Drug delivery via lipoprotein-based carriers answering the challenges in systemic therapeutics
599
ISSN 2041-5990
Therapeutic Delivery (2012) 3(5), 599–608
10.4155/TDE.12.41 ? 2012 Future Science Ltd
P ersPective
The application of nanotechnology in medicine has undergone rapid advances in the past several years. In the field of cancer therapeutics, there is currently a strong trend for combining the positive features of nanotechnology and drug action to produce novel theranostic formula-tions [1–5]. Accordingly, several submicron car-rier systems have emerged with improved drug retention capabilities towards specific cells and tissues [3,4]. These drug-delivery models are com-prised of macromolecules made up of natural or artificial polymers ranging in size from 10 to 1000 nm, where the drug is attached, adsorbed to or entrapped in nanoparticles to improve their circulating residence time subsequent to administration. By enhancing the bioavailability and the protection against enzymatic degrada-tion of the drug payload, these formulations have proven progressively more effective in noninvasive tumor imaging and drug delivery [5]. The favorable pharmacokinetics, vast sur-face area and varied surface chemistry makes these smaller particles a uniquely effective drug-delivery model, as demonstrated by their supe-rior performance compared with conventional therapeutic approaches [6–18].
Diverse ingredients have been utilized to produce nanoparticle formulations from both chemical and biological components. The
particles of ‘chemical’ origins include those clas-sified as polymer-based nanoparticles [6], metal-based particles [7], dendrimers [8], silica-coated micelles (FloDots) [9], ceramic formulations [10], perfluorocarbon emulsions [11], magnetic sur-face-coated [12] and semiconductor (quantum dots) [13] nanoparticles. Those containing ‘bio-logical’ components include phospholipids and other lipids, chitosan, dextran, lactic acid and cross-linked liposomes [14–18].
The majority of these nanostructures are engineered to accommodate an optimal drug payload targeted to cancer cells or the tumor vasculature using monoclonal antibodies or cell-surface receptor transporter ligands. Short- and long-term toxicity remains a common concern regarding the clinical applicability of these drug-delivery platforms [3–5]. Currently, the nano p articles approved for clinical use by the US FDA are polymer-based poly(lactide-co-gly-colide) nanocarriers and liposomes [2,4,18]. While these formulations have proven to be effective in the delivery of drugs, they have significant limitations, including restricted diffusion into solid tumors due to the extended diameter of the particles, which generally exceed the inter-fibrillar openings (<40 nm) at the tumor site [4]. Although some lipid micellar polymers can be synthesized with a diameter below 40 nm,
Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics
Plasma lipoproteins are transporters of lipids and other hydrophobic molecules in the mammalian circulation. Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy. In this review, past and current studies on lipoproteins and similar alternative drug carriers are discussed regarding their suitability as agents to deliver drugs, primarily to cancer cells and tumors. A lipoprotein-based delivery strategy may also provide a novel platform for improving the therapeutic efficacy of drugs that have previously been judged unsuitable or had only limited application due to poor solubility. An additional, and perhaps the most important aspect of the drug-delivery process via lipoprotein-type carriers, is the receptor-mediated uptake of the payload from the lipoprotein complex. Monitoring the expression of specific receptors prior to treatment could, thus, give rise to efficient selection of optimally responsive patients, resulting in a successful personalized therapy regimen.
Nirupama Sabnis & Andras G Lacko*
Department of Molecular Biology & Immunology, UNT Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA *Author for correspondence: E-mail: https://www.360docs.net/doc/9315442301.html,cko@https://www.360docs.net/doc/9315442301.html,
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they tend to have limited circulation times and thereby inferior drug retention compared with liposomes. While inorganic nanoparticles, such as quantum dots and gold nanoparticles, could be synthesized in this size range, researchers are still optimizing their surface chemistries for in vivo applications, which are currently limited by their potential long-term toxicity [3,4,7]. Solid lipid nanoparticles (SLNs) and nano-structured lipid carriers (NLCs) represent an alternative delivery system to traditional carri-ers, such as emulsions, liposomes and polymeric nanoparticles, especially for the delivery of lipo-philic drugs [14–16]. These formulations are pre-ferred due to their biocompatibility, modified release, lack of organic solvent involved in the production process and the potential for easy scale up to the industrial level. Nevertheless, SLNs have serious limitations, including non-selective toxicity, storage instability and lim-ited drug payload [19]. Although NLCs are reported to overcome the limitations of SLNs, more research, preclinical and clinical stud-ies, will be required to guarantee their safety for human administration. Lipoprotein -based nanoparticles have the potential to overcome these limitations and have already proven to be a superior drug-delivery platform for cancer theranostics due to their extremely small size, lack of immunogenic response and selective targeting [15,20–24]. Recently, the repositioning of a drug, valrubicin, via enhancing its solubil-ity and selective targeting by incorporation into reconstituted HDL (rHDL) nanoparticles has been demonstrated [23].
