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WIREs Nanomed Nanobiotechnol
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Envisioning the future of polymer therapeutics for brain disorders

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The growing incidence of brain‐related pathologies and the problems that undermine the development of efficient and effective treatments have prompted both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Polymer therapeutics (PT) display properties well suited to the treatment of neuro‐related disorders, which help to overcome the many hidden obstacles on the journey to the central nervous system (CNS). The inherent features of PT, derived from drug(s) conjugation, in parallel with the progress in synthesis and analytical methods, the increasing knowledge in molecular basis of diseases, and collected clinical data through the last four decades, have driven the translation from “bench to bedside” for various biomedical applications. However, since the approval of Gliadel® wafers, little progress has been made in the CNS field, even though brain targeting represents an ever‐growing challenge. A thorough assessment of the steps required for successful brain delivery via different administration routes and the consideration of the disease‐specific hallmarks are essential to progress in the field. Within this review, we hope to summarize the latest developments, successes, and failures and discuss considerations on designs and strategies for PT in the treatment of CNS disorders. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Schematic representation of polymer therapeutics examined for central nervous system (CNS) drug delivery systems. (a) Polymer‐protein conjugate (e.g., Pluronic85®‐leptin), (b) polymer‐drug conjugate bearing a targeting ligand (e.g., Lf‐HA‐Dox) (c–e) Polyplexes: (b) with a linear polymer, (c) with a block copolymer forming micelles, (d) with dendrimers (e.g., arginine‐modified PAMAM G4 dendrimer + siRNA)
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(a) Bioluminescence after intranasally administering luciferase‐expressing mRNA. (a) Bioluminescence images obtained by an IVIS imaging system 4 hr after administering luciferase expressing mRNA‐loaded polyplex nanomicelles (upper) and an equal quantity of naked mRNA (lower). (b) Time course of bioluminescence after intranasally administering mRNA using polyplex nanomicelles (closed circle) and naked mRNA (open circle). Statistical analyses were performed by two‐tailed Student's t‐test, ***p < .001, **p < .01. RLU = relative luminescence units. Results are means ±SEMs (n = 4). (c) Histological analysis after intranasally administering GFP‐expressing mRNA. Mice were sacrificed and decapitated 24 hr after administering GFP‐expressing mRNA. (A) GFP expression visualized by immunostaining using an anti‐GFPmonoclonal antibody. (B) Cell nuclei stained by Hoechst. (C) Merged image. GFP‐positive staining was widely observed in the lamina propria (arrowheads), but not in nasal septal cartilages and bones (asterisk). Scale bar: 50 μm. (Reprinted with permission from Baba et al. (). Copyright 2015 Elsevier)
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Detailed pathways for reaching the brain after intranasal (IN) delivery. CSF = cerebrospinal fluid
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Schematic representation of polymer therapeutics (PT) administration through intranasal administration. The olfactory and the trigeminal routes
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(a) Schematic illustration for the synthesis of PPA and the formation of PPA/DNA nanoparticles. Tumor volumes imaging (b), fold change in tumor volume by calculating the mean fluorescence of the luciferase signal (c) and survival rates (d) of U87MG orthotopic glioma bearing mice after treatment. The weight ratio of polymer/DNA was 5/1. ***p < .001. Data represent mean ±standard deviation (n = 3). (e) Schematic elucidation of in vivo circulation, blood–brain barrier (BBB) crossing, tumor targeting, cellular uptake, and biological effects of the PPA/HSV‐TK NPs. U87MG (human primary glioblastoma cell), HBMEC (human brain microvascular endothelial cells), PPA = PEI‐PLL‐PEG‐ANG2.(Reprinted with permission from Gao et al. (). Copyright 2018 Elsevier)
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Schematic representation of PT administration through intravenous route. The neurovascular unit from blood–brain barrier (BBB) and its structure. PT = polymer therapeutics; BM = basement membrane
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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