Biomaterials Science This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online REVIEW View Journal | View Issue (r)HDL in theranostics: how do we apply HDL’s Cite this: Biomater. Sci., 2021, 9, biology for precision medicine in atherosclerosis Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. 3185 management?† Kepa B. Uribe, a Asier Benito-Vicente, b Cesar Martin, b Francisco Blanco-Vacac,d,e,f and Noemi Rotllan *d,f High-density lipoproteins (HDL) are key players in cholesterol metabolism homeostasis since they are responsible for transporting excess cholesterol from peripheral tissues to the liver. Imbalance in this process, due to either excessive accumulation or impaired clearance, results in net cholesterol accumu- lation and increases the risk of cardiovascular disease (CVD). Therefore, significant effort has been focused on the development of therapeutic tools capable of either directly or indirectly enhancing HDL- guided reverse cholesterol transport (RCT). More recently, in light of the emergence of precision nano- medicine, there has been renewed research interest in attempting to take advantage of the development Received 28th October 2020, of advanced recombinant HDL (rHDL) for both therapeutic and diagnostic purposes. In this review, we Accepted 3rd February 2021 provide an update on the different approaches that have been developed using rHDL, focusing on the DOI: 10.1039/d0bm01838d rHDL production methodology and rHDL applications in theranostics. We also compile a series of rsc.li/biomaterials-science examples highlighting potential future perspectives in the field. 1. Introduction development of atherosclerosis, the underlying cause of most CVD. The main particles responsible for cholesterol transport Cardiovascular disease (CVD) is the leading cause of mortality throughout the body are lipoproteins, macromolecular com- worldwide, resulting in an estimated global mortality of plexes primarily composed of lipids and apolipoproteins. These 17.9 million people each year1 and remains a leading cause lipoproteins are classified by density, ranging from very low despite pharmacological interventions for numerous risk density lipoproteins (VLDL) to high density lipoproteins (HDL).5 factors.2 The main risk factors for CVD are smoking, age, sex, Interestingly, of the different types of lipoproteins capable of diabetes, obesity, hypertension and dyslipidaemias.3,4 In the cholesterol transport, only HDLs are able to remove excessive group of dyslipidaemias, dysregulation of cholesterol homeo- cholesterol from peripheral tissues to the liver, a process known stasis is one of the primary risk factors associated with the as reverse cholesterol transport (RCT).6 Moreover, HDLs also have additional beneficial characteristics that made these lipo- proteins attractive candidates for managing or preventing ather- a Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque osclerosis, such as their small size and ability to interact with Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014 Donostia other receptors, their ability to encapsulate hydrophobic/hydro- San Sebastián, Spain. E-mail: kbelloso@cicbiomagune.es b Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad philic molecules, and other antiatherogenic functions. However, del País Vasco, Apdo.644, 48080 Bilbao, Spain. E-mail: asier.benito@ehu.eus, the use of natural HDLs has some limitations and in order to cesar.martin@ehu.eus overcome them there has been significant research focused on c Servei de Bioquímica, Hospital Santa Creu i Sant Pau-Institut d’Investigacions the development of reassembled HDL (rHDL), a field that has Biomèdiques (IIB) Sant Pau, 08041 Barcelona, Spain. grown due to the rise of precision nanomedicine. The potential E-mail: fblancova@santpau.cat d CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, advantages of these rHDL are wide-ranging, including potential Spain use as natural drug-delivery carriers or contrast agents for e Departament de Bioquímica i Biología Molecular, Universitat Autònoma de medical imaging. This review aims to overview a detailed proto- Barcelona, Spain col of the different purification, manipulation and modification f Institut de Recerca de l’Hospital Santa Creu i Sant Pau-Institut d’Investigacions methods for developing (r)HDLs. In addition, this review also Biomèdiques (IIB) Sant Pau, 08025 Barcelona, Spain. E-mail: nrotllanv@santpau.cat ; Tel: +34 935537588 describes the application of (r)HDL in therapeutics and has † Electronic supplementary information (ESI) available. See DOI: 10.1039/ compiled the most relevant pre-clinical studies and clinical d0bm01838d trials that are using (r)HDLs. This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3185 View Article Online Review Biomaterials Science 2. HDL in health and disease ester transfer protein (CETP) and phospholipid transfer protein (PLTP), are crucial for HDL metabolism. 2.1 Natural HDL composition and metabolism The use of proteomic and lipidomic technologies have In 1960, HDL was first described after human plasma isolation enabled the identification of over 85 proteins and more than This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. by ultracentrifugation. HDLs are the densest (1.063 < d < 200 additional lipids which may reside within HDL particles, 1.21 g mL−1) and smallest (5 nm to 17 nm) plasma lipopro- as well as genetic material in the form of microRNAs that are teins. HDL is a protein-rich particle with a hydrophobic core, associated with HDL.8–10 consisting of cholesteryl esters, triglycerides and unesterified Briefly, biogenesis of HDL occurs in the liver and intestine, cholesterol, surrounded by a monolayer of phospholipids, which are able to synthesize and secrete ApoA-I. The first step unesterified cholesterol and apolipoproteins. HDLs are hetero- in the formation of HDL is the interaction of a lipid poor geneous in shape, size, density, composition and surface ApoA-I with the ATP binding cassette A1 transporter (ABCA1). Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. charge and can be classified by density (ultracentrifugation), ABCA1 is a cholesterol-phospholipid transporter expressed by size (gradient gel electrophoresis), surface charge (agarose gel enterocytes, hepatocytes and other cell types such as macro- electrophoresis) or apolipoprotein composition (immunoaffin- phages, that allows the nascent HDL to acquire lipids and ity chromatography) (see Table 1). form preβ-HDL particles. ATP binding cassette G1 transporter HDL particles contain various apolipoproteins, of which (ABCG1) is another protein that plays an important role in reg- ApoA-I and ApoA-II are quantitatively the most abundant.7 In ulating cholesterol efflux, although its mechanism of action is addition to different apolipoproteins, a variety of enzymes and still controversial. Next, HDL acquires additional lipids and lipid transport proteins are associated with HDL, composing apolipoproteins derived from the hydrolysis of triglyceride-rich the protein component of this lipoprotein. These proteins, lipoproteins. LCAT acts on cholesterol in nascent HDL par- such as lecithin : cholesterol acyltransferase (LCAT), cholesteryl ticles to generate cholesterol esters, which form the core of the mature HDL particle. Considering HDL catabolism, there are three main meta- Table 1 Classification of HDL subpopulations using different bolic pathways of cholesterol ester clearance in HDL: (1) methodologies through direct uptake by the liver or steroidogenic tissues via UC HDL2 (1.063 < density < 1.125 g ml−1) the HDL scavenger receptor BI (SR-BI); (2) through specific HDL3 (1.126 < density < 1.210 g ml−1) and non-specific transfer of unesterified cholesterol to LDL;11 GGE HDL2b (mean diameter, 10.6 nm) HDL2a (mean diameter, 9.2 nm) or (3) through transfer to apoB-containing lipoproteins by HDL3a (mean diameter, 8.4 nm) CETP. CETP activity increases the triglyceride component of HDL3b (mean diameter, 8 nm) HDL, which is susceptible to lipolysis by hepatic lipase (HL) HDL3c (mean diameter, 7.6 nm) AGE α-HDL (lipid-containing spherical particles) and endothelial lipase (EL). Upon modification by these two preβ-HDL (lipid-free or lipid-poor ApoA-I) enzymes, a smaller HDL particle is formed, which is suscep- IAC LpA-I (with ApoA-I but without ApoA-II) tible to faster catabolism. Consequently, HDL consist of a LpA-I/A-II (with both ApoA-I and ApoA-II) group of particles with marked structural, compositional, phy- UC, ultracentrifugation; GGE, gradient gel electrophoresis; AGE, siochemical and functional heterogeneity and with significant agarose gel electrophoresis; IAC, immunoaffinity chromatography; differences in their biological activities. LpA-I/A-II, lipoprotein A-I/A-II. Kepa B. Uribe completed his PhD Noemi Rotllan earned her Ph.D. in 2013. His first attempts on degree in 2003 from Barcelona research were focused on the University. She did postdoctoral study of bacterial protein toxins trainee at New York University and their effects on target cells. and Yale University, where she As a postdoctoral researcher, his was an Associate Research studies were centered on different Scientist. In 2019, she got the aspects of cholesterol metabolism prestigious Ramon y Cajal fel- and, particularly, in the design/ lowship and she moved back to development of multifunctional Barcelona in order to start her nanoparticles with applications own laboratory. Her research in biomedicine. Nowadays he is interests are focused mainly on Kepa B. Uribe working in the design of new Noemi Rotllan the role of new microRNAs in hybrid protein-based tools for hiperhomocysteinemia related application in vivo imaging and atherosclerosis and to use an innovative therapeutic approach for therapeutics. targeting miRNAs in vivo using rHDL. 3186 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review 2.2 The role of HDL in CVD protection/development HDL-C levels.26 Recently, it has been considered that a key measure of HDL functionality is HDL cholesterol efflux The main function of HDL in lipid metabolism is to allow capacity (CEC) from macrophages. Specifically, a cross-sec- RCT, which consists of removing excess cholesterol from peri- tional study found that the CEC from macrophages is inversely This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. pheral tissues and delivering it to the liver, where cholesterol associated with both carotid intima-media thickness and the is redistributed to other tissues or removed from the body in likelihood of angiographic CAD, independent of HDL-C the stool. In addition to this beneficial function, HDL has levels.27 Some studies have found that increased efflux is other anti-atherosclerotic effects such as anti-inflammatory, associated with reduced risk for CVD,28–30 while other studies anti-oxidative, and anti-apoptotic functions and also improves did not find this association.31 The discrepancies in these endothelial function.6 Historically, epidemiological studies studies may be due to the use of different techniques to quan- have shown an inverse association between serum HDL chole- tify CEC. Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. sterol (HDL-C) and the risk of cardiovascular events, support- ing the theory that HDL is “the good cholesterol”.12,13 Because of this, increasing plasma levels of HDL-C has long been con- 3. (r)HDL methodology: purification sidered a promising complementary therapy to the classical statin-based LDL-C lowering strategy. However, studies con- or preparation, manipulation and ducted in the past decade trying to prove a causal relationship modification between high HDL-C values and lower CVD risk did not obtain the expected results. On one hand, it has been shown that Since the first papers describing alpha-lipoproteins purifi- there is no correlation between epidemiological and genetic cation were published in early 1950s using Cohn’s method32 studies. There are several monogenetic studies conducted in and subsequent attempts to their characterization,33 much human individuals carrying genetic variants that naturally con- progress has been made in (r)HDL related laboratory tech- dition them to low or high HDL-C levels that have unexpect- niques and methodologies. Now, there are multiple well-estab- edly demonstrated that high HDL-C levels are associated with lished protocols for plasma HDL purification, plasma or increased risk of coronary heart disease (CAD) and, by con- recombinant ApoA-I purification and rHDL preparation. trast, no harmful effects were observed when the concen- Similarly, a set of biophysical approaches have been defined as trations were lower.14,15 In addition, a mendelian randomiz- “standards” in order to make rHDL preparations. In the next ation study found that although carriers of a loss-of-function few sections, some schemes have been included to graphically variant in the endothelial lipase gene presented with higher summarize the different purification/reconstitution methods. HDL-C levels, with similar levels of other lipids and non-lipid In addition, we encourage the reader to look at the “3-step (r) risk factors compared with non-carriers, they were not more HDL purification/methods” that were included in the ESI† of protected to myocardial infarction than would be expected this article, where these methods have been explained in more from observational epidemiology.16 Moreover, a GWAS-type detail. approach that reached hundreds of thousands of people and studied 157 genetic loci associated with lipids levels could not 3.1. HDL and ApoA-I purification find any association between HDL-C and CAD risk when Plasma HDL purification. Plasma is a blood biofluid com- focused on loci uniquely related to HDL-C levels.17 On the ponent primarily consisting of water along with proteins, other hand, studies that focused on evaluating the suitability lipids and other metabolites. It is the main means of lipopro- of the chemical intervention to raise HDL-C with therapeutic teins transport in their route throughout the body, and there- purposes found this strategy not beneficial. Neither pharmaco- fore represents the major source of HDL and other lipopro- logical CETP inhibition18–20,21 nor niacin administration22,23 teins in purification. Lipoproteins can be obtained by sequen- resulted in meaningful therapeutic efficacy in the most recent tial density ultracentrifugation (SD-UC) (Fig. 1) or fast protein clinical trials. liquid chromatography (FPLC). Although the latter separation In part, this set of unfavourable results could be explained method more accurately separates different lipoproteins speci- by the results of a recent study that has shown the existence of mens, is not suitable for purification of large amounts of a U-shaped association between HDL cholesterol concen- HDL.34,35 tration and all-cause mortality.24 Together, the HDL-C levels ApoA-I purification from plasma. Some authors have used hypothesis has evolved to the HDL function hypothesis, human-derived ApoA-I directly purified from plasma for their arising from evidence that suggests HDL “quality” may be rHDL preparations. This is the case of CSL Behring labora- more clinically relevant than “quantity”.25 Thus, the specific tories, which developed HDL-mimetic nanoparticles (SRC- composition of HDL particles is crucial to the anti-atherogenic rHDL/CSL-111 and CSL-112).36,37 This procedure is based on functions mentioned before. As an example, high levels of the different properties of stability at varying pH, ethanol con- HDL-C in which HDL is dysfunctional may not only have no centration, ionic strength, protein concentration and tempera- clinical benefits but may even increase the risk of CVD. That is ture of plasma components (Fig. 2). why the focus in therapeutics has shifted to increasing the r-ApoA-I purification. The second primary ApoA-I source is anti-atherogenic function of HDL instead of simply increasing the production and purification of a human recombinant This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3187 View Article Online Review Biomaterials Science version from bacterial, yeast, mammalian or cell-free opti- ated. This technique generates a uniform nanodisc population mized systems.38–41 Although concerns could arise from the and is the most efficient method in terms of low waste use of bacterial origin products and their potential immuno- generation. reactivity, their use has been proven to be safe. Indeed, compa- Microfluidics: In 2013, microfluidics was introduced to the This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. nies such as The Medicines Company (MDCO-216)42 and rHDL field in order to produce nanoparticles (denominated as Cerenis Therapeutics (CER-001)43 have chosen this solution to μHDL) in a more controlled fashion with less heterogeneity prepare their rHDL formulations. An excellent solution to (Fig. 7).50 This approach starts by directly mixing the lipids, obtain enough concentration of a good quality human recom- dissolved in an organic solution, with ApoA-I in buffer in a binant ApoA-I and in a quick fashion was developed in ref. 44. very controlled condition provided by the architecture of a They engineered a human wild type, full-length and mature microfluidic device. Once both fluids are injected into the form of ApoA-I linked to a N-terminal histidine tag to allow microfluidic device, the transition of lipids from organic to Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. nearly one-step protein purification from E. coli cultures aqueous solution leads to the formation of lipid aggregates in (Fig. 3). Furthermore, the incorporation of cysteine substi- a microvortice that facilitates the spontaneous incorporation tutions (i.e. L240C) keeps the functionality of the protein intact of ApoA-I into nanoparticles. Microfluidics has also been and allows its labelling or modification. applied with ApoA-I mimetic peptides in a recently developed microfluidic platform51 and to the study of membrane proteins 3.2. rHDL preparation and biophysical characterization incorporated into nanodiscs.52 Recombinant HDL nanoparticles are prepared using many High-pressure homogenization (HPH): Another technique that different procedures. As lipoprotein-mimetic nanostructures, has been used for rHDL preparations is the HPH procedure they consist of two main elements: proteins (or peptides) and (Fig. 8). This is the case of the MDCO-216 formulation.53 This lipids. Studies on rHDL formation thermodynamics demon- type of methodology is commonly used in industry to prepare strated that although rHDL formation is favoured by an enthal- nanosuspensions, as it is easily scalable for commercial pur- pic component (mainly by α-helices folding after protein-lipid poses. HPH is a high-energy consuming procedure where the complexation), rHDL cannot be formed spontaneously since final components of the preparation are broken down to nano- the activation barrier is markedly high.45 Various strategies to scale particle size by the application of cavitation, shear and overcome this energetic barrier have led to the development of collision forces.54 No specific information is available in the different methodologies for rHDL synthesis. literature regarding how MDCO-216 is produced by HPH. Sonication: Sonication was the first documented method Recently, more research laboratories have started adapting used for rHDL formation,46 but current use of this method- their production methods to the HPH methodology in order to ology has made some adaptations to the original protocol.47 scale up production.55 The rationale of this method is based on the application of The biophysical characterization of rHDLs has to be designed ultrasound radiation to a lipid dispersion, which promotes the to analyse predominantly (1) the size (small, medium, large) and formation of small unilamellar vesicles (SUV), reducing the morphology (disc vs. sphere) of the particles, (2) the protein/ activation energy and facilitating ApoA-I incorporation and lipid final composition (protein : lipid final mole or weight ratio; nanoparticle production (Fig. 4). final lipid composition and proportions; number of ApoA-I Sodium cholate dialysis: This method was developed by Matz molecules per particle), (3) the scaffold protein structure (% and Jonas in the 1980s and has been one of the more com- alpha-helix), (4) the heterogeneity of the sample (polydispersity monly used methods.48 Conceptually, this technique seeks to index) and (5) the stability of the formulation (aggregation generate membrane disruptions by adding a non-denaturing index). Although not needed in routine work, the characteriz- detergent (sodium cholate) to facilitate ApoA-I folding and its ation of rHDL requires a combination of different biophysical insertion into the lipid bilayer, where is leads to generation of techniques in order to have a complete and exhaustive vision of rHDL particles (Fig. 5). It is a very effective and versatile meth- rHDLs. In the case of modified or multifunctional nanoparticles, odology for rHDL synthesis since the modification of the complementary functional analyses must be undertaken. Even initial lipid composition (usually phospholipids, sterols and though an in-depth comparative analysis of the different bio- their derivatives) and/or the ApoA-I : lipid mole ratio enables physical characterization techniques is not the subject of this the formation of nanoparticles with different sizes and shapes. review, we will provide some illustrative bibliography of each This method has been chosen for SRC-rHDL/CSL-111 and technique that may serve the reader (see Table 2). CSL112 preparations.36,37 Thermal cycling: Recently, a new methodology has been 3.3. Tailoring of (r)HDL described for rHDL formation using only ApoA-I peptides and The major determinants of the rHDL physicochemical charac- lipids as initial components.49 However, this methodology teristics and hence rHDL functionality are their constituents. could also potentially be applied using the whole ApoA-I In this sense, many different rHDL preparations have been (Fig. 6). This method reduces the activation barrier by cycling described in which the composition of ApoA-I/peptides, lipids the temperature between lipid phase transition temperature and other modifications or cargo molecules are unique in (Tm) and room temperature, facilitating the appearance of dis- their configuration, yielding a final particular (r)HDL prepa- continuities in the membrane where ApoA-I can be incorpor- ration with its own unique composition and characteristics. 3188 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review Table 2 Biophysical characterization of (r)HDL using different types of ApoA-I but the predominant types are the human plasma-derived or recombinant mature ApoA-I,37,43 Characteristic to the recombinant pro-ApoA-I form (Pro-ApoA-I-liposome prepa- study Technique Ref. ration from UCB SA laboratories),87,88 and natural ApoA-I vari- This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Size • AUC 56 and 57 ations such as ApoA-I Milano.42 It has also been synthetized in • SEC 58 and 59 • Native-PAGE/2D-PAGE 60 and 61 a trimeric mature ApoA-I form.89 • AGE 62 ApoA-I mimetic peptides. Alternatively, and in order to • DLS 63 reduce production costs, the amphipathic alpha-helices of • NTA 64 • AFM 52, 65 and ApoA-I have been used as template to design a set of mimetic 66 peptides with similar properties to those of the whole apolipo- • TEM/cryo-TEM 67 and 68 protein, but also with unique features. These peptides do not Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. • SAXS/SANS 69 and 70 • NMR 71 and 72 have sequence homology with ApoA-I but all resemble class A Morphology • TEM/cryo-TEM 67 and 68 amphipathic helices and have lipid binding capacities similar • AUC 57 to ApoA-I. They are able to stimulate ABCA1-mediated chole- • AFM 52, 65 and 66 sterol efflux and have anti-inflammatory and antioxidant pro- • NMR 71 and 72 perties. To present, there are at least six families of mimetic • SAXS/SANS 69 and 70 peptides: the 18A peptide and its derivatives (2F, 4F, 6F, Protein : lipid • Biochemical determinations composition (colorimetric assays) etc.);90,91 the bihelical peptide 37pA and its derivative 5A;92,93 • Crosslinking/SDS-PAGE 60 and 73 the ETC-642 preparation, composed of the 22A peptide • AUC 57 ESP-242118 plus lipids;94 the A10 peptide and its derivatives • SEC 74 • MS 9 (S1A10 and S2A10);95 the Fukuoka University ApoA-I Mimetic Protein structure • CD 75 Peptide (FAMP) family of peptides;96 and mono- or bi-helical • SANS 70 ELK peptides.97 • NMR 71 and 72 • ATR-FTIR 59 and 76 Lipids. Lipidomic studies have shown that the most abun- Polydispersity • DLS 57 dant lipids in HDL, measured as mol% of total, in healthy nor- • AUC 57 molipidemic patients are:9 phospholipids ( phosphatidyl- Stability • ζ-Potential 77 • SEC 58 and 59 choline 32–35%; lysophosphatidylcholine 1.4–8.1%), sphingo- • DLS 57 lipids (sphingomyelin 5.6–6.6%) and neutral lipids (cholesteryl esters 35–37%; free cholesterol 8.7–13.5%; triacylglycerides AUC, analytical ultracentrifugation; SEC, size-exclusion chromatography; PAGE, polyacrylamide