Peptide-based vectors for blood–brain barrier targeting and delivery of drugs to the central nervous system

Abstract

Therapeutic DeliveryVol. 1, No. 4 Special Focus Issue: Blood-brain barrier - EditorialFree AccessPeptide-based vectors for blood–brain barrier targeting and delivery of drugs to the central nervous systemPatrick Vlieghe and Michel KhrestchatiskyPatrick Vlieghe† Author for correspondenceVECT-HORUS S.A.S., Faculté de Médecine Secteur Nord, CS80011, Boulevard Pierre Dramard, 13344 Marseille Cedex 15, France. Search for more papers by this authorEmail the corresponding author at patrick.vlieghe@vect-horus.com and Michel KhrestchatiskyLaboratoire de Neurobiologie des Interactions Cellulaires et Neurophysiopathologie (NICN, UMR6184 CNRS), Université de la Méditerranée, Faculté de Médecine Secteur Nord, CS80011, Boulevard Pierre Dramard, 13344 Marseille Cedex 15, FranceSearch for more papers by this authorPublished Online:13 Oct 2010https://doi.org/10.4155/tde.10.44AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: drug conjugateprodrugreceptor-mediated transcytosiscarrier-mediated transportadsorptive-mediated transporttranscellular diffusionliposomesnanoparticlesbiotechnology companiesThe CNS is protected by various barriers that regulate nervous tissue homeostasis and control the selective and specific uptake, efflux and metabolism of endogenous and exogenous compounds. Among these barriers is the blood–brain barrier (BBB), a physical and physiological barrier that controls very efficiently and selectively the entry of compounds from blood into the CNS, and protects nervous tissue from harmful substances and infectious agents present in circulating blood. Unfortunately, the BBB also prevents the entry of the vast majority of potential drugs, which are not able to reach their brain targets. As a result, various BBB targeting and CNS drug delivery strategies are currently being developed by biotechnology companies to enhance the transport of drugs from blood into the CNS.Crossing the BBB is a long-unsolved industry challengeIn the CNS, the BBB consists mainly of brain capillary endothelial cells (BCECs), although other cell types, such as capillary pericytes, perivascular astrocyte foot processes and neuronal cells play an important role in the structure and function of the BBB and in the formation of the so-called neurovascular unit. The BBB not only acts as a physical barrier, but also functions as a physiological (metabolic or enzymatic [1,2], efflux and immunological [3]) barrier, which very efficiently limits the passage of many molecules from the circulation into the nervous tissue.Although other reasons besides the BBB, such as complexity of the CNS, can be invoked, it is a fact that the CNS remains one of the riskiest therapeutic areas in terms of clinical success rates [4,5]. For instance, between 1991 and 2000, the success rate from first-in-man to registration for CNS drugs was only 8%, as compared with 20% for cardiovascular drugs [4]. The development of CNS drugs takes 12–16 years, compared with 10–12 years for non-CNS drugs [4]. The low number of potential CNS drugs reaching commercial success is primarily due to the complexity and difficulty of CNS drug development. More than 90% of the molecules developed by the pharmaceutical industry for treating CNS diseases are abandoned in clinical Phases I to III, after costly developments. Current CNS drug treatments (e.g., lipid-soluble small organic drugs) predominantly address a few CNS disorders: chronic pain, insomnia, epilepsy and affective disorders such as depression and schizophrenia [6], whereas curative treatment options for stroke, brain cancer, neurodegenerative diseases and most CNS disorders remain quite limited [7].The BBB is a major hurdle for the development of CNS drugs as it prevents over 98% of all small-molecule drugs and close to 100% of large-molecule drugs (biologic drugs) from penetrating the CNS [6]. As a consequence, most drugs have insufficient CNS exposure to be effective, or induce severe secondary effects or toxicity if administered at high doses to increase CNS exposure. Hence, promising CNS drug candidates have to cross the BBB, a major challenge that can only rely on better understanding the structure, physiology and molecular basis of transport functions of the BBB, and utilizing this knowledge during drug development.Bypassing the BBBTo bypass the BBB and deliver drugs to the brain, several invasive methods have been used, such as direct injection of a drug into the CNS tissue (intraparenchymal or intracerebral administration, use of implants or convection-enhanced delivery), into the brain cerebrospinal fluid (intracerebroventricular administration) or into the spinal cord (intrathecal administration) [8].Transient disruption of the BBB, such as temporal BBB opening by intracarotid arterial infusion with hyperosmotic solutions of saccharides (e.g., mannitol), biochemical opening of the BBB by vasoactive compounds (e.g., RMP-7) or MRI-guided focused ultrasound, are also used to bypass the BBB [8].These methods are efficient in the absence of alternatives, but nonadapted for widescale implementation due to elevated cost of treatment, patient comfort issues and risks of infection or toxicity (e.g., passage of circulating infectious agents or of plasma proteins toxic for the brain).To circumvent the problems encountered with invasive approaches and methods of transient disruption of the BBB, noninvasive approaches have been developed to specifically target the BBB and deliver drugs into the CNS.Drug transport to the brain: crossing the BBBAs already evoked, to gain access to the brain parenchyma, molecules have to cross the BCECs. Simple diffusion of small-molecule drugs across the plasma membrane of BCECs is dependent on their lipophilicity. Hence, increasing the lipophilicity of such molecules is an efficient strategy to increase BBB permeability. This has been applied to drug development in the pharmaceutical industry for a long time. However, progress in BBB research has revealed that multiple transporters and receptors are expressed at the BBB that modulate the passage of numerous ligands [9]. Under physiological conditions, control of transport across the BBB is achieved by minimization of trans-barrier transport: active expulsion by efflux pumps of the unwanted molecules that cross the barrier, and selective and active transport of the required substrates through a range of transporters and internalizing receptors [10].Some molecules (or drugs) that are able to cross the BBB can be actively exported from brain to blood by energy-dependent transporters such as multidrug resistant (MDR) transport proteins [11]. The efflux of small molecules from the brain to the blood is generally mediated by active efflux transport (AET) systems. The model AET system at the BBB is the ATP-binding cassette (ABC) transporter, P-glycoprotein (P-gp/MDR1/ABCB1) [12]. There are many other AET systems present/expressed at the BBB that belong to the ABC transporter family such as, among others, the MDR-associated protein 4 (MRP4/ABCC4), and the breast cancer resistance protein (BCRP/ABCG2) [9,13].Despite these efflux systems, and knowing that paracellular hydrophilic diffusion of small water-soluble molecules between BCECs is very limited owing to the tight junctions that characterize these cells, some drug candidates are nevertheless able to cross the BBB in one of the following ways [6,14]: ▪ Transcellular diffusion, generally for small lipid-soluble molecules;▪ Adsorptive-mediated transport for cationic molecules or cationic nanovectors;▪ Carrier-mediated transport for some very specific small molecules such as l-dopa;▪ Receptor-mediated transcytosis (RMT) for specific macromolecules, but also for small molecules and targeted nanovectors.Receptor-mediated transcytosisReceptor-mediated transcytosis involves binding of ligands to specific membrane receptors on the luminal surface of the BCECs that make up the BBB. This initiates engulfing of the receptor and its ligand into a vesicle that forms at the surface of the BCECs and that enters the cells (endocytosis) after aggregation within coated pits. Then, the ligand–receptor complex, fused with an endosome, crosses the BCECs and is released after dissociation of the ligand from the receptor by exocytosis at the abluminal membrane into the brain parenchyma (transcytosis). Not all internalized vesicles (ligand–receptor complexes) are transcytosed and some may enter a pathway that causes them to fuse with a lysosome, forming a secondary lysosome, which then constitutes a deadend and may result in hydrolysis of the bound ligand [15].Receptor-mediated transcytosis systems are involved in importing notably large molecules or macromolecular complexes from blood into the brain and comprise, among others, the transferrin receptor, insulin receptor, insulin-like growth factor receptor, low-density lipoprotein receptor (LDLR) and the low-density lipoprotein receptor-related proteins 1 (LRP1) and 2 (LRP2) [12].As RMT is not too limiting on the size or shape of what is being engulfed, this route across the BBB can be used for small-molecule drugs whether they are lipophilic or not, and provides a promising strategy for brain targeting and delivery of bulky drug payloads. Therapeutic agents can be targeted and delivered into the brain via conjugation to vectors that are ligands of BBB receptors involved in RMT. It is particularly suitable for therapeutic macromolecular compounds such as peptides, proteins and antibodies, for CNS drug delivery via third-generation nanovectors targeted to the BBB (stealth liposomes or nanoparticles on which a targeting ligand is conjugated), and for BBB targeting and delivery of drugs to the CNS via peptide-vector-based prodrug approaches.Receptor-mediated transcytosis seems to be one of the safest and most effective ways of targeting drugs to the CNS and is recognized by the scientific community as one of the approaches most likely to succeed [8,16]. This has opened the door to a range of molecular-based strategies for BBB targeting and CNS drug delivery.BBB targeting & CNS drug deliveryOne of the great challenges in CNS drug therapy is the selective delivery (i.e., drug targeting or targeted drug delivery) of drugs to the intended target (i.e., the brain parenchyma). An effective vectorization strategy (drug targeting or targeted drug delivery) should be defined for a given drug according to its physicochemical and pharmacokinetic characteristics, to its target site of action, and to the pathology to be addressed. An optimal CNS drug development strategy should consider the design of suitable drug targeting and delivery approaches as soon as drug candidates are demonstrated to be active in vitro, but which unable to reach their targets in vivo (i.e., in the animal brain). Such an approach would certainly improve CNS drug development productivity by increasing the number of drugs that could reach clinical Phases and the market.Efforts are currently directed towards BBB targeting and CNS drug delivery in academia, the pharmaceutical industry and in small biotechnology companies. We will now focus briefly on approaches implemented by biotechnology companies to emphasize the complementary strategies that are being developed.Nanovectors targeted to the BBB for CNS drug deliveryDrug delivery is one of the most important applications of nanotechnology in the medicinal field (nanomedicine technology). Current efforts in the area of drug delivery include the development of brain-specific nanovectors, in which the encapsulated/adsorbed drug is specifically targeted to its site of action (i.e., the CNS). To be recognized by BBB transporters/receptors, additional targeting moieties conjugated to nanovectors are needed in order to deliver encapsulated/adsorbed drugs in effective therapeutic concentrations to the CNS. Technical problems associated with developing third-generation nanovectors targeted to the brain include their increased complexity and scalability, as well as their potential toxicity, which presently limit their industrial use. A few small biotechnology companies are addressing this challenge.The company to-BBB develops the G-Technology®, which utilizes the endogenous ligand glutathione to target drug-loaded liposomes (glutathione–PEG–LPs) to the brain [101–104]. These third-generation liposomes enable transport of drugs, such as doxorubicin or ribavirin, across the BBB with good safety and pharmacokinetic profiles, and at an effective therapeutic concentration. As a proprietary brain-targeted version of the marketed product Caelyx®/Doxil® (PEG–liposomal doxorubicin), 2B3–101, to-BBB’s lead compound involves doxorubicin encapsulated in glutathione–PEG–LPs. This product is ready to enter clinical trials at the end of 2010.Capsulution Pharma, a merger between Capsulution Nanoscience and NanoDel Technologies, has developed a proprietary polysorbate 80-coated nanoparticle technology for CNS drug delivery [105–109]. After intravenous administration, the surface of these nanoparticles becomes further coated with absorbed plasma proteins, including apolipoprotein E (Apo-E) [17]. These nanoparticles are thought to mimic low-density lipoproteins (LDL) and could therefore be uptaken into the endothelium of the BBB, notably via the LDLR [18]. Doxorubicin bound to poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 is currently in preclinical development.Peptide-based vectors for BBB targeting & delivery of drugs to the CNSDrug targeting is a strategy aimed at the delivery of a compound to a particular tissue (e.g., the brain) in the body with high specificity. Drug targeting approaches primarily modify the biodistribution of the vectorized drug toward the target site. Drug targeting via a prodrug approach is usually obtained by conjugation of a BBB-targeting promoiety to the drug. BBB targeting and delivery of drugs to the CNS via prodrug approaches can only be achieved if certain criteria are met: ▪ The prodrug must have ready access to its intended site of action (i.e., the brain);▪ Ideally, prodrug bioconversion should be selective at this site;▪ Depending on the physicochemical and biological properties of the prodrug, the active parent drug, once formed at the site of action, must exhibit prolonged retention at this site.A few biotechnology companies are developing BBB targeting strategies that rely on the RMT and ‘Trojan horse’ concept, using chimeric peptides (also termed genetically engineered fusion proteins), antibodies and/or peptides as vectors.AngioChem developed the engineered peptide compound (EPiC) platform, a peptide-based vector for BBB targeting and delivery of drugs to the CNS. AngioPep-2 (19 amino acids, derived from aprotinin) is able to transport drugs across the BBB via LRP1 targeting. Angiochem’s lead conjugate, ANG1005 (a conjugate of AngioPep-2 and 3 paclitaxel molecules), is in Phase I/IIa clinical trials for the treatment of primary (glioblastoma) and metastatic brain tumors [19–21,110–120].ArmaGen Technologies have provided a technology platform (AGT fusion proteins) based on genetic engineering of recombinant fusion proteins wherein the (protein) drug is fused to ArmaGen Technologies’ molecular ‘Trojan horse’ (MTH) [121–124]. Fusion proteins have dual functions: they cross the BBB via one of the endogenous BBB RMT systems and bind neuronal or glial receptors in brain parenchyma. For example, AGT-181, a fusion protein between a human insulin receptor monoclonal antibody and the enzyme α-L-iduronidase, is an enzyme-replacement therapeutic for treatment of Hurler’s syndrome, a lysosomal storage disease.BiOasis develops the natural human protein p97 (melanotransferrin), which is used as a protein vector to deliver either therapeutic proteins (through a chimeric peptide strategy) or small organic drugs (through a vector/drug conjugate strategy) across the BBB. p97 presents a high transport rate across the BBB that may involve LRP1 [22]. It was demonstrated that p97 is a vector capable of shuttling therapeutic levels of organic anticancer drugs (doxorubicin and paclitaxel) from blood to brain.Raptor Pharmaceutical developed the NeuroTrans™ platform, which has a proprietary technology based on receptor-associated protein (RAP, 39 kDA), a generic endogenous protein. RAP is a ligand for members of the LRP receptor family [125–128]. Engineered RAP is able to transport either therapeutic proteins (through a chimeric peptide strategy) or small molecules such as doxorubicin (through a vector–drug conjugate strategy) into the brain.Vect-Horus developed a technology platform dedicated to the discovery and design of peptide-based vectors for BBB targeting and delivery of drugs to the CNS. Because members of the LDLR family are considered as relevant RMT-based drug transport systems [23–25], Vect-Horus identified a first series of noncompetitive hit peptide-based ligands for the human