than the impregnation method, showing γ-CD- However, a dramatic loss in crystallinity has been reported for pro­ MOF-2 slightly more OLV content than γ-CD-MOF-3 (Fig. 3). This effi­ longed reaction time in previous studies [47]. Thus, a reasonable reac­ ciency in the co-crystallization could be explained by the formation of tion time value should be employed to be able to obtain enough yield crystals itself. γ-CD-MOF-2 and γ-CD-MOF-3 precipitation may directly without compromise the structural properties of the samples. Power and trap the drug into the MOF cavities, regardless the hybrid polarity temperature are also crucial in the yield of the MOFs, since increasing behaviour of OLV. Moreover, drug loading values of co-crystallization these factors the solution is keeping away from the supersaturation and synthesis were in agreement with reported studies about γ-CD-MOFs the crystallization process does not occur. The opposite effect is obtaining encapsulation percentages from 2% to 10% for different observed if the temperature and power are too low, the rapid over­ compounds [12,17,38]. However, this factor could be optimized saturation of the reagents in the initial solution takes place and the modulating different parameters such as incubation temperature and crystal formation cannot happen. In the synthesis process of the time, methanol content in the initial solution and the olivetol amount γ-CD-MOF-1 using KOH, the reaction yield matched well with the values used during the encapsulation process. described in reported studies [13,37]. Nevertheless, in co-crystallization syntheses (γ-CD-MOF-2 and γ-CD-MOF-3) similar reaction yields were 3.3. Characterization of γ-CD-MOFs and olivetol interaction: ATR-FTIR obtained but much lower than for the γ-CD-MOF-1 (Table 1). These analysis differences are due to the pH change, as typical cubic CD-MOFs growing is favoured in alkali solutions [36]. As it was reported in the previous FTIR spectroscopy is a useful tool to detect the bonding changes section, γ-CD-MOF-2 and γ-CD-MOF-3 presented different morphology between functional groups of the MOFs, the drug and the resulting in­ and diffraction pattern, so the kinetics for the precipitation of the teractions of both components. There were characteristic peaks in all crystals should not be the same as for the γ-CD-MOF-1 crystal formation γ-CD-MOF samples at 1078 cm− 1, 1152 cm− 1, 1336 cm− 1, 2700–2995 because of the different pH values due to the alternative potassium cm− 1 and 3000–3670 cm− 1 (Fig. 4A). These peaks were in agreement sources. In fact, this could also explain the absence of MOFs using KCl or with previous reported literature of γ-CD-MOFs [10,39–41]. Moreover, KNO3 but following the procedure of conventional synthesis with KOH. these regions in the MOF spectra also coincided with the characteristic Not only reaction yields have changed depending on the potassium peaks in the γ-CD spectrum, showing the presence of the organic linker source but also the drug loading content (Fig. 3). For OLV γ-CD-MOF-1 in the crystals. At 1078 cm− 1, an antisymmetric stretching vibration the drug content was really poor using the impregnation method to mode derived from the C–O–C groups in aliphatic ethers can be perform the encapsulation. This could be explained due to the hybrid observed. These ether groups are presented in the γ-CD structure. The polarity behaviour of OLV. Olivetol dissolves perfectly in organic sol­ units of γ-CD are α-d-glucopyranose molecules with intra-monomeric vents but it is partially miscible in aqueous solutions. According to that, ether bonds 1 → 5. These units are linked to each other through OLV would tend to be more comfortable on a hydrophobic environment inter-monomeric ether bonds 1 → 4. The peak at 1152 cm− 1 was like the inner cavities of the MOFs, than in the ethanol solution used for assigned to the stretching vibration between carbon and oxygen atoms in C–OH groups of the two secondary alcohols that are in each unit of Table 1 α-d-glucopyranose. The peak at 1336 cm− 1 was related to the contri­ Reaction synthesis yield of γ-CD-MOF-1, γ-CD-MOF-2 and γ-CD-MOF-3 with bution of alkane groups and the band from 2700 to 2995 cm− 1 were the their respective standard deviations. contributions of the C–H antisymmetric and symmetric stretching vi­ MOF sample Reaction yield (%) σ brations of CH2 and CH3 in aliphatic compounds. These regions may γ-CD-MOF-1 59.44 0.03 come from the CH2 group in the hydroxymethyl side chain in each γ-CD-MOF-2 30.98 0.06 α-d-glucopyranose unit of γ-CD. A wide band ranging from 3000 to 3670 34.65 0.04 cm− 1 was assigned to stretching vibrations of the hydroxyl groups, the γ-CD-MOF-3 5 J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 Fig. 4. Attenuated Total Reflection-Fourier Trans­ form Infrared Spectroscopy spectra of: olivetol (black), γ-CD (orange), unloaded γ-CD-MOF-1 (pink), olivetol loaded γ-CD-MOF-1 (red), γ-CD-MOF-2 (blue) and γ-CD-MOF-3 (green) from 4000 cm− 1 to 600 cm− 1 (A). Magnified comparison of olivetol (black), γ-CD-MOF-2 (blue) and γ-CD-MOF-3 (green) spectra (B) in the region of interest from 1700 cm− 1 to 1500 cm− 1 marking the double peak at 1600 and 1628 cm− 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) ones that are secondary alcohols groups but also the primary alcohol in band due to C–OH stretching near 1210 cm− 1, and in this case, the two the hydroxymethyl side chain in each α-d-glucopyranose unit. In addi­ hydroxyl groups are in the benzene ring of the drug. At 1477 cm− 1 and tion to these characteristic bands of γ-CD-MOFs, the peak observed at the double peak at 1600 and 1628 cm− 1, two regions of stretching vi­ 1640 cm− 1 may be due to the hydroxyl groups of water molecules that brations derived from the interactions between the carbon atoms in the still remained into the cavities of the MOFs after the drying process. The aromatic ring of the olivetol structure and the skeletal stretching vi­ spectrum of olivetol showed the characteristic peaks of this drug ac­ – C- could be observed. The peaks at 2858 cm− 1 and 2929 bration of –C– cording to the literature at 690 cm− 1, 830 cm− 1, 1145 cm− 1, 1210 cm− 1, − 1 cm were related to the antisymmetric stretching vibrations of C–H 1310 cm− 1, 1376 cm− 1, 1477 cm− 1, 1600 cm− 1, 1628 cm− 1, 2858 cm− 1, bond of CH2 and CH3 groups that are presented in the pentyl chain of the 2929 cm− 1 and 3240 cm− 1 (Fig. 4A) [42–44]. At 690 cm− 1 and 830 molecule. The wide peak at 3240 cm− 1 was assigned to stretching vi­ cm− 1 wavenumbers, two peaks from CH out of plane deformations were brations between oxygen and hydrogen atoms of the two hydroxyls observed because of the triple substitution in one, three and five carbon groups in the aromatic ring. A direct comparison between the infrared positions in the benzene ring of