Polypeptides are a highly promising carrier for delivering hydrophobic drugs, due to their excellent biocompatibility, non-toxicity, and non-immunogenicity. Herein, a redox and pH dual-responsive poly(ethylene glycol)-SS-b-polypeptide micelles encapsulated with disulfide bridged paclitaxel-pentadecanoic acid prodrug was developed for cancer chemotherapy. First of all, disulfide bridged paclitaxel-pentadecanoic acid prodrug (PTX-SS-COOH) and poly(ethylene glycol)-SS-b-polylysine-b-polyphenylalanine (mPEG-SS-b-PLys-b-PPhe, ESLP) were synthesized and confirmed via NMR, MS, FT-IR or GPC. After that, PTX-SS-COOH (PSH) embedded mPEG-SS-b-PLys-b-PPhe (ESLP/PSH) micelles were prepared by mixing method based on electrostatic interactions and hydrophobic forces. For comparison, mPEG-b-PLys-b-PPhe (ELP) was mixed with PTX-SS-COOH to generate another kind of micelles (ELP/PSH). The characterization of ESLP/PSH micelles through dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed a spherical structure with a diameter of approximately 170 nm. It is noteworthy that ESLP/PSH micelles displayed a high drug-loading rate of 22.84%, and excellent stability, which can be attributed to the specific interactions between the prodrug and copolymer. Drug release analysis demonstrated that the micelles exhibited a substantial release of PTX in the presence of GSH at pH 5.0, indicating a pH and redox dual responsiveness. In vivo pharmacokinetic study revealed the ESLP/PSH micelles had increased bioavailability and an extended circulation time. Ultimately, antitumor efficacy and systemic toxicity evaluation in 4T1 tumor-bearing mice confirmed that ESLP/PSH micelles achieved the highest level of tumor growth inhibition (ca. 83%) and the lowest systemic toxicity in comparison with ELP/PSH micelles and commercialized Taxol®. Taken together, the dual responsive micelles represent a promising PTX formulation with potential clinical application in cancer chemotherapy.
Copyright © 2023. Published by Elsevier B.V.