Esterase-triggered rapid release of succinic anhydride conjugated curcumin co-prodrug for osteosarcoma therapy

Osteosarcoma (OS) is one of the most common primary bone malignancies in children and adolescents worldwide. The serious side effects and multi-drug resistance of high-dose chemotherapy have become the major cause of the failure in OS treatment. Curcumin (Cur) is reported to selectively kill OS cells and has a low cytotoxicity on healthy osteoblasts, but its delivery remains a great challenge. Herein, a co-polymer-Cur prodrug (co-prodrug) was developed by polymerizing Cur with hydrophilic polymer modified by succinic anhydride (SA) to explore the physicochemical properties, drug release and potential biological effects for OS treatment. This design endowed the co-prodrug with excellent solubility and stability under different solution conditions (pH = 4.5, 7.4 and 8.5), and improved the release efficiency of reactive oxygen species. Interestingly, co-prodrug exhibited an esterase-triggered rapid drug release in a concentration-dependent manner rather than the well-known acid response. Moreover, co-prodrug could be internalized into cells through endocytosis and significantly inhibit the proliferation of OS cells. Additionally, co-prodrug had no obvious systemic toxicity, and could suppress the OS growth by promoting apoptosis, inhibiting proliferation activity and vascularization in vivo. Our research furnishes a fresh perspective for the formulation design of controlled release of insoluble and instable anticancer agents within tumor cells.