gel electrophoresis; AGE, 2.8–3.2%). Since one of the main goals in rHDL generation agarose gel electrophoresis; DLS, dynamic light scattering; NTA, has been getting nanoparticles that resemble natural HDL, the nanoparticle tracking analysis; AFM, atomic force microscopy; TEM, commonly used lipid compositions are phosphatidylcholine transmission electron microscopy; SAXS, small angle X-ray scattering; SANS, small angle neutron scattering; NMR, nuclear magnetic lipid extracts [Pro-ApoA-I-liposomes: pro-ApoA-I + soybean resonance; HPLC, high-performance liquid chromatography; MS, mass phosphatidylcholine (SPC); CSL-111/CSL-112: ApoA-I + SPC], spectroscopy; CD, circular dichroism; ATR-FTIR, attenuated total pure phospholipids or sphingolipids of different acyl chain reflection Fourier transformed infrared spectroscopy. length and saturation (MDCO-216: ApoA-I Milano + 16:0/18:2 phosphatidylcholine), or combinations of lipids (CER-001: ApoA-I + sphingomyelin + 16:0 phosphatidylglycerol; ETC-642: Proteins. ApoA-I is the main apolipoprotein used as a mem- ESP24218 peptide + 16:0 phosphatidylcholine + brane scaffold protein for rHDL preparations. However, other sphingomyelin).36,37,43,48,49,59,88,94,98–100 For diagnostic pur- apolipoproteins such as ApoA-II, ApoA-IV, ApoE, ApoJ, serum poses, researchers have introduced some modified lipids in amyloid A (SAA) or synuclein variants have been described as their rHDL preparations. This is the case in the use of para- potential scaffolds for nanoparticle synthesis.78–83 Wild-type magnetic lipids for magnetic resonance imaging (MRI) or apolipoprotein A-I (UniProtKB #P02647) is a 243 amino acid phospholipid chelators for positron emission tomography/ long and 28 kDa weight amphipathic polypeptide. It is natu- computed tomography (PET/CT).55,101 Finally, the lipid compo- rally synthesized as pre-pro-ApoA-I, and after being intracellu- sition and the protein-to-lipid ratio will influence, among larly processed, adopts the pro-form ( pro-ApoA-I), which is others, size, shape and surface charge which can in turn influ- secreted for further processing in order to acquire its mature ence rHDL biological functions.102,103 form (ApoA-I). ApoA-I is secreted as lipid-free, or poor-lipidated rHDL modifications. Due to current increasing interest in apolipoprotein, and is further lipidated, generating nascent HDL-mimetic nanoparticles, the development of new prep- discoidal HDLs.84,85 A consensus ApoA-I monomeric and lipid arations with enhanced functionalities has led to the expan- free model has been recently described. In this model, ApoA-I sion of rHDL modifications. These modifications have been is presented as a helical bundle composed by six helix (126 adopted principally to tune HDL physicochemical properties α-helical residues, 52%) organized around the N-ter and two by (1) enhancing nanoparticle stability in biological fluids (via random coil regions, the largest located in the C-ter, that are rHDL PEGylation or lipid cross-linking),104,105 (2) improving further folded after being lipidated.86 rHDL are generated HDL targeting (dextran sulphate or hyaluronan modified This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3189 View Article Online Review Biomaterials Science rHDL) and/or controlling the release of cargo [poly(lactic-co- Many laboratories have attempted to adapt their rHDL- glycolic acid) modified rHDL],103,106–109 and (3) allowing HDL related translational research towards a more global theranos- tracking or its use in medical imaging applications (fluores- tic approach, although to date only a few attempts have cently labelled ApoA-I, lipids or hyaluronan; contrast agents reached human clinical trials. We have recapitulated in the This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. for MRI, PET or CT).44,55,100,103,107,108 main text some examples of the application of rHDLs as thera- Cargo molecules. As mentioned above, rHDL are nanosized nostic tool/drug-delivery nanocarrier, but we designed the ESI particles (8–20 nm) with high tolerability in humans (up to Table 2† with the intention of giving readers a great number of 6.8 g ApoA-I per infusion), long half-life in blood (>24 h) and sample cases where rHDL have been used as nanocarriers on intrinsic targeting properties.37,74,103 All these advantages have therapeutics. Thus, we encourage readers to visit the led to rHDLs being considered as excellent nanocarriers for a additional information arranged in the ESI section.† wide range of cargo molecules. rHDLs can accommodate both Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. hydrophilic compounds adsorbed or attached to the outer shell 4.1. (r)HDL application in therapeutics or hydrophobic compounds entrapped in the core. rHDL cargo The idea of using lipoproteins for therapeutics was first pro- can be designed to fulfil diagnostic or therapeutic functions posed in 1982.128 They have many characteristics that make and has been used in studies in multiple fields, ranging from them promising candidates for therapeutics, such as their cancer to neurodegenerative research.110–112 Within the CVD small size, ability to interact with different receptors, selective field, there are many cargo molecules which have been studied targeting capability, ability to encapsulate hydrophobic mole- with therapeutic and diagnostic purposes. Among the mole- cules, hydrophilic exterior surface, lack of immunogenicity, cules with therapeutic properties are statins,113,114 LXR and extended residence time in circulation. agonists,103,115 bioactive lipids,116 immunomodulators,117 ApoA-I/HDL infusion. The first pre-clinical attempts to study siRNA and miRNA molecules,118–120 as well as preparations the therapeutic roles of (r)HDL in the field of CVD were carried where more than one active component is combined.121,122 For out in the late 1980s studying the effect of homologous HDL imaging applications, rHDL has been loaded with fluorescent infusions. Using adult New Zealand rabbits fed high-chole- dyes or quantum dots for optical imaging,44,50,55,103,108,123,124 sterol diet as in vivo atherosclerosis model, the 50 mg per week contrast agents as iron oxide or gadolinium for MRI,50,113,123,125 intravenous (IV) administration of purified HDL isolated from radionuclides as zirconium-89 (89Zr) for PET,55,103,117 or gold- normal rabbits led to a 60% reduction in the development of based rHDL for CT,50,123,126 among others. atherosclerotic-like lipid-rich lesions and significantly decreased lipid depositions in the artery wall compared to control rabbits.129 Moreover, short-term (30 days) treatments of 50 mg per week infusions were able not only to reduce 4. (r)HDL in theranostics atherosclerosis progression but also to induce atherosclerotic plaque regression by nearly 50%.130 Later in the mid-1990s, an Nanomedicine has emerged as a powerful tool that promoted analogous approximation was carried out to test the anti- a qualitative leap in biomedicine, allowing us to see, under- atherogenic effect of non-lipidated ApoA-I infusions. In a stand and modify with a precision level never seen before. It similar atherosclerotic model, the effect of rabbit purified allows us to focus on the nanoscale, but also allows us to ApoA-I infusions was assessed using measurements of the pro- respond to daily challenges as well as to those that will come gression and regression of atheroma lesions. This study found from more comprehensive approaches, in which diagnosis and that although 4 × 40 mg per week purified ApoA-I IV adminis- treatment can be carried out in integrated steps. In this way, tration pattern reduced progression of these lesions by 48%, theranostics is a term that embraces innovative solutions no regression was observed.131 In the same decade, the natural attempting to combine agents that support “visualizing” and variant ApoA-I Milano was also tested in vivo. It was known diagnosing the problem together with the appropriate thera- that families carrying this mutation had very low levels of peutic in a single compound, preparation or device. One of the HDL, due to an accelerated catabolism of the apolipoprotein, prominent tools to study new theranostic approaches are and a drastically reduced CVD risk. Studies conducted in New rHDLs, mainly in the field of CVDs, but also in other fields. Zealand White rabbits on high-cholesterol diet and balloon HDLs are biocompatible lipid–protein complexes that rep- injury demonstrated that 10 day treatment, in a regiment con- resent a promising scaffold for numerous nanobiotechnologi- sisting of a 40 mg per dose every other day, reduced the cal applications and have the potential to become a better intimal thickness of injured arteries by 57–71% and reduced drug-delivery platform than liposomes, which are currently the the area of the intima covered by macrophages by more than most widely used nanocarriers.127 As mentioned in prior sec- 50%.132 tions, rHDLs are tailored and fully biocompatible nano-plat- It was not until the 2000s that studies like this were forms prepared in the laboratory that, together with their extended to primates and humans. In a first approach, the intrinsic anti-atherosclerotic properties, are ideal candidates effect of human purified lipid-free ApoA-I IV bolus injection or for theranostic tool designing due to improved targeted deliv- continuous infusion was studied in healthy patients with low ery of both therapeutic compounds and/or imaging agents plasma HDL levels. This study tried to assess the effects, in such as contrasts. terms of safety and fate, of ApoA-I after a single-dose (a single 3190 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review injection or a continuous infusion over 5 h of 25 mg kg−1 of treated with 40 mg kg−1 lipid-free ApoA-I infusions 2-to-3 ApoA-I) or a multi-dose treatment (6.25–50 mg kg−1 of ApoA-I times per week. The main result of the study was that while at different infusion rates over 5 h). The results showed that ApoA-I induced plaque size reduction by 30% and improved the procedures were well tolerated with no clinical, biochemi- plaque stability as well HDL functionality in the early-stage This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. cal or haematological changes and without evident immune model, none of these beneficial effects were observed in the response. ApoA-I concentration in plasma increased in a dose- late-stage model. Thus, the atheroprotective effects of ApoA-I/ dependent manner, with a mean half-life of >30 hours, and its HDL infusions likely depend, at least in part, on the plaque presence in plasma was concentrated in HDLs, particularly in development stage and/or the age of the subject of study.137 pre-β HDLs. Both attempts, ApoA-I bolus injection and con- ApoA-I mimetic peptides. Another set of pre-clinical studies tinuous infusion, led to significant increases in phospholipid has focused on the potential beneficial effects of ApoA-I short levels in HDL and phospholipid and triglycerides levels in mimetic peptide treatment. Due to the large number of papers Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. non-HDL fractions but did not alter cholesterol levels in published with pre-clinical data, those most relevant to athero- HDL.133 Years later, a second round of trials was performed to sclerosis are summarized in the ESI Table 1.† In addition to test the efficacy of selectively delipidated HDLs (HDL-sdl) to short peptides, a longer peptide of 54 amino acids derived promote reverse cholesterol transport and to promote athero- from the C-terminal region of ApoA-I ( peptide RG54) has been sclerosis regression. By a process in which collected plasma shown to be beneficial for glucose control and for inhibiting were treated with a series of organic solvents, researchers atherosclerosis.138 Moreover, some of the short mimetic pep- managed to reduce HDL cholesterol in plasma by 77%, which tides have been tested in humans. The first candidate on this in turn resulted in enrichment of the pre-β1 HDL subspecies. bench-to-bedside journey was ETC-642 in 2002. Two different When primates were infused intravenously with a unique dose single-dose studies in atherosclerotic patients and stable of 22–23 mg kg−1 HDL-sdl plasma, these delipidated preβ-1 cardiovascular patients showed that a single infusion of HDLs were rapidly converted into larger α-HDL with kinetic ETC-642 was safe and well tolerated in a 0.1–20 mg kg−1 behaviour depicting the RCT process. Subsequently, when the dosage. Then, a multiple-dose study was planned at 10–20 mg same HDL-sdl dosage was infused weekly for a period of 12 kg−1 dosages in patients with stable cardiovascular disease, weeks into monkeys that had developed atherosclerosis, treat- but to date, there is no publicly available data on the ment was associated with a significant reduction of 6.9% in results.139 In 2008, the 4F peptide was assessed in humans for the total atheroma volume analysed by IVUS, although the the first time. In a phase I trial, patients with stable coronary change in the percentage of atheroma volume (PAV) did not heart disease (CHD) or equivalent risk were treated with a reach statistical significance.134 Finally, 28 patients with acute single oral dose of 30–500 mg of an unformulated D-4F coronary syndrome (ACS) and ≥1 non-obstructive native coron- peptide preparation (also known as APP-018; Bruin Pharma ary artery atheroma were enrolled in the LS-001 (Lipid Sciences Inc.). The study found that although bioavailability was low, Selective Delipidation trial) study and treated for 7 weeks with the single dose was safe, well tolerated at all concentrations, HDL-sdl plasma obtained from each patient plasma, collected and could improve the HDL anti-inflammatory index.140 In a by apheresis and reinfused after delipidation. The results subsequent study, the effect of an L-4F peptide preparation showed that administration of the treatment was safe and well- (also known as APL180; Novartis Pharmaceuticals) was assayed tolerated and, although not reaching statistical significance, in patients with stable CHD or equivalent risk in a regimen of the change in mean atheroma volume represented a trend 7 days IV infusion or 28 days subcutaneous (SQ) injection. towards reduction which was not observed in the control Although the multi-dose IV or SQ administration was well-tol- group.135 In 2018, an innovative solution for treatment admin- erated at all doses, it was not effective in improving bio- istration consisting of oral delivery of “APO milk” was pre- markers of HDL anti-inflammatory function and a trend sented. In this study, researchers successfully genetically toward an increase in inflammatory markers (hs-CRP and IL-6) modified rice plants to express full-length ApoA-I Milano in was noted (Clinicaltrials.gov # NCT00568594 and rice seeds and, after processing, obtained a protein extract con- NCT00907998).141 The last study conducted to date was in taining the therapeutic asset. When tested in an atherosclero- 2017 and in this occasion, the benefits of treatment with D-4F sis rodent model as a 15-day treatment consisting of 5 days per as an oral multi-dose prescription were assessed. The study week by oral gavage of 0.83 mg kg−1 day−1 dose, there was a subjects were high-risk CHD patients and were treated for 13 significant reduction in atheroma plaque size of 35–50% as days with daily 100–500 mg dose. The D-4F oral treatment was well as favourable plaque remodeling.136 safe and well tolerated and resulted in reducing the HDL Lastly, an interesting pre-clinical study published also in inflammatory index by half. Interestingly, the peptide oral 2018 shed some light into why pre-clinical studies on HDL- dose was highly predictive of HDL inflammatory index raising approaches had not shown the benefits that are presup- improvement while plasma D-4F level was unrelated, leading posed when they were transferred to humans. In this work, to the conclusion that peptide penetration in the plasma may there was a focus on the timing of when the ApoA-I/HDL is be unnecessary.142 administered and the effects of ApoA-I infusions in early- vs. rHDL infusions. The study of rHDLs in a therapeutic context late-stage atherosclerotic lesions. ApoE−/− mice on a high-fat has a long history, and a large number of both pre-clinical diet for 8 weeks (early-stage) or 34 weeks (late-stage) were studies in diverse disease models and clinical trials in human This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3191 View Article Online Review Biomaterials Science This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. Fig. 1 Plasma HDL purification by SD-UC. A more detailed explanation can be found in the ESI section.