title: In situ crosslinked smart polypeptide nanoparticles for multistage responsive tumor-targeted drug delivery.
abstract: Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(L-lysine)-b-poly(L-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around -30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR(+)) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR(+) HeLa and FR(-) A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD-NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy.
authors.affiliation: Guangdong Key Laboratory of Nanomedicine, Key Lab for Health Informatics of Chinese Academy of Sciences, Shenzhen Institutes of Advance Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China. lt.cai@siat.ac.cn.
authors.forename: Huqiang
authors.initials: H
authors.lastname: Yi
authors.affiliation: Guangdong Key Laboratory of Nanomedicine, Key Lab for Health Informatics of Chinese Academy of Sciences, Shenzhen Institutes of Advance Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China. lt.cai@siat.ac.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Guangdong Key Laboratory of Nanomedicine, Key Lab for Health Informatics of Chinese Academy of Sciences, Shenzhen Institutes of Advance Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China. lt.cai@siat.ac.cn.
authors.forename: Nan
authors.initials: N
authors.lastname: Sheng
authors.affiliation: Guangdong Key Laboratory of Nanomedicine, Key Lab for Health Informatics of Chinese Academy of Sciences, Shenzhen Institutes of Advance Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China. lt.cai@siat.ac.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Guangdong Key Laboratory of Nanomedicine, Key Lab for Health Informatics of Chinese Academy of Sciences, Shenzhen Institutes of Advance Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China. lt.cai@siat.ac.cn.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Guangdong Key Laboratory of Nanomedicine, Key Lab for Health Informatics of Chinese Academy of Sciences, Shenzhen Institutes of Advance Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China. lt.cai@siat.ac.cn.
authors.forename: Lintao
authors.initials: L
authors.lastname: Cai
mesh_terms: D000072283:A549 Cells; D000812:Anhydrides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry*; D053138:Cyclohexenes / Q000737:chemistry; D004318:Doxycycline / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005492:Folic Acid / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy*; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D011107:Polylysine / Q000737:chemistry
chemical_list: D000812:Anhydrides; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D053138:Cyclohexenes; D004337:Drug Carriers; D010455:Peptides; C052568:cyclohexene; D011107:Polylysine; C057713:polycysteine; D005492:Folic Acid; D004318:Doxycycline