LDLR, such as VH0411 a 15-mer peptide. From this compound, a medicinal chemistry-based optimization (Ala-scan, d-scan, truncation, non natural residues insertion) was carried out. This led to the design of a new lead peptide-based vector: VH0445, a cyclic 8-mer peptide containing natural and non-natural amino acids [129,130]. In vivo proof-of-mechanism of action (assessment of brain uptake) and proof-of-principle (assessment of biological activity) in acute pain were established following conjugation of VH0445 to a model opioid peptide, which results in a sharp improvement in antinociceptive effect in mice. Vect-Horus is also conducting works on several RMT-based receptors for which peptide-vectors are currently in the discovery phase.ConclusionA new paradigm has recently emerged in CNS drug discovery, which concentrates on finding drug candidates with the right balance between free fraction in plasma and brain (especially in the interstitial fluid) [16], and between rate and extent of CNS penetration [26]. Three main factors may explain all aspects of drug penetration (and arising biological activity) to the brain: the rate of permeation across the BBB (permeability clearance), extent of brain penetration (unbound drug in the interstitial fluid) and intra-brain distribution of drugs [27]. The strategies described in this editorial represent important milestones for BBB targeting and CNS drug delivery, and for the future development of therapies to address CNS diseases.As reviewed recently, the decreasing number of approved drugs produced by the pharmaceutical industry and R&D from biotechnology companies has contributed to a revival of interest in peptides as potential drug candidates [28]. More than 200 peptidic compounds comprising therapeutic peptides, proteins and antibodies have already reached the pharmaceutical market. However, with very few exceptions, none of these biomolecules address CNS diseases, while the expectations are high in terms of new biotechnology-based therapeutic strategies. It is anticipated that peptide-based vectors developed for CNS drug targeting will certainly contribute to the development of peptide-based prodrugs with facilitated access to the CNS [28].The approaches and results described in this editorial demonstrate that peptide-based vector strategies, which exploit binding of ligands to physiological transport receptors at the BBB, are not only able to achieve increased drug transport across the BBB, but show promise for the delivery of innovative drug candidates (small organic drugs, peptides and biologic drugs) into the CNS in vivo. A combination of knowledge on the molecular/cellular processes of BBB physiology and pathology and pharmacokinetic and pharmacodynamic data on CNS drugs (or vector–drug conjugates) with their biological actions [29] will certainly improve the success rate in CNS drug development in the coming years.Financial & competing interests disclosurePatrick Vlieghe is employed as Head of Development by Vect-Horus, SAS. Michel Khrestchatisky is a founder of and scientific advisor to Vect-Horus, SAS. Additionally, both Michel Khrestchatisky and Patrick Vlieghe are named as inventors on patents and/or patent applications relating to technologies described in this article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Ciechanover A. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat. Rev. Mol. Cell Biol.6(1),79–87 (2005).Crossref, Medline, CAS, Google Scholar2 El-Bacha RS, Minn A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell Mol. Biol.45(1),15–23 (1999).Medline, CAS, Google Scholar3 Wekerle, H. Immune protection of the brain – efficient and delicate. J. Infect. Dis.186(Suppl. 2),S140–144 (2002).Crossref, Medline, Google Scholar4 Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov.3(8),711–715 (2004).Crossref, Medline, CAS, Google Scholar5 Pangalos MN, Schechter LE, Hurko O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat. Rev. Drug Discov.6(7),521–532 (2007).Crossref, Medline, CAS, Google Scholar6 Pardridge WM. blood–brain barrier drug targeting: the future of brain drug development. Mol. Interv.3(2),90–105 (2003).Crossref, Medline, CAS, Google Scholar7 Pardridge WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx2(1),3–14 (2005).Crossref, Medline, Google Scholar8 Gabathuler R. Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurbiol. Dis.37(1),48–57 (2010).Crossref, Medline, CAS, Google Scholar9 Ohtsuki S, Terasaki T. Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm. Res.24(9),1745–1758 (2007).Crossref, Medline, CAS, Google Scholar10 Mazza M, Uchegbu IF, Schätzlein AG. Cancer and the blood–brain barrier: ‘Trojan horses’ for courses? Br. J. Pharmacol.155(2),149–151 (2008).Crossref, Medline, CAS, Google Scholar11 Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol. Therapeut.104(1),29–45 (2004).Crossref, Medline, CAS, Google Scholar12 De Boer AG, Gaillard PJ. Drug targeting to the brain. Annu. Rev. Pharmacol. Toxicol.47,323–355 (2007).Crossref, Medline, CAS, Google Scholar13 Zhang Y, Han H, Elmquist WF, Miller DW. Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res.876(1–2),148–153 (2000).Crossref, Medline, CAS, Google Scholar14 Pardridge WM. Blood–brain barrier delivery. Drug Discov. Today12(1–2),54–61 (2007).Crossref, Medline, CAS, Google Scholar15 Broadwell RD, Balin BJ, Selcman M. Transcytotic pathways for blood-borne protein through the blood–brain barrier. Proc. Natl Acad. Sci. USA85(2),632–636 (1988).Crossref, Medline, CAS, Google Scholar16 Palmer AM. The role of the blood –CNS barrier in CNS disorders and their treatment. Neurbiol. Dis.37(1),3–12 (2010).Crossref, Medline, CAS, Google Scholar17 Kreuter J, Shamenkov D, Petrov V et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood–brain barrier. J. Drug Target.10(4),317–325 (2002).Crossref, Medline, CAS, Google Scholar18 Kreuter J, Ramge P, Petrov V et al. Direct evidence that polysorbate-80-coated poly (butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles. Pharm. Res.20(3),409–416 (2003).Crossref, Medline, CAS, Google Scholar19 Demeule M, Régina A, Ché C et al. Identification and design of peptides as a new drug delivery system for the brain. J. Pharmacol. Exp. Ther.324(3),1064–1072 (2008).Crossref, Medline, CAS, Google Scholar20 Demeule M, Currie JC, Bertrand Y et al. Involvement of the low-density lipoprotein receptor related protein in the transcytosis of the brain delivery vector angiopep-2. J. Neurochem.106(4),1534–1544 (2008).Crossref, Medline, CAS, Google Scholar21 Régina A, Demeule M, Ché C et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br. J. Pharmacol.155(2),185–197 (2008).Crossref, Medline, CAS, Google Scholar22 Demeule M, Poirier J, Jodoin J et al. High transcytosis of melanotransferrin (P97) across the blood–brain barrier. J. Neurochem.83(4),924–933 (2002).Crossref, Medline, CAS, Google Scholar23 Brown MS, Goldstein JL. Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc. Natl Acad. Sci.76(7),3330–3337 (1979).Crossref, Medline, CAS, Google Scholar24 Dehouck B, Fenart L, Dehouck MP, Pierce A, Torpier G, Cecchelli R. A new function for the LDL receptor: transcytosis of LDL across the blood–brain barrier. J. Cell Biol.138(4),877–889 (1997).Crossref, Medline, CAS, Google Scholar25 Chung NS, Wasan KM. Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake. Adv. Drug Deliv. Rev.56(9),1315–1334 (2004).Crossref, Medline, CAS, Google Scholar26 Reichel, A. Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem. Biodivers.6(11),2030–2049 (2009).Crossref, Medline, CAS, Google Scholar27 Hammarlund-Udenaes M, Fridén M, Syvänen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm. Res.25(8),1737–1750 (2008).Crossref, Medline, CAS, Google Scholar28 Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov. Today15(1–2),40–56 (2010).Crossref, Medline, CAS, Google Scholar29 Mehdipour AR, Hamidi M. Brain drug targeting: a computational approach for overcoming blood–brain barrier. Drug Discov. Today14(21–22),1030–1036 (2009).Crossref, Medline, CAS, Google Scholar101 Industrial Technology Research Institute: US0141133 (2007).Google Scholar102 To-BBB, Holding BV: WO08118013 (2008).Google Scholar103 Industrial Technology Research Institute: US0095836 (2008). Google Scholar104 Industrial Technology Research Institute: US0123531 (2009).Google Scholar105 NanoDel Technologies, Gmbh: WO04017945 (2004).Google Scholar106 NanoDel Technologies, Gmbh: WO06029845 (2006).Google Scholar107 NanoDel Technologies, Gmbh: WO06056362 (2006).Google Scholar108 NanoDel Technologies, Gmbh: WO07088066 (2007).Google Scholar109 NanoDel Technologies, Gmbh: WO08003706 (2008).Google Scholar110 AngioChem, Inc.: WO04060403 (2004).Google Scholar111 AngioChem, Inc.: WO06086870 (2006).Google Scholar112 AngioChem, Inc.: WO07009229 (2007).Google Scholar113 AngioChem, Inc.: WO08046228 (2008).Google Scholar114 AngioChem, Inc.: WO09079790 (2009).Google Scholar115 AngioChem, Inc.: WO09127072 (2009).Google Scholar116 AngioChem, Inc.: WO10043047 (2010).Google Scholar117 AngioChem, Inc.: WO10043049 (2010).Google Scholar118 AngioChem, Inc.: WO10063122 (2010).Google Scholar119 AngioChem, Inc.: WO10063123 (2010).Google Scholar120 AngioChem, Inc.: WO10063124 (2010).Google Scholar121 ArmaGen Technologies, Inc.: WO07044323 (2007).Crossref, Google Scholar122 ArmaGen Technologies, Inc.: WO08022349 (2008).Crossref, Google Scholar123 ArmaGen Technologies, Inc.: WO09018122 (2009).Crossref, Google Scholar124 ArmaGen Technologies, Inc.: WO09070597 (2010).Crossref, Google Scholar125 Raptor Pharmaceutical, Inc.: WO06138343 (2006).Google Scholar126 Raptor Pharmaceutical, Inc.: WO07035716 (2007).Google Scholar127 Raptor Pharmaceutical, Inc.: WO08036682 (2008).Google Scholar128 Raptor Pharmaceutical, Inc.: WO08116171 (2008).Google Scholar129 Vect-Horus, SAS: FR2937322 (2010).Google Scholar130 Vect-Horus, SAS: WO10046588 (2010).Google ScholarFiguresReferencesRelatedDetailsCited ByCD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation22 March 2022 | Advanced NanoBiomed Research, Vol. 2, No. 6Multi-disciplinary Approach for Drug and Gene Delivery Systems to the Brain3 December 2021 | AAPS PharmSciTech, Vol. 23, No. 1Evolving new-age strategies to transport therapeutics across the blood-brain-barrierInternational Journal of Pharmaceutics, Vol. 599Innovative approaches in CNS clinical drug development: Quantitative systems pharmacologyTherapies, Vol. 76, No. 2Microglia-targeting nanotherapeutics for neurodegenerative diseasesAPL Bioengineering, Vol. 4, No. 3Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseasesEuropean Journal of Pharmaceutics and Biopharmaceutics, Vol. 149Short Peptide-Mediated Brain-Targeted Drug Delivery with Enhanced Immunocompatibility22 January 2019 | Molecular Pharmaceutics, Vol. 16, No. 2Towards Improvements for Penetrating the Blood–Brain Barrier—Recent Progress from a Material and Pharmaceutical Perspective23 March 2018 | Cells, Vol. 7, No. 4Use of LDL receptor—targeting peptide vectors for in vitro and in vivo cargo transport across the blood‐brain barrier20 January 2017 | The FASEB Journal, Vol. 31, No. 5Enhanced serum proteolysis resistance of cell-penetrating peptidesJesús Fominaya, Jerónimo Bravo, Didier Decaudin, Jean Yves Brossa, Fariba Nemati & Angelita Rebollo18 February 2015 | Therapeutic Delivery, Vol. 6, No. 2Strategies To Deliver Peptide Drugs to the Brain21 March 2014 | Molecular Pharmaceutics, Vol. 11, No. 4Nano-enabled delivery systems across the blood–brain barrier30 October 2013 | Archives of Pharmacal Research, Vol. 37, No. 1Endogenous and synthetic MMP inhibitors in CNS physiopathologyMedicinal Chemistry Based Approaches and Nanotechnology-Based Systems to Improve CNS Drug Targeting and Delivery20 March 2012 | Medicinal Research Reviews, Vol. 33, No. 3Nanoparticulate targeted drug delivery using peptides and proteinsRecent Advances in Drug Delivery SystemsJournal of Biomaterials and Nanobiotechnology, Vol. 02, No. 05 Vol. 1, No. 4 Follow us on social media for the latest updates Metrics Downloaded 2,243 times History Published online 13 October 2010 Published in print October 2010 Information© Future Science LtdKeywordsdrug conjugateprodrugreceptor-mediated transcytosiscarrier-mediated transportadsorptive-mediated transporttranscellular diffusionliposomesnanoparticlesbiotechnology companiesFinancial & competing interests disclosurePatrick Vlieghe is employed as Head of Development by Vect-Horus, SAS. Michel Khrestchatisky is a founder of and scientific advisor to Vect-Horus, SAS. Additionally, both Michel Khrestchatisky and Patrick Vlieghe are named as inventors on patents and/or patent applications relating to technologies described in this article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download