title: Integrin-targeted pH-responsive micelles for enhanced efficiency of anticancer treatment in vitro and in vivo.
abstract: The key to developing more nanocarriers for the delivery of drugs in clinical applications is to consider the route of the carrier from the administration site to the target tissue and to look for a simple design to complete this whole journey. We synthesized the amphiphilic copolymer cRGDfK-poly(ethylene glycol)-b-poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate) (cRGD-PETM) to construct multifunctional micelles. These micelles combined enhanced drug-loading efficiency with tumor-targeting properties, visual detection and controllable intracellular drug release, resulting in an improved chemotherapeutic effect in vivo. Doxorubicin (DOX) was encapsulated within the cRGD-PETM micelles as a model drug (termed as cRGD-PETM/DOX Ms). The size and morphology of the micelles were characterized systematically. As a result of the hydrophobic interaction and the π-π conjugation between the DOX molecules and the PTTMA copolymers, the cRGD-PETM/DOX Ms showed an excellent drug-loading capacity. The results of in vitro drug-release studies indicated that the cumulative release of DOX from cRGD-PETM/DOX Ms at pH 5.0 was twice that at pH 7.4. The results of fluorescent microscopic analysis showed that the cRGD-PETM/DOX Ms could be internalized by 4T1 and HepG2 cells via receptor-mediated endocytosis with rapid intracellular drug release, which resulted in increased cytotoxicity compared with free DOX. Ex vivo imaging studies showed that the cRGD-PETM/DOX Ms improved the accumulation and retention of the drug in tumor tissues. Studies of the in vivo anticancer effects showed that the cRGD-PETM/DOX Ms had a significantly higher therapeutic efficacy with lower side-effects than free DOX and PETM/DOX Ms. These results show that the multifunctional cRGD-PETM/DOX Ms have great potential as vehicles for the delivery of hydrophobic anticancer drugs.
authors: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, P.R. China. lewis78@163.com.
authors: Jinjian
authors: J
authors: Liu
authors: Hongzhang
authors: H
authors: Deng
authors: Qiang
authors: Q
authors: Liu
authors: Liping
authors: L
authors: Chu
authors: Yumin
authors: Y
authors: Zhang
authors: Cuihong
authors: C
authors: Yang
authors: Xuefei
authors: X
authors: Zhao
authors: Pingsheng
authors: P
authors: Huang
authors: Liandong
authors: L
authors: Deng
authors: Anjie
authors: A
authors: Dong
authors: Jianfeng
authors: J
authors: Liu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D016023:Integrins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000819:agonists* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011409:Propylene Glycols
chemical_list: D000903:Antibiotics, Antineoplastic; D016023:Integrins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011409:Propylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin