title: Zwitterionic nanoparticles constructed with well-defined reduction-responsive shell and pH-sensitive core for "spatiotemporally pinpointed" drug delivery.
abstract: Enabling nanocarriers to complete the sophisticated journey from the initial injection site to the targeted tumor cells and achieve "spatiotemporally pinpointed" drug release intracellularly is a challenging task in anticancer drug delivery. Herein, versatile shell-cross-linked nanoparticles (SCNPs) were prepared by one-step assembly of triblock zwitterionic copolymers, polycarboxybetaine methacrylate-block-poly(N-(2-(2-pyridyl disulde) ethyl methacrylamide-block-poly(2-(diisopropylamino) ethyl methacrylate) (PCB-b-PDS-b-PDPA, termed as PCSSD), which was well-defined via reversible additive fragment transfer (RAFT) polymerization, followed by functionalization with Arg-Gly-Asp (RGD). Thus, the RGD-PCSSD SCNPs cooperatively combine the ultra pH-sensitive PDPA core for efficient drug loading and pH-responsive drug release, the disulfide-cross-linked PDS shell that prevents premature drug release, the zwitterionic PCB corona to stabilize the SCNPs and prolong its systemic circulation, the RGD ligand for active tumor targeting and receptor-mediated endocytosis. Doxorubicin (DOX) was loaded as a model medicine (termed as RGD-PCSSD/DOX SCNPs). The dual-sensitivity studies showed that the pH-sensitivity of PDPA core could be adjusted by the shell-cross-linking density, accompanied by better control over premature drug release. Furthermore, results obtained by flow cytometry and fluorescence microscopy analysis demonstrated that once the RGD-PCSS10D/DOX SCNPs were internalized into tumor cells via receptor-mediated endocytosis, boost drug release was observed with considerable cytotoxicity in vitro. The results of ex vivo imaging studies further confirmed the successful drug delivery from the injection site to the tumor tissue. In summary, the well-constructed RGD-PCSS10D/DOX SCNPs with cooperative multifunctionality showed great potential as novel nanocarriers for tumor targeted anticancer drug delivery.
authors.affiliation: 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.forename: Pingsheng
authors.initials: P
authors.lastname: Huang
authors.forename: Jinjian
authors.initials: J
authors.lastname: Liu
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhou
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Liandong
authors.initials: L
authors.lastname: Deng
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Anjie
authors.initials: A
authors.lastname: Dong
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D004317:Doxorubicin