Enzymatic synthesis of PEG-poly(amine-co-thioether esters) as highly efficient pH and ROS dual-responsive nanocarriers for anticancer drug delivery

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Materials for biology and medicine, 2019-01, Vol.7 (4), p.651-664
• Main Authors: Gong, Yi-Hong, Shu, Man, Xie, Jian-Hua, Zhang, Chao, Cao, Zhong, Jiang, Zhao-Zhong, Liu, Jie
• Format: Article
• Language: English
• Subjects: Amino groups; Antineoplastic drugs; Antitumor agents; Aqueous solutions; Biocompatibility; Biodegradability; Biodegradation; Block copolymers; Cancer; Chemical synthesis; Controlled release; Drug delivery; Drug delivery systems; Encapsulation; Enzymatic synthesis; Esters; Hydrophobicity; Kidneys; Liver; Nanoparticles; Organs; Oxidation; pH effects; Protonation; Reactive oxygen species; Toxicity; Tumor cells; Tumors; Xenografts
• ISSN: 2050-750X; 2050-7518
• DOI: 10.1039/c8tb02882f

Novel multifunctional drug nanocarriers have been successfully fabricated from a new type of enzymatically synthesized, biodegradable block copolymer, PEG-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-thiodipropionate) (PEG-PPMT), which was responsive to tumor-relevant acidic pH (5.0-6.5) and intracellular reactive oxygen species (ROS) of tumor cells. The PEG-PPMT copolymers could self-assemble to form nano-scaled particles in aqueous solutions, which are stable in physiological solutions, but swell substantially upon reducing the pH from 7.4 to 5.0 and/or in the presence of ROS on account of the protonation of the tertiary amino groups and oxidation of the thioether groups, causing a hydrophobic to hydrophilic transition in the nanoparticle cores. Consistently, docetaxel (DTX) encapsulated in PEG-PPMT nanoparticles can be triggered in a synergistic manner by acidic pH and a high-ROS environment in tumor cells to release the hydrophobic drug at accelerated rates for efficient tumor growth inhibition. In particular, DTX encapsulated in PEG-PPMT-11% PDL and PEG-PPMT-28% PDL nanoparticles exhibit extraordinarily enhanced potency (95% and 93% tumor-inhibiting efficiency, respectively) in inhibiting the growth of ROS-rich CT-26 tumors xenografted in mice. Importantly, biosafety analyses show minimal toxicity of DTX-loaded PEG-PPMT nanoparticles toward normal organs including liver and kidneys during the in vivo antitumor treatments. These results demonstrate that the PEG-PPMT nanoparticles are promising pH and ROS dual-responsive multifunctional nanocarriers for tumor site specific, controlled release of anticancer drugs to treat ROS-rich tumors.