Enzyme and Reduction Dual-Responsive Peptide Micelles as Nanocarriers for Smart Drug Delivery

Chemotherapy remains the primary treatment for cancer; however, conventional chemotherapeutic drugs have several shortcomings, including poor solubility, lack of targeting, low bioavailability, and high toxicity to healthy tissues. In order to overcome these limitations, drug delivery systems (DDS) have emerged as a promising alternative. In this study, we synthesized TPGS3350-PVGLIG-SS-DOX polymeric micelles that incorporate both extracellular MMP2/9 enzyme response and intracellular reduction response at a nanoscale level. The micelles remained stable throughout the blood circulation and only aggregated at the tumor sites, thanks to the enhanced permeability and retention (EPR) effect. Moreover, the tumor tissue showed a high expression of MMP2/9 enzymes, which resulted in the cleavage of the PVGLIG peptide sequence, ultimately leading to an improved phagocytosis efficiency. Under the action of high intracellular GSH concentration, the disulfide bond was broken and DOX was released to induce tumor cell death. The TPSD&D micelles exhibited good tumor inhibitory activity in vivo and significantly reduced toxic side effects on normal tissues. Our work provides a simple method to assemble tumor-targeted prodrug micelles to improve cancer therapy, which holds potential for clinical applications in antitumor therapy.