the OLV. The four peaks at 1145 cm− 1, spectra of OLV and γ-CD-MOF-1 before and after the encapsulation 1210 cm− 1, 1310 cm− 1 and 1376 cm− 1 corresponded to the stretching process with the drug did not show any differences (Fig. 4A). This could vibrations between the carbon and oxygen atoms of the two C–OH be due to the poor encapsulation of the drug in γ-CD-MOF-1 that it was groups that are presented in the drug molecule. Moreover, phenols not enough to observe perceptible changes. Nevertheless, γ-CD-MOF-2 absorb near 1350 cm− 1 due to the OH deformation and give a second and γ-CD-MOF-3 spectra showed in the peak at 1640 cm− 1 a double peak 6 J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 at 1600 and 1628 cm− 1 corresponding to the skeletal stretching –C– – C- administration, Funding acquisition. vibration of OLV (Fig. 4B). It was observed that the 1640 cm− 1 peak in MOFs is partially occluded by this OLV signal. These results confirmed Declaration of competing interest the interaction between γ-CD-MOFs and olivetol in the co-crystallization, because if this interaction did not take place, OLV The authors declare that they have no known competing financial would have been removed during the washing steps with the organic interests or personal relationships that could have appeared to influence solvents. Moreover, this interaction in γ-CD-MOF-2 and γ-CD-MOF-3 the work reported in this paper. was in agreement with the quantification of the drug explained before, that showed a high OLV encapsulation in the co-crystallization samples. Data availability In accordance with previous literature, the interaction between OLV and γ-CD-MOFs may take place through the two phenolic hydroxyl groups of Data will be made available on request. the olivetol structure and the inner cavity of the γ-CD molecules. It has been described that cyclodextrin molecules provide their cavities as a non-polar field, in which OLV is complexed through its hydroxyl groups Acknowledgments and non-covalent interactions [45]. Furthermore, a study that encap­ sulates curcumin in γ-CD-MOFs to improve the stability of this com­ The Spanish Ministerio de Economía y Competitividad is acknowl­ pound concluded that the interaction between curcumin and the MOFs edged for the financial support provided (Project: CTM2015-65414-C2- is through the phenolic hydroxyl group of the curcumin [46]. Therefore, 1-R). Jorge Rodríguez-Martínez acknowledges Agència de Gestió d’Ajuts based on the infrared results of this investigation and previous reported Universitaris i de Recerca from Generalitat de Catalunya (Sapin) for the studies, the interactions between olivetol and γ-CD-MOFs may be due to FI-2018 fellowship. van der Waals forces and hydrophobic effects between the different atoms of the olivetol structure and the inner parts of the non-polar MOF Appendix A. Supplementary data cavities, since shifts on wavenumbers are due to changes on vibrations through the molecules involved and there were not significant shifts in Supplementary data to this article can be found online at https://doi. the spectra [45]. org/10.1016/j.jddst.2022.104085. 