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WIREs Nanomed Nanobiotechnol
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Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

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Abstract Nearly one in six people worldwide suffer from disorders of the central nervous system (CNS). There is an urgent need for effective strategies to improve the success rates in CNS drug discovery and development. The lack of effective technologies for delivering drugs and genes to the brain due to the blood–brain barrier (BBB), a structural barrier that effectively blocks most neurotherapeutic agents from reaching the brain, has posed a formidable hurdle for CNS drug development. Brain‐homing and brain‐penetrating molecular transport vectors, such as brain permeable peptides or BBB shuttle peptides, have shown promise in overcoming the BBB and ferrying the drug molecules to the brain. The BBB shuttle peptides are discovered by phage display technology or derived from natural neurotropic proteins or certain viruses and harness the receptor‐mediated transcytosis molecular machinery for crossing the BBB. Brain permeable peptide–drug conjugates (PDCs), composed of BBB shuttle peptides, linkers, and drug molecules, have emerged as a promising CNS drug delivery system by taking advantage of the endogenous transcytosis mechanism and tricking the brain into allowing these bioactive molecules to pass the BBB. Here, we examine the latest development of brain‐penetrating peptide shuttles and brain‐permeable PDCs as molecular vectors to deliver small molecule drug payloads across the BBB to reach brain parenchyma. Emerging knowledge of the contribution of the peptides and their specific receptors expressed on the brain endothelial cells, choice of drug payloads, the design of PDCs, brain entry mechanisms, and delivery efficiency to the brain are highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease
Schematic presentation of the blood–brain barrier (BBB) and other components of the neurovascular unit. The BBB is a multicellular barrier composed of continuous brain endothelial membrane that is sealed tightly by the tight junction, pericytes, and astrocyte end‐feet. The BBB separates the brain parenchyma from the peripheral blood circulation, and functions as a vascular interface that mediates communication between the CNS and periphery. Brain penetrating BBB shuttle peptide‐drug conjugates can mediate drug delivery across the BBB by harnessing the endogenous transport molecular machinery to reach brain parenchyma
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The structures of brain penetrating PDCs (peptides: Black, linkers: Red, therapeutic payloads: Blue). The BBB shuttle peptides include Angiopep‐2, SynB1, SynB3, Penetratin, TP10, RGD, gHoPe2, GSH, and E1‐3. The therapeutic payloads include paclitaxel, etoposide, doxorubicin, morphine, morphine‐6‐β‐glucuronide, coumaric acid, PD0325901, benzylpenicillin, vancomycin, dopamine, memantine (MEM), dalargin, and neurotensin
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Structure of peptide–drug conjugate (PDC) and commonly used linkers and representative drug payloads. PABC stands for para‐aminobenzyloxycarbonyl. Drug conjugation sites are shown in red circles
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Characterization of BBB shuttle Angiopep‐2 and Angiopep‐2‐paclitaxel conjugate (ANG1005) in preclinical evaluation. (a) Fluorescence microscopy analysis of brain slice after 1 h intravenous injection of Cy5.5‐Angiopep‐2 in mice. Cy5.5‐Angiopep‐2 (red) was mainly localized in the brain parenchyma in close proximity to the nuclei of brain cells (blue), contrary to Cy5.5‐Angiopep‐7 (negative control peptide, insert) which did not cross the brain capillaries (green). (Reprinted with permission from Gabathuler (2010). Copyright 2020 Elsevier). (b) Accumulation of fluorescent‐labeled Angiopep‐2 (green) in meninges and parenchyma of living mouse brain using intravital imaging 5 days after intravenous injection. Brain vasculature (red) was stained with dextran Texas red. (Reprinted with permission from Kumthekar et al. (2020). Copyright 2020 AACR). (c) In vivo fluorescence brain imaging of Cy5.5‐Angiopep‐2 and Cy5.5‐Angiopep‐7 (negative control) from 0.5 to 24 h after intravenous injections of 100 μg peptides via the tail vein. Brain fluorescence intensities were quantified for Cy5.5‐Angiopep‐2 (○) and Cy5.5‐Angiopep‐7 (•) and expressed as a function of time. (Reprinted with permission from Bertrand et al. (2010). Copyright 2020 Wiley). (d) 125I‐ANG1005 showed ~10‐ and 86‐fold greater brain uptake as compared to 125I‐Angiopep‐2 and 3H‐paclitaxel during in situ rat brain perfusion. (Reprinted with permission from Thomas et al. (2009). Copyright 2020 Springer). (e) Brain uptake of 125I‐ANG1005 and 14C‐paclitaxel in mice bearing brain metastases of breast cancer 231‐BR cells. 125I‐ANG1005 uptake into brain exceeded that of free 14C‐paclitaxel by more than 10‐fold at equivalent radiotracer dose after intravenous injection for 30 min and analyzed by quantitative autoradiography. (Reprinted with permission from Thomas et al. (2009). Copyright 2020 Springer)
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Schematic illustration of BBB shuttle peptides derived from phage display biopanning technology and Neurotropic proteins. (a) The procedure of phage display biopanning against targets in vitro or tissues in vivo. A phage library binds to a target immobilized on a surface in vitro or injected into an animal in vivo. After incubation, the unbound phages are washed away and the bound phages are collected by elution and further amplified. Additional rounds of selection are carried out to enrich the affinitive phages. The high‐affinity phage binders are purified and sequenced by DNA sequencing to determine the sequences of target binding peptides. The targeting peptides are further synthesized and evaluated in an in vitro BBB transwell assay to identify the BBB shuttle peptides. (b) Identification of the fragment of a neurotropic protein responsible for its transport across the BBB. (c) Phage display technology identified BBB shuttle peptide LRPep2 targeting the low‐density lipoprotein receptor (LDLR) in the mouse brain. The structure of LRPep2 and computational docking of peptide–protein binding (top panel) and colocalization of rhodamine‐labeled LRPep2‐rho (red) with LDLR (green) on mouse brain slices (bottom panel) are shown. The LRPep2 image is reproduced with permission from André et al. (2020). Copyright 2020 MDPI
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Schematic illustration of main routes of transport for molecular traffic across the BBB, a structural barrier between blood vessels and brain parenchyma. The main pathways for transport of molecules across the BBB including passive diffusion (paracellular and transcellular pathways), carrier‐mediated transcytosis (CMT), receptor‐mediated transcytosis (RMT), adsorptive‐mediated transcytosis (AMT), and cell‐mediated transcytosis. Drug efflux transporters are expressed on the BBB to limit many molecules from accessing the brain. Brain penetrating BBB shuttle peptides and peptide–drug conjugates (PDCs) can take advantage of receptors or transporters overexpressed at the BBB and mediate drug delivery across the BBB via receptor‐mediated transcytosis
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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