† QM, chylomicron; d, density. Purification protocol adapted from ref. 34. Fig. 2 ApoA-I purification from plasma. A more detailed explanation can be found in the ESI section.† EtOH, ethanol; GdnHCL, guanidinium chlor- ide. Purification protocol adapted from ref. 36 and references included in it. Fig. 3 r-ApoA-I purification from bacterial production system. A more detailed explanation can be found in the ESI section.† IMAC, immobilized metal affinity chromatography. Purification protocol adapted from ref. 44. 3192 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review populations of various conditions have been conducted. Some MDCO-216, both were formulated using ApoA-I Milano and of the most relevant studies are summarized in the ESI Tables 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) at a 2 ( pre-clinical trials) and 3 (clinical trials).† Although rHDLs 1 : 40 mol ratio. After an extensive pre-clinical validation, have received high commercial interest, only a few compo- ETC-216 was shown to be able to mobilize body cholesterol in This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. sitions have been tested in clinical trials. We describe below healthy volunteers and was well tolerated up to doses of the formulations that have been tested in humans. 50–75 mg kg−1.151 In 2003, the results of the phase II “The Pro-ApoA-I liposomes (UCB). This formulation consisting of ApoA-I Milano Trial” study showed that ETC-216 promoted a human pro-ApoA-I and SPC (1 : 45 mol ratio) demonstrated mean 2.7% coronary atherosclerosis regression in ACS patients that a single infusion of 40–50 mg kg−1 in patients with treated with 15 mg kg−1 or 45 mg kg−1 IV infusions.152 Despite Heterozygous Familial Hypercholesterolemia (HeFH) induced these promising results, clinical development of ETC-216 was body cholesterol mobilization and excretion with no safety discontinued due to serious adverse effects in some patients. Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. issues.88 Although promising, no other studies with this for- After significant improvements in the manufacturing process, mulation were found in the literature. the new formulation MDCO-216 was tested and proven to be SRC-rHDL (ZLB Central Lab)/CSL-111 (CSL Limited)/CSL112 safe in terms of immunostimulatory effects.153 Therefore, the (CSL Behring). These are the only formulations prepared with phase I/II MILANO-PILOT study was designed to assess the ApoA-I extracted from human plasma and the difference efficacy of 5 weekly 20 mg kg−1 MDCO-216 IV infusions in between them lies in the ApoA-I : lipid mol ratio. All the formu- statin-treated patients with ACS. The analysis of the results lations contain ApoA-I and parenteral SPC grade; SRC-rHDL showed that although MDCO-216 tended to reduce the PAV, and CSL-111 were prepared using 1 : 150 mol ratio while the reduction was not significantly different from placebo.154 CSL112 was prepared at 1 : 55 mol ratio. Both SRC-rHDL and Hence, it became clear that MDCO-216 treatment was not CSL-111 were the first to be tested and shown that a single effective in patients with established and intensive ACS treat- dose of 25–80 mg kg−1 promoted body cholesterol mobiliz- ment as it was not able to reduce the residual risk in these ation and improved anti-inflammatory markers and atheroma patients. A second phase II trial, MILANO-DRIVE, was plaque.143,144 In 2007, the phase 2 ERASE trial was conducted designed to be conducted in subjects with CAD and recent with 183 patients with ACS to test the effect of four weekly 40 ACS, but it was discontinued in 2016 due to lack of efficacy. or 80 mg kg−1 CSL-111 treatment on plaque burden. CSL-111 After that, The Medicine Company stopped investigating treatment failed at PAV reduction on IVUS, showing no signifi- MDCO-216 in 2016. cant differences compared to placebo. Moreover, the study arm CER-001 (Cerenis Therapeutics). CER-001 represents the most receiving 80 mg kg−1 dose had to be discontinued early due to complex formulation. The scaffold protein is a recombinant safety concerns.145 Therefore, the formulation was modified in version of human ApoA-I produced in eukaryotic cultures and order to improve its efficacy and safety profile. The new formu- the lipid mixture is composed of sphingomyelin and 1,2-dipal- lation, CSL112, was satisfactorily tested in phase I/2a trials mitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DPPG). The final with a favorable efficacy profile and no safety concerns in both mol ratio of ApoA-I : SM : DPPG is of 1 : 103 : 3. In 2013 the single and multiple dosages,37,146–148 but again failed in phase II CHI SQUARE trial was completed in ACS patients to efficacy when studied in a larger trial. AEGIS-1 was a phase 2b test the efficacy of the treatment on total atheroma volume trial completed in 2016 in which four weekly doses of 2 or 6 g reduction by the end of the study compared to baseline. ApoA-I per dose were infused in 1258 patients with a recent CER-001 was not effective and there were some safety issues history of type I myocardial infarction. The results showed that related to the treatment in some study subjects.43 the coprimary safety endpoints, hepatotoxicity rate and renal Nevertheless, CER-001 was further tested in a new phase II toxicity, did not show differences when compared to placebo. MODE trial in patients with phenotypic characteristics of Although the study was not primarily designed to analyze the homozygous familial hypercholesterolemia (HoFH). Unlike efficacy of CSL112, the time to first occurrence of a major what was observed in the CHI-SQUARE trial, the results of the adverse cardiovascular event (MACE) was registered during a MODE trial were favorable and found that 12 biweekly treat- 12-month follow up in the intent-to-treat group, showing that ments at 8 mg kg−1 dose resulted in a significant carotid mean the risk of MACE was similar to placebo, indicating absence of vessel wall area reduction.155 A post-hoc analysis of data therapeutic effect.149 Currently, the AEGIS-II study extracted from the CHI-SQUARE trial showed that the subjects (NCT03473223) is being carried out to analyze the effect of with the most extensive plaque-burden (baseline plaque ather- CSL112 in a large population of more than 17 000 people. This oma volume ≥30%) receiving 3 mg kg−1 had the greatest study will evaluate the safety and the efficacy of CSL112 in sub- benefit since the treatment with CER-001 was statistically jects with ACS diagnosis and myocardial infarction and is esti- effective compared to placebo in these conditions.156 Hence, a mated to be completed by the first half of 2022. Hopefully, the phase II CARAT trial was attempted in ACS patients with these rationale used in the design of the study will enable testing characteristics. In this trial, patients on statin-therapy were the CVD benefits of an rHDL preparation with improved CEC administered 10 weekly doses of 3 mg kg−1 CER-001 by IV infu- capacity.150 sion and the efficacy on reduction of PAV from baseline was ETC-216 (Esperion Therapeutics-Pfizer)/MDCO-216 (The analyzed after 78 days. Once again, the results were not favor- Medicines Company-Novartis). First ETC-216 and later able as CER-001 was unable to promote atherosclerosis This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3193 View Article Online Review Biomaterials Science This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. Fig. 4 rHDL preparation/reconstitution by the sonication method. A more detailed explanation can be found in the ESI section.† Tm, lipids phase transition temperature; SEC, size-exclusion chromatography. Reconstitution protocol partially adapted from ref. 47. Fig. 5 rHDL preparation/reconstitution by the sodium cholate dialysis method. A more detailed explanation can be found in the ESI section.† Tm, lipid phase transition temperature; SEC, size-exclusion chromatography. Reconstitution protocol adapted from ref. 48. Fig. 6 rHDL preparation/reconstitution by the thermal cycling method. A more detailed explanation can be found in the ESI section.† Tm, lipid phase transition temperature; RT, room temperature; SEC, size-exclusion chromatography. Reconstitution protocol adapted from ref. 49. 3194 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review regression.157 The last of the assays with CER-001 on humans reconstituted in disk-shaped instead of spherical rHDLs or carried out in the phase II SAMBA trial was focused on deter- when full ApoA-I was substituted by the 18A or 37pA mimetic mining CER-001 effects on RCT and the arterial vessel wall on peptides.163–165 Subsequent studies showed a significant patients with Familial Hypoalphalipoproteinemia (FHA). The improvement in MRI signal when substituting the ApoA-I for its This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. study concluded that a 28 infusion treatment mobilized body oxidized form, apparently due to an increased uptake by plaque lipids, with a positive trend toward increased fecal sterol macrophages.166,167 Furthermore, it is feasible to track the excretion, but more importantly, it was effective in thinning signal of ApoA-I or any of its mimetic peptides in vivo by co- the carotid artery vessel wall and reducing arterial wall inflam- valently binding Gd3+ to ApoA-I by selective cysteine substi- mation.158 In 2018, a phase III TANGO trial was designed to be tution, zirconium-89 to lysine residues via deferoxamine B con- carried out in a larger population of FHA patients but, due to jugation (89Zr-AI-HDL) or gallium-68 radiolabeling of FAMP pep- lack of efficacy, it was terminated prematurely. tides (68Ga-DOTA-FAMP).168–170 The synthesis of a phospholipid Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. Other preparations. Many other innovative formulations coordinated to 68Ga for its use with rHDL (68Ga- developed in recent years have only been tested in vitro and in PCTA-DSPE-HDL) has also been reported.171 In 2009, a new animal models, with some of them showing high potential for rHDL nanoplatform concept was designed for imaging pur- further evaluation in clinical trials. Most of the new rHDL poses by combining Au, FeO or quantum dots (QD) nanocrystal preparations sought to exploit their characteristics as specific core with a phospholipid corona bearing fluorescent or para- and targetable nanocarriers to “load” them with therapeuti- magnetic lipids. When tested, it was shown that this multi- cally active compounds (e.g. statins, immunomodulatory drugs modal contrast agent was useful for in vivo T1- and T2-weighted or siRNA/miRNA molecules) and enhance their intrinsic MRI, CT and fluorescence imaging.123 The in vivo application of efficacy, reducing in turn the side effects of the Au-rHDL was further validated in a multicolor CT study in com- payloads.113,117,122 On the other hand, other preparations bination with other contrast agents.172 The last step carried out sought to increase the residence time of rHDL-cargo in the in imaging mediated pre-clinical diagnostics is the multimodal system in order to increase the vector’s therapeutic effect (e.g. approach. Thus, in a study published in 2019, the authors rHDL PEGylation, LCAT inhibitors or cargo liberation control- showed how combining 89Zr-rHDL and other functional radio- ling polymers) or improve/adapt its targeting capacity (e.g. hya- tracers with PET, CT, MRI and NIRF imaging allows studying luronic acid or anionic lipids), thus limiting cargo release in the pharmacokinetics, biodistribution, and the anti-athero- unwanted cells/tissues.104,121,159,160 sclerotic effects of an rHDL-based nanoimmunotherapy.55 To date, only a single human imaging study related to ather- 4.2. (r)HDL application in diagnostics osclerosis has been conducted, the Netherlands Trial Registry – Similar to the applications of rHDLs in therapeutics, several NTR5178, with the purpose of studying in vivo the delivery of 89 works have shown an increasing role of rHDL in diagnostics Zr-labelled CER-001 to atheroma plaques of patients with too. Although the focus of this review is the application of CAD. After a single infusion of 3 mg kg−1 of CER-001 together rHDL in atherosclerotic cardiovascular disease, increasing evi- with 89Zr-CER-001 (10 mg–18 MBq), patients were monitored by dence suggests that rHDLs could be successfully used as diag- serial PET/CT imaging and contrast-enhanced MRI for nostic tools in additional fields such as oncology. This feature 48 hours. The study concluded that CER-001 targets the ather- is due to their nanoscale size, their receptor-guided specificity oma plaque and that is actively uptaken by cells, and can corre- and their capacity to be loaded with contrast agents or tracers late with plaque contrast enhancement.173 of diverse natures. In the case of atherosclerosis, these advan- tages enable specifically targeting the tracer to the atheroma plaque, penetrating into it and marking the regions where 5. Concluding remarks lesions are in an active state. At the pre-clinical level, rHDLs have been tested for use with MRI, CT, PET and Near-infrared CVD management continues to be one of the leading bio- (NIR) imaging for diagnostic applications. medical challenges of recent times, in part due to the rise of The development of the rHDLs was initially dominated by ageing populations, as well as the growing trend of CVD-pro- their potential role in therapeutics, which is why it was not moting lifestyle factors. The pharmacologic objectives that until the 21st century that rHDLs were evaluated in diagnostic have been pursued for atherosclerosis prevention and in vivo studies. Preliminary attempts studied the biodistribution regression include reduction of the underlying systemic of 125I-HDLs in animal models and their binding to regions of inflammation and correction of the dysregulation generated by the aorta especially affected by lipid depositions by autoradiog- increases in atherogenic lipid fractions. Cholesterol is one of raphy.161 Since 2004, however, rHDLs have begun to be systema- the central lipid molecules whose dysregulation is associated tically used as in vivo imaging tools. That year and for the first with CVD development. Guided by knowledge acquired about time, the combination of a gadolinium chelating modified cholesterol metabolism, two basic strategies have been phospholipid (Gd3+-DTPA-DMPE) with rHDLs was shown to be implemented: reducing pro-atherogenic particles rich in chole- a useful contrast agent for MRI-based atheroma plaque detec- sterol (“bad cholesterol”) or increasing those particles whose tion, specifically in atherosclerosis model animals.162 Similar purpose is to remove excess cholesterol (“good cholesterol”). positive results were obtained when Gd3+-DTPA-DMPE was HDLs are included in this second group and for that reason This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3195 View Article Online Review Biomaterials Science This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. Fig. 7 rHDL preparation/reconstitution by microfluidics. A more detailed explanation can be found in the ESI section.† μHDL, recombinant HDL made by microfluidic devices. Reconstitution protocol adapted from ref. 50. Fig. 8 rHDL preparation/reconstitution by HPH method. A more detailed explanation can be found in the ESI section.† Reconstitution protocol par- tially adapted from ref. 55. have attracted the attention of many investigators as potential has come up throughout this review, this is a key feature therapeutic targets. HDLs are a dynamic and heterogenous rHDLs offer to researchers: the capability to improve on the group of lipoproteins whose main function is to redistribute quality of HDLs through the enhancement of current anti- excess cholesterol from peripheral tissues to the liver to be ulti- atherosclerotic capabilities or by acquiring new properties mately excreted as stool, a process known as reverse cholesterol through incorporation of specific compounds. Inspired by transport. this, we may name such optimized rHDL particles as tailored Although the epidemiological studies identified a positive or “smart” rHDLs. correlation between increased HDL-C levels and a reduction in Of all the proposed rHDLs studied in vitro, only four rHDL CVD risk, subsequent genetic studies and large clinical trials formulations (Pro-ApoA-I liposomes; SRC rHDL/CSL-111/ with HDL-C promoting drugs did not obtain positive expected CSL112; ETC-216/MDCO-216; CER-001) have been studied in results that demonstrated a clear causal relationship. humans. After thorough validation in pre-clinical studies, they Furthermore, it has been described that certain HDL popu- have been predominantly tested in patient cohorts with CVD lations could have pro-atherogenic properties. For these as a single or multi-weekly IV dose regimen. Unfortunately, reasons, the exogenous administration of purified HDLs or results have not been satisfactory for most of these candidates. reconstituted (r)HDLs has been proposed as an alternative In fact, only one Phase 3 study (AEGIS-II) sponsored by CSL therapeutic solution that could accommodate current “quality” Behring in a cohort of 17 400 patients with ACS is currently parameters by designing or modifying rHDL on demand. As taking place. The lack of statistically significant outcomes in 3196 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. Fig. 9 Scheme/summary of the main results obtained in the different pre-clinical and clinical studies and some of the innovative modifications applied to rHDLs. To have a broader view of the studies carried out as well as the particular formulations that have been studied, we encourage the reader to see the different tables in the ESI section.