title: iNGR-modified PEG-PLGA nanoparticles that recognize tumor vasculature and penetrate gliomas.
abstract: A major cross-cutting problem for glioma therapy is the poor extravasation and penetration of the payload drug in target glioma parenchyma. Here, to overcome these obstacles, a tumor vessel recognizing and tumor penetrating system is developed by functionalizating the poly (ethyleneglycol)-poly (L-lactic-co-glycolic acid) nanoparticles with an iNGR moiety (iNGR-NP). The nanoparticulate formulation is expected to achieve specific deep penetration in the tumor tissue by initially binding to aminopeptidase N, with iNGR proteolytically cleaved to CRNGR, and then bind with neuropilin-1 to mediate deep penetration in the tumor parenchyma. iNGR-NP exhibits significantly enhanced cellular uptake in human umbilical vein endothelial cells, improves the anti-proliferation and anti-tube formation abilities of paclitaxel in vitro. Following intravenous administration, iNGR-NP present favorable pharmacokinetic and tumor homing profiles. Glioma distribution and penetration assays confirm that iNGR-NP achieve the highest accumulation and deepest penetration at the glioma sites. The anti-glioma efficacy of paclitaxel-loaded iNGR-NP is verified by its improved anti-angiogenesis activity and the significantly prolonged survival time in mice bearing intracranial glioma. These evidences highlight the potential of iNGR-decorated nanoparticles in overcoming the leading edge problem in anti-glioma drug delivery.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Quanyin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Xingye
authors.initials: X
authors.lastname: Feng
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. Electronic address: chenjun@fudan.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D003374:Coumarins / Q000378:metabolism; D004338:Drug Combinations; D004705:Endocytosis / Q000187:drug effects; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000737:chemistry*; D007797:Laminin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D009842:Oligopeptides / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011509:Proteoglycans / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019265:Spectroscopy, Near-Infrared; D013844:Thiazoles / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D003374:Coumarins; D004338:Drug Combinations; D007797:Laminin; D009842:Oligopeptides; D011509:Proteoglycans; D013844:Thiazoles; C517282:coumarin 6; C579134:cysteinyl-arginyl-asparagyl-glycyl-arginyl-glycyl-prolyl-aspartyl-cysteine; C059485:matrigel; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003094:Collagen; D017239:Paclitaxel
keywords: Drug delivery; Glioma therapy; Nanoparticles; Penetration; iNGR peptide