Abstract
The co-delivery of drug combination at a controlled ratio via the same vehicle to the cancer cells is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and increased therapeutic potency. In an attempt to develop such multidrug vehicle this work focuses on functional biodegradable and biocompatible polypeptide-based polymeric micelles. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG-PGlu-PPhe) were successfully synthesized via NCA-based ring-opening copolymerization and their composition was confirmed by (1)H NMR. Self-assembly behavior of PEG-PGlu90-PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked (cl) micelles were about 90nm in diameter (ξ-potential=-20mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of cl-micelles was observed in the presence of proteolytic enzymes (cathepsin B). The resulting cl-micelles can incorporate the combination of drugs with very different physical properties such as cisplatin (15 w/w% loading) and paclitaxel (9 w/w% loading). Binary drug combination in cl-micelles exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded micelles or free cisplatin in cancer xenograft model in vivo. Tunable composition and stability of these hybrid biodegradable micelles provide platform for drug combination delivery in a broad range of cancers.