Zwitterionic Nanoparticles Constructed with Well-Defined Reduction-Responsive Shell and pH-Sensitive Core for 鈥淪patiotemporally Pinpointed鈥?Drug Delivery
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- 作者：Pingsheng Huang ; Jinjian Liu ; Weiwei Wang ; Chen Li ; Junhui Zhou ; Xue Wang ; Liandong Deng ; Deling Kong ; Jianfeng Liu ; Anjie Dong
- 刊名：ACS Applied Materials & Interfaces
- 出版年：2014
- 出版时间：August 27, 2014
- 年：2014
- 卷：6
- 期：16
- 页码：14631-14643
- 全文大小：958K
- ISSN：1944-8252
文摘
Enabling nanocarriers to complete the sophisticated journey from the initial injection site to the targeted tumor cells and achieve 鈥渟patiotemporally pinpointed鈥?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.