† large clinical trials to date has led to doubts about the clinical than their predecessors. Also, it has been recently demon- application of this therapeutic strategy. It is noteworthy strated in vitro that different lipid compositions of rHDL can however that two of the successful earlier-stage studies were modulate cholesterol efflux activity stimulation,174 thus focused on familial hypercholesterolemia, a disease in which demonstrating the importance of optimal lipid compositions we know there is an impairment of reverse cholesterol trans- of rHDL in maximizing cholesterol efflux and achieving thera- port.11 Additionally, in animal models, HDL has shown to be peutic objectives. In addition to optimizations of rHDL com- more protective in initial that advanced lesions. Given the ponents, rHDL has also been improved through chemical current knowledge that modified HDL can be converted into modifications or addition of active compounds that enhance pro-inflammatory particles with impaired reverse cholesterol rHDL’s biodistribution and bioavailability (e.g. rHDL transport capacities, this could at least partially explain the PEGylation or addition of gangliosides, hyaluronic acid or limited advances towards clinical application so far. In con- LCAT activity modulators). On the other hand, what is more trast, there is accumulating evidence that is positioning the interesting is the incorporation of active compounds into tailored manufactured, new generation of rHDLs as suitable rHDLs with therapeutic purposes, since rHDLs gather drug- biocompatible nanocarriers for the development of future delivery nanocarrier properties. The combination of rHDL with theranostic approaches (Fig. 9 and ESI Tables 1 and 2†). statins, immunomodulatory drugs or siRNA/miRNA molecules Although none of these advanced formulations have been has a profound synergistic effect, as it improves the efficacy tested on humans yet, accumulating evidence from both parameters compared to treatment with bare rHDL. in vitro and in pre-clinical studies has demonstrated promise. Specifically, when a bioactive compound is given in conjunc- For atherosclerosis management, the designed tailored rHDL tion with rHDLs, the effects of the carried compound occurs undergo modifications/adaptations that enhance their athero- more locally, where it is needed, and unwanted side effects are protective function. In pre-clinical studies, newly assayed minimized. A clear example of this is noted when compared ApoA-I variations (e.g. V156K variant or trimeric ApoA-I) or an the efficacy of the treatments of the ETC-642 formulation with improved generation of mimetic peptides (e.g. the trimeric the LXR agonist T1317 inside or administered in parallel, as it A-10 or i-FAMP-D1 peptides) have better functional profiles is published very recently.175 In both cases the concomitant This journal is © The Royal Society of Chemistry 2021 Biomater. Sci., 2021, 9, 3185–3208 | 3197 View Article Online Review Biomaterials Science administration of rHDL + T1317 shows a positive synergistic LDL/ Low-density lipoprotein/LDL-associated cholesterol effect, although it is clearly superior in terms of atheroma LDL-C burden reduction the treatment of the loaded nanocarrier. LXR Liver X receptor Complementing the advances in the therapeutic plane and MACE Major adverse cardiovascular event This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. giving it the dimension of a theranostic tool, tailored rHDL μHDL rHDL produced with microfluidics techniques have also been developed to fulfil needs in imaging-based miRNA micro-RNA studies. In this sense, rHDL have been specifically labelled MRI Magnetic resonance imaging for PET, MRI, CT or NIRF imaging, leading to demonstration NIR Near-infrared of rHDL’s usefulness not only for diagnosis but also as a PAV Percentage of atheroma volume tracer for functional studies. A great example of the potency of PCTA Polycyclohexylenedimethylene terephthalate acid tailored rHDL as a theranostic tool is the very recently pub- PEG Polyethylene glycol Open Access Article. Published on 19 March 2021. Downloaded on 1/5/2023 8:31:58 AM. lished work carried out by Binderup and colleagues55 and PET Positron emission tomography which will be called to serve as an example for the next PLTP Phospholipid transfer protein developments. POPC 1-Palmitoyl-2-oleoyl-glycero-3-phosphocholine For future, the development of a new generation of tailored pro-ApoA-I Pro-form of apolipoprotein A-I rHDL with improved characteristics and added functionalities QD Quantum dot that, in general, constitute better “quality” HDL should serve r-ApoA-I Recombinant version of apolipoprotein A-I to attract the attention of researchers and investors and RCT Reverse cholesterol transport relaunch interest in the development of new clinical trials in (r)HDL Combination of recombinant and natural HDL humans to assess the capabilities of optimized rHDL as a ther- SAA Serum amyloid A anostic tool. SD-UC Sequential density ultracentrifugation SEC Size-exclusion chromatography siRNA Small interfering RNA Abbreviations SM Sphingomyelin SPC Soybean L-α-phosphatidylcholine ACS Acute coronary syndrome SQ Subcutaneous Apo Apolipoprotein SR-BI Scavenger receptor class B type I ABCA1/G1 ATP-binding cassette A1 or G1 transporter SUV Small-unilamellar vesicle CAD Coronary artery disease Tm Phase transition temperature CEC Cholesterol efflux capacity VLDL Very low-density lipoprotein CHD Coronary heart disease CVD Cardiovascular disease CETP Cholesteryl ester transfer protein Author contributions CT Computed tomography DOTA 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra- K. B. U., A. B-V. and N. R. drafted the manuscript, which was acetic acid critically reviewed by C. M. and F. B-V. All authors have read DMPE 1,2-Dimyristoyl-sn-glycero-3-phosphoethanol- and agreed to the published version of the manuscript. amine DPPG 1,2-Dipalmitoyl-sn-glycero-3-phospho-(1′-rac- glycerol) DSPE 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine DTPA Diethylenetriamine penta acetic acid Funding EL Endothelial lipase FAMP Fukuoka apolipoprotein A-I mimetic peptide This review was funded by Ministerio de Ciencia, Innovación y FH Familial hypercholesterolemia Universidades (PID2019-104367RB-100), as well as the FHA Familial hypoalphalipoproteinemia Subprograma Ramón y Cajal (RYC-201722879) to N.R. and FPLC Fast performance liquid chromatography PI18/0164 to F.B.-V., FEDER “Una manera de hacer Europa”. HDL/ High-density lipoprotein/HDL-associated CIBER de Diabetes y Enfermedades Metabólicas Asociadas HDL-C cholesterol (CIBERDEM) is a project of Instituto de Salud Carlos III. HeFH/ Heterozygous/homozygous familial Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau is HoFH hypercholesterolemia accredited by the Generalitat de Catalunya as Centre de HL Hepatic lipase Recerca de Catalunya (CERCA). This work was also supported HPH High-pressure homogenization by the Basque Government (Grupos Consolidados IT-1264-19) IV Intravenous to C.M. and A.B.-V. was supported by Programa de IVUS Intravascular ultrasound especialización de Personal Investigador Doctor en la UPV/ LCAT Lecithin : cholesterol acyltransferase EHU (2019) 2019–2020. 3198 | Biomater. Sci., 2021, 9, 3185–3208 This journal is © The Royal Society of Chemistry 2021 View Article Online Biomaterials Science Review Conflicts of interest 7 P. T. Duong, H. L. Collins, M. Nickel, S. Lund-Katz, G. H. Rothblat and M. C. 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