Lipoproteins: nanocarriers of nature Lipoproteins are endogenous carriers of l ipids and lipophilic compounds [25]. In the last 70 years, the major focus of studies of lipo-protein structure/function and metabolism were designed to gain a better understanding of lipid transport to improve strategies for the prevention and treatment of atherosclerosis and coronary heart disease [26]. The different classes of lipo-proteins share a common structure consisting of a hydrophobic core surrounded by a shell of a phospholipid/cholesterol monolayer and several apolipoproteins . Based on their buoyant density, size and the type of major apolipoproteins pres-ent, lipoproteins are segregated into four classes: chylomicron (75–1000 nm/ApoB-48), VLDL (30–80 nm/ApoB-1000), LDL (18–25 nm/ApoB-100) and HDL (5–12 nm/ApoA-I , A-II, -E and -C) [25]. The amphipathic property of their
phospholipid component facilitates the forma-tion of a micellar outer shell, an ideal compart-ment for the transport of lipids and lipophilic compounds in an aqueous environment. The structural characteristics and metabolic func-tions of lipoproteins have been extensively reviewed and, thus, will be referred to only briefly here [26–30].
The unique structural/functional properties of lipoproteins allow them extended residence time in the circulation and the versatility to accommodate a broad range of lipophilic mol-ecules in their core region, providing an attract-ive carrier for transporting and delivering thera-peutic and diagnostic agents. In order to utilize the lipoproteins as nanocarriers of drugs or diagnostic imaging agents, several protocols have been developed, including covalent modifica-tion of the lipoprotein complex that contains the hydrophobic compounds in its core [14,15,27,28]. Covalent modification of lipoproteins extends the functionality of the lipoprotein complex to accommodate the targeted delivery of a drug or diagnostic agent [31]. The encapsulation of lipo-philic drugs into the lipoprotein nanoparticles is achieved by methods including co-sonication, cholate dialysis and solvent extraction [24,32]. Pluen et al . have demonstrated the diffusive transport of a wide range of nanoparticles in tumors grown in dorsal and cranial chambers [28]. The results of Pluen et al . show that the pres-ence of collagen type I and fibrillar collagen in the stromal cells of some tumors may hinder the diffusion of larger nanoparticles in the tumor environment [28]. The smaller size lipoprotein nanoparticles thus have the potential to pen-etrate rapidly into the tumors and deliver their therapeutic payload. Furthermore, lipoproteins can be targeted via endogenous receptors, includ-ing the scavenger receptor class B type I (SR-B1), which have been shown to be o v erexpressed in most cancer cells and tumors [22,23,33]. LDL: an archetype in drug delivery Use of LDL as a drug-delivery vehicle was first suggested by Krieger et al. through replacing the core of native LDL with cholesteryl linoleate, suggesting that a broad range of hydrophobic compounds could be similarly incorporated into LDL [34]. Later, Gal et al. suggested that certain tumor cells might have a higher affin-ity for LDL than normal tissues, and cytotoxic drugs and radionucleotides ligated to the LDL may thus be utilized for the specific delivery of these agents [35]. Kader and Pater investigated
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the incorporation efficiency of native LDL and HDL for four cytotoxic drugs [36], 5-fluorouracil (5-FU), 5-iododeoxyuridine, doxorubicin and vindesine, and examined the effect of incor-poration on drug cytotoxicity against HeLa, cervical and MCF-7 breast carcinoma cells. Ponty and colleagues studied the biodistribu-tion of 99mTc-labeled LDL by nuclear scin-tigraphy in B16-melanoma-bearing mice and found accumulation of radiolabeled LDL within tumors, suggesting that LDL carriers may have therapeutic applicability [37].
More recently, Corbin et al. successfully incorporated amphiphilic gadolinium (Gd)-diethylene-triamine-pentaacetic acid chelates into the LDL to produce a novel LDL-targeted MRI agent for assessing tumor growth in nude mice carrying human hepatoblastoma G2 xeno-grafts [38]. LDL-mediated drug targeting along with its pros and cons are detailed in the review by De Smidt and Van Berkel [39]. The LDL-based targeted drug-delivery approach is based on the concept that there is an enhanced expres-sion of LDL receptors by most malignant cells, as compared with the corresponding normal (nonmalignant) cells [40,41]. Vitols et al. demon-strated an inverse correlation between plasma LDL cholesterol concentrations and the in vivo cellular uptake of [14C]-sucrose-LDL into leu-kemic cells [40]. In another study by Dorlhiac-Llacer et al., daunorubicin-loaded LDL carriers exhibited 2.3-times more cytotoxicity in acute myelogenous leukemia blast cells than against normal cells [41]. Subsequently, several hydro-phobic biologically active molecules, including anticancer drugs (AD-32, doxorubicin, dau-norubicin and derivatives), photosensitizers, nucleosides, iso fl avones, acrylophenone, anti-HIV drugs and fluor e scent imaging agents have been incorporated into LDL [42–47].
Despite the attractive targeted delivery fea-ture of LDL, the clinical acceptance of native LDL particles as a drug-delivery platform has not materialized. Owen et al. and Shaw et al. discussed the key limiting issues involved with LDL nanocarriers [48,49]. One concern has been the tendency of LDL to aggregate upon stor-age. An adequate supply of uniform quality LDL for scale-up purposes has not been avail-able due to the complex isolation procedures, methods of incorporation of the therapeutic agent and related safety concerns [50,51]. These practical barriers have so far limited the use of native LDL as a drug-delivery carrier in a clinical setting, thus changing the focus of the search for alternate strategies to synthetically prepared reconstituted LDL for targeted drug delivery. Although the receptor-mediated approach appears to be the preferred route for LDL-based drug delivery, there are some anomalous obser-vations regarding LDL-receptor expression by malignant cells [52,53]. Clayman et al. reported a loss of LDL-receptor activity in malignantly transformed renal tissues in vivo [52]. Fabricant and Broitman reported that five of six colon adenocarcinoma cell lines were deficient in LDL receptors [53]. While LDL has the potential as a drug-delivery platform to target cancer cells, reports in the last 20 years do not indicate sig-nificant progress towards clinical applications. Although these studies included reformulation of hydrophobic drugs and the possibility of overcoming drug resistance in leukemic cells, there is a need for expanded in vivo eval u ation to enhance this drug-delivery strategy as a t h erapeutic tool [54].
Structural & functional properties
of HDL
HDL is an endogenous nanocarrier with unique structural and functional properties. This class of lipoproteins is characterized by the highest buoyant density, smallest diameter (<12 nm) and highest protein-to-lipid ratio. The major apolipoprotein constituents (ApoA-I, ApoA-II, ApoE and ApoC) provide stabilization of the lipoprotein structure supporting the spherical lipid outer shell, encasing a lipid core made up primarily of cholesteryl esters. Reconstitution of HDL from lipid and protein components is feasible via a variety of methods [27]. While the mechanism underlying the reconstitution pro-cess of lipoproteins is not yet fully understood, the combining of ApoA-I with phospholipid and highly lipophilic components leads to the formation of stable spherical rHDL structures upon cholate dialysis [24]. Biologically, the con-figuration of HDL is transient as it matures into spherical particles via enzymatic esterification of its cholesterol component by lecithin-cho-lesterol acyltransferase in the blood circulation [55]. Discoidal HDL prepared, from a protein/ peptide component and phospholipids, by recon-stitution in vitro; however, is stable until it is introduced into the blood plasma or another biological environment [30]. The distinction between the discoidal and spherical reconsti-tuted lipo p rotein complexes has been exten-sively discussed earlier [14]. The lipid and protein components of the rHDL nanoparticles may be
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modified, via covalent derivatization and other chemical modifications to produce a vast array of nanocarriers, potentially for clinical applications [14]. By modifying the type of apolipo p rotein and the stoichiometry of protein and lipid in the for-mulation, the diameter of lipoprotein complex may also be manipulated. It has been reported that an increased protein-to-lipid ratio typically results in a smaller diameter lipoprotein complex [29,30]. Based on physical/chemical principles, Denisov et al . established a framework for the design of soluble amphiphilic nanoparticles of controlled size [30]. These tunable structural features make rHDL a versatile platform for biocompatible applications.
Receptor-mediated uptake of the HDL payload
Lipoproteins are pivotal components of the lipid transport system. Glomset et al . first proposed a definitive role for HDL in reverse cholesterol transport as a promoter of the return of excess cholesterol from peripheral cells to the liver [55]. In this process, the cholesterol from the circ-ulating HDL particles can be taken up via receptor- m ediated mechanisms, either directly from HDL through SR-B1 or by the LDL recep-tor, subsequent to the transfer of cholesteryl esters from HDL to LDL. The major difference in the uptake of HDL payloads via SR-B1 versus the LDL receptors is that the SR-B1-mediated process is nonendocytotic, resulting in a transfer of cholesteryl ester molecules (or drugs) from the core of HDL across the cell membrane. The process avoids the lysozomal exposure of the payload (including drugs) and is, therefore, favored compared with the endocytotic process utilized by the LDL receptors. Thus, while the uptake of cholesteryl esters (and drug payloads) via the LDL receptor is a relatively nonspecific mechanism, the SR-B1 (selective) uptake is highly specific.
The SR-B1 mediated process has also been shown to operate in the uptake of antican-cer agents from rHDL by cancer cells [22–24]. Several studies have shown that malignant cells have an elevated requirement for cholesterol resulting in reduced HDL cholesterol levels in cancer patients, as compared with healthy subjects [14,15]. Accordingly, most cancer cells and tumors overexpressed the SR-BI receptors to meet their cholesterol needs for enhanced proliferative rates [14,20]. Acton et al . showed that that the scavenger SR-B1, a member of the CD36 family, can not only mediate HDL
binding, but also facilitate selective cholesterol ester uptake in murine SR-B1 transfected CHO cells [56]. et al . demonstrated that SR-B1 and other key proteins in cholesterol transport are altered during the progression to hormone-resis-tant prostate cancer in xenografts of a mouse model [57]. Mooberry et al . showed that the overexpression of SR-B1 in prostate cancer cell lines facilitated the enhanced uptake of pacli-taxel from rHDL nanoparticles where the SR-B1 mediated ‘selective uptake’ represented 82% of the total paclitaxel incorporation by these cells [22]. Using quantitative real-time PCR tech-nique, Shahzad et al . found markedly elevated SR-B1 expression in most tumor samples of ovarian, pancreatic, breast and colorectal cancer compared with those of normal tissues [20]. HDL as a drug-delivery platform for cancer chemotherapy
HDL type nanocarriers possess many of the features of an ideal drug-delivery model. The particles are biocompatible and share a small size (<40 nm) and drug-loading capacity with polymeric micelles. Like liposomes, they have long circulating half-lives and enhanced cargo shielding comparable to PEGylated liposomes [21]. In addition, their stability and mono-dispersity is comparable to inorganic nanopar-ticles. The potential of HDL-type nanopar-ticles for drug delivery was recognized almost 20 years ago. Kader et al . have reported that loading anti c ancer drugs into HDL as well as LDL had minimal effect on the properties of the complexes, while the encased drugs showed enhanced cytotoxicity towards human carci-noma cells [58]. Studies of the encapsulation of an anti-tumoral drug aclacinomycin in rHDL nanoparticles indicated a preferential cytotoxic-ity of the drug towards SMMC-7721 hepatoma cells over normal L02 hepatocytes [59]. A large number of anti n eoplastic chemotherapeutic drugs that have shown promise during preclini-cal studies subsequently failed clinical trials due to prominent toxic side effects against periph-eral tissues. The selective delivery of hydro-phobic drugs, specifically to malignant tissues and tumors makes the rHDL drug-delivery system unique and provides it with significant potential in cancer theranostics. Sabnis et al . found that valrubicin, a potent anticancer agent, could be solubilized to substantially increase its cytotoxicity against cancer cells via encapsula-tion into rHDL nanoparticles [23]. The same valrubicin/rHDL formulation was also found
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to have reduced toxicity towards non m alignant cells, demonstrating the selective tumor delivery capabilities of rHDL nanoparticles [23]. Potential applications of HDL-type
