title: Anti-tumor and anti-angiogenic effect of metronomic cyclic NGR-modified liposomes containing paclitaxel.
abstract: In the present study, we prepared NGR-modified sterically stabilized liposomes containing paclitaxel (NGR-SSL-PTX) in order to evaluate their potential targeting to aminopeptidase N receptors expressed on tumor endothelial cells and the tumor cell surface and its anti-angiogenic activity following metronomic administration. NGR-SSL-PTX was prepared by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified liposomes on HUVEC (human umbilical vein endothelial cells), HT1080 (human ﬁbrosarcoma cells) and MCF-7 (human breast adenocarcinoma cells) were then investigated. The effect of NGR-SSL-PTX on HUVEC proliferation and migration was also tested. The pharmacokinetics of NGR-SSL-PTX was studied in rats. The in vivo targeting activity of NGR-modified liposomes was investigated in HT1080 tumor-bearing mice. The anti-tumor activity of NGR-SSL-PTX following metronomic administration was evaluated in HT1080 tumor-bearing mice in vivo. The targeting activity of the NGR-modified liposomes was demonstrated by in vitro flow cytometry and confocal microscopy as well as in vivo confocal immunofluorescence microscopy and bio-distribution experiments. The results of endothelial cell proliferation and migration and microvessel density (MVD) confirmed the anti-angiogenic activity of NGR-SSL-PTX in vitro and in vivo. The sustained circulation of NGR-SSL-PTX was shown in the pharmacokinetic study. NGR-SSL-PTX is able to improve treatment efficacy producing the most significant anti-tumor activity and anti-angiogenic following metronomic administration.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Beijing 100191, China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Luo
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Bing-Xiang
authors.initials: BX
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Yu
authors.initials: Y
authors.lastname: Duan
authors.forename: Ruo
authors.initials: R
authors.lastname: Du
authors.forename: Ke-Fu
authors.initials: KF
authors.lastname: Yu
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D059250:Administration, Metronomic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004058:Diffusion; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry*; D009928:Organ Specificity; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D008081:Liposomes; C526428:NGR peptide; D053769:Nanocapsules; D009842:Oligopeptides; D017239:Paclitaxel