4. Conclusions References The present work shows that MOFs based on γ-cyclodextrin and [1] B. Liu, Y. He, L. Han, V. Singh, X. Xu, T. Guo, F. Meng, X. Xu, P. York, Z. Liu, J. Zhang, Microwave-assisted rapid synthesis of γ-cyclodextrin metal-organic potassium ions serve as an effective drug delivery system of olivetol. frameworks for size control and efficient drug loading, Cryst. Growth Des. 17 OLV was used as a guest model compound of cannabinoids for its (2017) 1654–1660, https://doi.org/10.1021/acs.cgd.6b01658. encapsulation into these CD-MOFs using impregnation and co- [2] P. Raju, K. Balakrishnan, M. Mishra, T. Ramasamy, S. Natarajan, Fabrication of pH responsive FU@Eu-MOF nanoscale metal organic frameworks for lung cancer crystallization methods. Microwave technique was used to get a fast therapy, J. Drug Deliv. Sci. Technol. 70 (2022), 103223, https://doi.org/10.1016/ synthesis using different potassium sources such as the conventional J.JDDST.2022.103223. KOH, as well as KCl and KNO3 as innovative approach. [3] B. Liu, H. Li, X. Xu, X. Li, N. Lv, V. Singh, J.F. Stoddart, P. York, X. Xu, R. Gref, J. Zhang, Optimized synthesis and crystalline stability of γ-cyclodextrin metal- SEM and PXRD analysis revealed a trigonal morphology and a organic frameworks for drug adsorption, Int. J. Pharm. 514 (2016) 212–219, different diffraction pattern when the alternative potassium compounds https://doi.org/10.1016/j.ijpharm.2016.09.029. were employed, in comparison with the typical cubic structures ob­ [4] H. Cai, Y.L. Huang, D. Li, Biological metal–organic frameworks: structures, host–guest chemistry and bio-applications, Coord. Chem. Rev. (2019), https://doi. tained with KOH. This fact could be explained due to the different pH of org/10.1016/j.ccr.2017.12.003. the initial solutions. It was demonstrated that olivetol could be loaded [5] R.A. Smaldone, R.S. Forgan, H. Furukawa, J.J. Gassensmith, A.M.Z. Slawin, O. into these carriers by co-crystallization method, solving the problem of M. Yaghi, J.F. Stoddart, Metalorganic frameworks from edible natural products, Angew. Chem. Int. Ed. 49 (2010) 8630–8634, https://doi.org/10.1002/ its poor encapsulation when the impregnation method was performed. anie.201002343. FTIR analysis corroborated the success of this encapsulation. Therefore, [6] I. Kritskiy, T. Volkova, A. Surov, I. Terekhova, γ-Cyclodextrin-metal organic the combination of alternative potassium sources and the co- frameworks as efficient microcontainers for encapsulation of leflunomide and crystallization process resulted in γ-CD-MOFs with a strong potential acceleration of its transformation into teriflunomide, Carbohydr. Polym. 216 (2019) 224–230, https://doi.org/10.1016/j.carbpol.2019.04.037. as drug carriers for cannabinoids compounds, including CBD. Moreover, [7] Y. Sun, L. Zheng, Y. Yang, X. Qian, T. Fu, X. Li, Z. Yang, H. Yan, C. Cui, W. Tan, these materials may become alternative drug delivery systems of un­ Metal–organic framework nanocarriers for drug delivery in biomedical stable molecules in an alkaline or acid solution. Nevertheless, further applications, Nano-Micro Lett. 12 (2020) 1–29, https://doi.org/10.1007/s40820- 020-00423-3. studies would be convenient to optimize the different crystal precipi­ [8] V.P. Torchilin, Multifunctional nanocarriers, Adv. Drug Deliv. Rev. 58 (2006) tation parameters during the co-crystallization process in order to obtain 1532–1555, https://doi.org/10.1016/j.addr.2006.09.009. suitable materials for biomedical applications. Cyclodextrin-based [9] X. Unamuno, E. Imbuluzqueta, F. Salles, P. Horcajada, M.J. Blanco-Prieto, Biocompatible porous metal-organic framework nanoparticles based on Fe or Zr for MOFs (CD-MOFs) are considered environmentally friendly and gentamicin vectorization, Eur. J. Pharm. Biopharm. 132 (2018) 11–18, https://doi. biocompatible MOFs. The biocompatibility of γ-CD-MOF was excellent org/10.1016/J.EJPB.2018.08.013. since cyclodextrin was widely used in drug delivery and proven to be [10] M.P. Abuçafy, B.L. Caetano, B.G. Chiari-Andréo, B. Fonseca-Santos, A.M. do Santos, M. Chorilli, L.A. Chiavacci, Supramolecular cyclodextrin-based metal-organic safe. However, crystalline stability needs to be evaluated as a funda­ frameworks as efficient carrier for anti-inflammatory drugs, Eur. J. Pharm. mental requirement of a potential vehicle for drug delivery, thus, further Biopharm. (2018), https://doi.org/10.1016/j.ejpb.2018.02.009. studies are needed regarding this point. [11] A.R. Khan, P. Forgo, K.J. Stine, V.T. D’Souza, Methods for selective modifications of cyclodextrins, Chem. Rev. 98 (1998) 1977–1996, https://doi.org/10.1021/ cr970012b. Author statement [12] Y. Chen, K. Tai, P. Ma, J. Su, W. Dong, Y. Gao, L. Mao, J. Liu, F. Yuan, Novel γ-cyclodextrin-metal–organic frameworks for encapsulation of curcumin with improved loading capacity, physicochemical stability and controlled release Jorge Rodríguez-Martínez: Conceptualization, Formal analysis, properties, Food Chem. 347 (2021), https://doi.org/10.1016/j. Investigation, Writing - Original, Draft, Writing - Review & Editing, foodchem.2020.128978. Visualization. María-Jesús Sánchez-Martín: Conceptualization, Writing - [13] Y. Han, W. Liu, J. Huang, S. Qiu, H. Zhong, D. Liu, J. Liu, Cyclodextrin-Based Review & Editing, Supervision, Project administration. Oscar López- Metal-Organic Frameworks (CD-MOFs) in Pharmaceutics and Biomedicine, Pharmaceutics, 2018, https://doi.org/10.3390/pharmaceutics10040271. Patarroyo: Formal analysis, Investigation. Manuel Valiente: Conceptu­ [14] J. Qiu, X. Li, R. Gref, A. Vargas-Berenguel, Carbohydrates in Metal Organic alization, Resources, Writing - Review & Editing, Supervision, Project Frameworks: Supramolecular Assembly and Surface Modification for Biomedical 7 J. Rodríguez-Martínez et al. Journal of Drug Delivery Science and Technology 79 (2023) 104085 Applications, Elsevier Inc., 2020, https://doi.org/10.1016/b978-0-12-816984- [31] A. Brizzi, F. Aiello, S. Boccella, M.G. Cascio, L. De Petrocellis, M. Frosini, F. Gado, 1.00022-6. A. Ligresti, L. Luongo, P. Marini, C. Mugnaini, F. Pessina, F. Corelli, S. Maione, [15] N.A. Khan, S.H. Jhung, Synthesis of metal-organic frameworks (MOFs) with C. Manera, R.G. Pertwee, V. Di Marzo, Synthetic bioactive olivetol-related amides: microwave or ultrasound: rapid reaction, phase-selectivity, and size reduction, the influence of the phenolic group in cannabinoid receptor activity, Bioorg. Med. Coord. Chem. Rev. 285 (2015) 11–23, https://doi.org/10.1016/j.ccr.2014.10.008. Chem. 28 (2020), 115513, https://doi.org/10.1016/j.bmc.2020.115513. [16] K. Pintado-Palomino, O. Peitl Filho, E.D. Zanotto, C. Tirapelli, A clinical, [32] N. Motakef-Kazemi, S.A. Shojaosadati, A. Morsali, In situ synthesis of a drug-loaded randomized, controlled study on the use of desensitizing agents during tooth MOF at room temperature, Microporous Mesoporous Mater. (2014), https://doi. bleaching, J. Dent. 43 (2015) 1099–1105, https://doi.org/10.1016/J. org/10.1016/j.micromeso.2013.11.036. JDENT.2015.07.002. [33] H. Guo, Y. Zhu, S. Wang, S. Su, L. Zhou, H. Zhang, Combining coordination [17] Z. Hu, S. Li, S. Wang, B. Zhang, Q. Huang, Encapsulation of menthol into modulation with acid-base adjustment for the control over size of metal-organic cyclodextrin metal-organic frameworks: preparation, structure characterization frameworks, Chem. Mater. 24 (2012) 444–450, https://doi.org/10.1021/ and evaluation of complexing capacity, Food Chem. 338 (2021), 127839, https:// cm202593h. doi.org/10.1016/j.foodchem.2020.127839. [34] D. Ke, J.F. Feng, D. Wu, J.B. Hou, X.Q. Zhang, B.J. Li, S. Zhang, Facile stabilization [18] Y. He, X. Hou, J. Guo, Z. He, T. Guo, Y. Liu, Y. Zhang, J. Zhang, N. Feng, Activation of a cyclodextrin metal-organic framework under humid environment: via of a gamma–cyclodextrin–based metal–organic framework using supercritical hydrogen sulfide treatment, RSC Adv. 9 (2019) 18271–18276, https://doi.org/ carbon dioxide for high–efficient delivery of honokiol, Carbohydr. Polym. 235 10.1039/c9ra03079d. (2020), 115935, https://doi.org/10.1016/j.carbpol.2020.115935. [35] M. Al Haydar, H.R. Abid, B. Sunderland, S. Wang, Metal organic frameworks as a [19] N. Noreen, F. Muhammad, B. Akhtar, F. Azam, M.I. Anwar, Is cannabidiol a drug delivery system for flurbiprofen, Drug Des. Dev. Ther. (2017), https://doi. promising substance for new drug development? A review of its potential org/10.2147/DDDT.S145716. therapeutic applications, Crit. Rev. Eukaryot. Gene Expr. 28 (2018) 73–86, https:// [36] R.S. Forgan, R.A. Smaldone, J.J. Gassensmith, H. Furukawa, D.B. Cordes, Q. Li, C. doi.org/10.1615/CritRevEukaryotGeneExpr.2018021528. E. Wilmer, Y.Y. Botros, R.Q. Snurr, A.M.Z. Slawin, J.F. Stoddart, Nanoporous [20] S. Atalay, I. Jarocka-karpowicz, E. Skrzydlewskas, Antioxidative and anti- carbohydrate metal-organic frameworks, J. Am. Chem. Soc. 134 (2012) 406–417, inflammatory properties of cannabidiol, Antioxidants 9 (2020) 1–20, https://doi. https://doi.org/10.1021/ja208224f. org/10.3390/antiox9010021. [37] I. Roy, J.F. Stoddart, Cyclodextrin metal–organic frameworks and their [21] S.A. Millar, R.F. Maguire, A.S. Yates, S.E. O’Sullivan, Towards better delivery of applications, Acc. Chem. Res. (2021), https://doi.org/10.1021/acs. cannabidiol (CBD), Pharm. Times 13 (2020) 219, https://doi.org/10.3390/ accounts.0c00695. PH13090219, 13 (2020) 219. [38] G. Zhang, F. Meng, Z. Guo, T. Guo, H. Peng, J. Xiao, B. Liu, V. Singh, S. Gui, [22] A.I. Fraguas-Sánchez, A. Fernández-Carballido, R. Simancas-Herbada, C. Martin- P. York, W. Qian, L. Wu, J. Zhang, Enhanced stability of vitamin A palmitate Sabroso, A.I. Torres-Suárez, CBD loaded microparticles as a potential formulation microencapsulated by γ-cyclodextrin metal-organic frameworks, J. Microencapsul. to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer, Int. J. 35 (2018) 249–258, https://doi.org/10.1080/02652048.2018.1462417. Pharm. 574 (2020), 118916, https://doi.org/10.1016/j.ijpharm.2019.118916. [39] T. Dong, Y. He, K.M. Shin, Y. Inoue, Formation and characterization of inclusion [23] R.A. Ross, Anandamide and vanilloid TRPV1 receptors, Br. J. Pharmacol. 140 complexes of poly(butylene succinate) with α- and γ-cyclodextrins, Macromol. (2003) 790–801, https://doi.org/10.1038/sj.bjp.0705467. Biosci. 4 (2004) 1084–1091, https://doi.org/10.1002/mabi.200400054. [24] A.I. Fraguas-Sánchez, A. Fernández-Carballido, C. Martin-Sabroso, A.I. Torres- [40] M. Wei, A.E. Tonelli, Compatibilization of polymers via coalescence from their Suárez, Stability characteristics of cannabidiol for the design of pharmacological, common cyclodextrin inclusion compounds, Macromolecules 34 (2001) biochemical and pharmaceutical studies, J. Chromatogr. B 1150 (2020), 122188, 4061–4065, https://doi.org/10.1021/ma010235a. https://doi.org/10.1016/J.JCHROMB.2020.122188. [41] Y. Xiong, L. Wu, T. Guo, C. Wang, W. Wu, Y. Tang, T. Xiong, Y. Zhou, W. Zhu, [25] C. Itin, D. Barasch, A.J. Domb, A. Hoffman, Prolonged oral transmucosal delivery J. Zhang, Crystal transformation of β-CD-MOF facilitates loading of of highly lipophilic drug cannabidiol, Int. J. Pharm. 581 (2020), https://doi.org/ dimercaptosuccinic acid, AAPS PharmSciTech 20 (2019) 1–9, https://doi.org/ 10.1016/j.ijpharm.2020.119276. 10.1208/s12249-019-1422-z. [26] A.I. Fraguas-Sánchez, A.I. Torres-Suárez, M. Cohen, F. Delie, D. Bastida-Ruiz, [42] M. Kumar Trivedi, A. Branton, Characterisation of physical, spectral and thermal L. Yart, C. Martin-Sabroso, A. Fernández-Carballido, PLGA nanoparticles for the properties of biofield treated resorcinol, Org. Chem. Curr. Res. (2015), https://doi. intraperitoneal administration of CBD in the treatment of ovarian cancer: in vitro org/10.4172/2161-0401.1000146, 04. and in Ovo assessment, Pharmaceutics 12 (2020) 1–19, https://doi.org/10.3390/ [43] D.J. Prasad Reddy, A.V. Rajulu, V. Arumugam, M.D. Naresh, M. Muthukrishnan, pharmaceutics12050439. Effects of resorcinol on the mechanical properties of soy protein isolate films, [27] P. Lv, D. Zhang, M. Guo, J. Liu, X. Chen, R. Guo, Y. Xu, Q. Zhang, Y. Liu, H. Guo, J. Plastic Film Sheeting 25 (2009) 221–233, https://doi.org/10.1177/ M. Yang, Structural analysis and cytotoxicity of host-guest inclusion complexes of 8756087910365030. cannabidiol with three native cyclodextrins, J. Drug Deliv. Sci. Technol. 51 (2019) [44] X. Ren, H. Cai, H. Du, J. Chang, The preparation and characterization of pyrolysis 337–344, https://doi.org/10.1016/j.jddst.2019.03.015. bio-oil-resorcinol-aldehyde resin cold-set adhesives for wood construction, [28] A.P. Matarazzo, L.M.S. Elisei, F.C. Carvalho, R. Bonfílio, A.L.M. Ruela, G. Galdino, Polymers 9 (2017), https://doi.org/10.3390/polym9060232. G.R. Pereira, Mucoadhesive nanostructured lipid carriers as a cannabidiol nasal [45] H. Gu, Olivetol-cyclodextrin Complexes and Regio-Selective Process for Preparing delivery system for the treatment of neuropathic pain, Eur. J. Pharmaceut. Sci. 159 Delta 9-tetrahydrocannabinol, WO2004092101A3, 2004. (2021), https://doi.org/10.1016/j.ejps.2020.105698. [46] Z. Moussa, M. Hmadeh, M.G. Abiad, O.H. Dib, D. Patra, Encapsulation of curcumin [29] P. Taslimi, İ. Gulçin, Antioxidant and anticholinergic properties of olivetol, J. Food in cyclodextrin-metal organic frameworks: dissociation of loaded CD-MOFs Biochem. 42 (2018), https://doi.org/10.1111/jfbc.12516. enhances stability of curcumin, Food Chem. (2016), https://doi.org/10.1016/j. [30] T.J. Raharjo, W. Te Chang, Y.H. Choi, A.M.G. Peltenburg-Looman, R. Verpoorte, foodchem.2016.06.013. Olivetol as product of a polyketide synthase in Cannabis sativa L, Plant Sci. 166 [47] J.S. Choi, W.J. Son, J. Kim, W.S. Ahn, Metal–organic framework MOF-5 prepared (2004) 381–385, https://doi.org/10.1016/J.PLANTSCI.2003.09.027. by microwave heating: factors to be considered, Microporous Mesoporous Mater. 116 (2008) 727–731, https://doi.org/10.1016/J.MICROMESO.2008.04.033. 8