drug carriers other than for cancer chemotherapy
In addition to being a carrier of anticancer drugs [21–24] and effectively promote arterial plaque removal [60], rHDL has been considered as a therapeutic agent for treating other diseases. A schematic representation of rHDL and its poten-tial in nanomedicine is provided in F igure 1. As indicated, several chemotherapeutic imaging agents, fluorophores and diagnostic agents can be encapsulated in the rHDL core for extended circulation and sustained release at target tissues [14–22]. In addition, the rHDL could be cova-lently or noncovalently modified (e.g., folate and EGF modification) [14,15] at the phospholipid or ApoA-1/mimetic peptide sites to enhance its functionality and targeting efficiency. Recently, Cho has demonstrated that rapamycin, a multi-purpose fungicide, can be effectively transported by rHDL in a zebra fish model [61]. Shiflett et al. have showed that antimicrobial agents deliv-ered via rHDL can serve as a model for innate immunity function in a pathogenic protozoa Trypanosoma brucei [62]. In another study, lacto-sylated HDL-mediated delivery of a hydro p hobic drug 9-(2-phosphonyl m ethoxyethyl) adenine against hepatitis B virus was found to be effica-cious in a rat model [63]. Membrane-associated glycoprotein–rHDL nanoscaffolds have been shown to trick pathogens into preventing infection in healthy cells against influenza, HIV,
rabies, polyoma virus and many other diseases [27]. Nasal or subcutaneous administration of rHDL particles containing viral hemagglutinin
is shown to stimulate the immunity in mice
models [64]. An rHDL system has also been
extensively studied as a drug-delivery platform
for treatment of hepatitis B [65] and Leishmania
infections [66].
Recently, intriguing potential has been indi-
cated for rHDL therapeutics in Alzheimer’s dis-
ease (AD) [67,68]. In the study by Handattu et al.,
aggregates of the amyloid-b peptide (A b)–ApoA-I
complexes were detected in cerebro s pinal fluid
of AD patients, subsequent to treatment with an
rHDL preparation [67]. Lipid-free ApoA-I and
ApoA-I-containing rHDL particles were also
found to protect hippo c ampal neuronal cultures
from ‘A b-induced’ oxidative stress and neuro-
degeneration [68]. In addition, a ‘phage peptide’
that was homologous to the amino acid sequence
of the N-terminal domain of ApoA-I was also
found to bind A b and, thus, may have therapeu-
tic value for AD patients. In an in vitro model,
HDL was able to deliver small molecules such
as vitamin E across a simulated blood–brain
barrier [69]. These results suggest that ApoA-I
and ApoA-I-containing rHDL could be used as
therapeutic agents for patients with AD. Earlier
studies implicated that HDL or rHDL may
exert a neuro p rotective or antistroke effect [70,71].
More recently, in a rat model of embolic stroke,
Lapergue et al. showed that HDL infusion was
neuroprotective [71]. These data show that HDL
type preparations, possibly combined with drugs
Figure 1. Reconstituted HDL drug-delivery system and its potential in theranostics.
‘Targeting ligands’ represent the covalent or noncovalent modification of the lipoprotein at the surface of the apolipoprotein or onto the phospholipid head groups to reroute the therapeutic or imaging agents for targeted delivery [15,21,31].
Reprinted with permission from [20] ? Neoplasia Press, Inc. All rights reserved (2011).
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enclosed in the core of the nanoparticles, could be used as effective antistroke agents.
Recently, rHDL infusion has been shown to decrease plasma glucose levels in Type 2 diabetes patients via raising plasma insulin levels [72]. In addition, rHDL infusions have shown improve-ment in endothelial function in Type 2 diabetes patients via reducing oxidative stress and increas-ing NO bioavailability [73] as well as improv-ing endothelial progenitor cell function [74]. These data taken together suggest that infused rHDL preparations may provide acute benefits by improving the cardiovascular risk profile as well as glucose metabolism in Type 2 diabetes patients. A schematic representation of rHDL and its potential in nanomedicine is provided in F igure 1.
Limitations & alternatives to using native HDL & its components as therapeutic agents
One of the limitations of using native HDL as a therapeutic nanocarrier originates from its source – pooled fresh human plasma. This source is likely to produce variations in the quality of the preparation and may pose difficulties during the scaling up of the process. Furthermore the infu-sion of native HDL poses the danger of transmit-ting infectious/pathogenic agents from the origi-nal human material. The isolation/purification of the major protein component of HDL, ApoA-I, is arduous and expensive although industrial sources have the facility to guarantee production level supplies. For laboratory research and proof-of-concept studies [22–24], we have employed the method of Ryan et al ., which relies on an engineered Escherichia coli strain that produces relatively large amount of human ApoA-I [75]. Nevertheless, recombinant ApoA-I derived from bacterial source may pose concerns when consid-ered for clinical preparations. While most recon-stituted lipoprotein studies employ wild-type or modified human apolipoprotein, other animal sources have also been explored. Zebra fish ApoA-I is similar to human-type but with sub-tle structural differences and reaction kinetics, which suggest enhanced stability in the final lipo-protein assembly [76]. The search for a practical alternative to ApoA-I may lead to the utilization of ApoA-I mimetic peptides [77]. These peptides contain amphipathic helical regions, structur-ally and functionally similar to those found in ApoA-I while having a much smaller molecular weight (4–5000) compared with the full length protein (~28,000). The amphipathic peptides
that structurally and functionally mimic ApoA-1 have been shown to have anti-inflammatory, anti-oxidant, anti-atherogenic and anti-tumor effects [77]. While these mimetic peptides have been extensively investigated as anti-atherosclerotic agents, their use as component of drug-delivery vehicles has been limited so far. Yang et al . have demonstrated selective delivery of a lipophilic drug, paclitaxel oleate via HDL-mimicking pep-tide–phospholipid nanoscaffold [78]. These data strongly suggest that HDL-mimicking peptide–phospholipid nanoscaffolds can attenuate toxic-ity of anticancer drugs to nonmalignanent cells, thus resulting in selective cytotoxicity towards cancer cells.
Anantharamaiah et al . have reported an 18-amino acid ApoA-1-mimicking peptide (18A) (with a sequence of DWLKAFYDKVAEKLKEAF) could be used as a component of an HDL-type synthetic drug delivery system [79]. Although this peptide does not have any sequence homology to apoA-1, it adopts an a -helical conformation in the pres-ence of phospholipids, with charged groups and hydrophobic side chains on opposing faces of the backbone to retain the predominant amphipathic features of ApoA-I. In another study, Zhang et al . have successfully synthesized HDL-mimicking peptide–lipid nanoparticles through a self-assem-bling interaction between amphi p athic a -helical peptides, phospholipids and a hydrophobic cargo to mimic nascent HDL [80]. These studies demonstrate the potential of HDL-type nano-particles to target tumors and their environment for multimodal imaging of tumors.
Future perspective
Traditional chemotherapy from the beginning of its application has been plagued with toxic off-target effects. Lipoprotein-based technologies are anticipated to be able to mediate or elimi-nate these concerns via their biocompatibility and the capacity to selectively deliver their payload to cancer cells and tumors. Several clinical studies have shown that apoA-1 containing HDL-type formulations are safe for human systemic admin-istration, while the SR-B1 receptor-mediated uptake of lipophilic anticancer drugs via rHDL has strengthened the potential for these prepa-rations as theranostic agents. By determining the pretreatment expression level of these recep-tors in individual cancer patients, the effective-ness of the chemotherapeutic regimen could be maximized to specifically benefit the high SR-B1 expressor patients. Alternatively functionalized
Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics | P ersPective
rHDL nanoparticles could be employed to tar-
get a wide range of surface tumor antigens for
the treatment of low SR-B1 expressor patients.
There are a multi t ude of membrane components
available as possible targets for functionalized
rHDL, which can be easily modified to feature
the desired vector for targeting [31–32]. This can
reroute the lipoproteins from their natural recep-
tors and navigate them to the specific disease
sites, thereby personalizing the rHDL-based
treatment [21].
The idea of using lipoproteins as targeted
drug-delivery agents was introduced 30 years ago [81]. Nevertheless, there are currently no lipopro-tein-based drug-delivery formulations in clinical
use or in clinical trials. The lack of aggressive
development of lipoproteins as drug-delivery
vehicles to be used at the bedside is surprising
as these formulations are biologically compatible
and offer selective tumor delivery via receptor-
mediated mechanisms. Some of the barriers to
enhance lipoprotein-based formulations towards clinical applications have been discussed above; however, the delay or lack of progress appears to be primarily due to hesitancy or limited interest on the part of venture capital investors and large drug companies. The old paradigm of seeking cellular and subcellular targets to be followed by extensive drug-screening strategies is expensive and relatively inefficient. Nevertheless, the repo-sitioning and reformulation of pharmaceutical agents for increased effectiveness and broader applications remains to be of minor interest, compared with the development of new drugs. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t e stimony, grants or patents received or pend-ing, or royalties. No writing assistance was utilized in the
production of this manuscript.
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