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PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery
Author(s) -
Yao Jiuxu,
He Pan,
Zhang Yu,
Zhang Hongyu,
Zhang Peng,
Deng Mingxiao,
Xiao Chunsheng
Publication year - 2019
Publication title -
polymer international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.592
H-Index - 105
eISSN - 1097-0126
pISSN - 0959-8103
DOI - 10.1002/pi.5892
Subject(s) - micelle , drug delivery , polylysine , peg ratio , copolymer , ethylene glycol , chemistry , nanocarriers , biophysics , doxorubicin , glutathione , combinatorial chemistry , materials science , polymer chemistry , organic chemistry , aqueous solution , polymer , medicine , surgery , finance , chemotherapy , economics , biology , enzyme
Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐ block ‐poly(ϵ‐propargyloxycarbonyl‐ l ‐lysine) (PEG 113 ‐ b ‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG 113 ‐ b ‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N ‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG 113 ‐ b ‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L –1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG 113 ‐ b ‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL –1 . In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry