title: Integrin-targeted zwitterionic polymeric nanoparticles with acid-induced disassembly property for enhanced drug accumulation and release in tumor.
abstract: Reasonably structural design of nanoparticles (NPs) to combine functions of prolonged systemic circulation, enhanced tumor targeting and specific intracellular drug release is crucial for antitumor drug delivery. Combining advantages of Arg-Gly-Asp (RGD) for active tumor targeting, zwitterionic polycarboxybetaine methacrylate (PCB) for prolonged systemic circulation, poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) for acid-triggered intracellular release, novel RGD-PCB-b-PDPA (RGD-PCD) block copolymers were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization and followed by functionalization with RGD. Doxorubicine (DOX) was encapsulated within the RGD-PCD NPs as model medicine (RGD-PCD/DOX NPs). With ultra pH-sensitivity of PDPA, the drug release was restrained at pH 7.4 for only 24% within 36 h, which was increased to 60% at pH 6.0 within 24 h, and released more rapidly at pH 5.0 for 100% within 5 h, indicating that the RGD-PCD/DOX NPs were able to turn drug release "off" at neutral pH (e.g., systemic circulation) whereas "on" under acidic conditions (e.g., inside endo/lysosomes). Furthermore, the results of fluorescence microscopy and flow cytometry analysis demonstrated improved internalization of RGD-PCD/DOX NPs in HepG2 cells via integrin-mediated endocytosis with rapid DOX release intracellularly. Consequently, the RGD-PCD/DOX NPs showed considerable cytotoxicity against HepG2 and HeLa cells in comparison with free DOX. Importantly, the RGD-PCD/DOX NPs exhibited little protein adsorption property with excellent serum stability, which led to prolonged systemic circulation and enhanced tumor accumulation in tumor-bearing nude mice. Therefore, this multifunctional RGD-PCD NPs, which represented the flexible design approach, showed great potential for the development of novel nanocarriers in tumor-targeted drug delivery.
authors: Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors: Pingsheng
authors: P
authors: Huang
authors: Huijuan
authors: H
authors: Song
authors: Weiwei
authors: W
authors: Wang
authors: Yu
authors: Y
authors: Sun
authors: Junhui
authors: J
authors: Zhou
authors: Xue
authors: X
authors: Wang
authors: Jinjian
authors: J
authors: Liu
authors: Jianfeng
authors: J
authors: Liu
authors: Deling
authors: D
authors: Kong
authors: Anjie
authors: A
authors: Dong
mesh_terms: D000818:Animals; D001622:Betaine / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016023:Integrins / Q000737:chemistry*; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D016023:Integrins; D009842:Oligopeptides; D011108:Polymers; D011109:Polymethacrylic Acids; C517178:polycarboxybetaine methacrylate; D001622:Betaine; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin