Hydroxyethyl starch-based enzyme/pH dual-responsive polymer prodrug micelles for improved stability and antitumor efficacy of 10-hydroxycamptothecin

An enzyme/pH dual-responsive HES-10-HCPT prodrug micelle was developed. • The micelles achieved high drug loading (20%) and good stability. • Drug release was accelerated under acidic pH and enzymatic conditions. • HH-2 showed 42.5-fold lower IC50 than free 10-HCPT in 4T1 cells. • HH-2 achieved 52.22% tumor inhibition. Cancer remains a major global public health challenge, posing a substantial threat to human health and socioeconomic development. 10-hydroxycamptothecin (10-HCPT), a potent topoisomerase I inhibitor, exhibits broad antitumor activity; however, its clinical application is limited by poor aqueous solubility, rapid lactone-ring opening under physiological pH, and low bioavailability. To address these limitations, we developed an enzyme- and pH-dual-responsive polymer prodrug nanocarrier based on hydroxyethyl starch (HES). 10-HCPT was conjugated to the HES backbone through a hydrolysable succinate ester linkage, yielding an amphiphilic HES-10-HCPT prodrug capable of self-assembling into micelles. The resulting polymer prodrug micelles exhibited favorable storage and plasma stability. Importantly, drug release was accelerated under acidic and enzymatic conditions, suggesting tumor microenvironment-responsive release behavior. In vitro cytotoxicity assays against 4T1 breast cancer cells showed that the high-drug-loading micelles, HH-2, displayed markedly enhanced potency, with an IC50 value of 0.651 μg/mL, compared with free 10-HCPT, which showed an IC50 value of 27.7 μg/mL. In vivo studies in 4T1 tumor-bearing mice demonstrated that, at an equivalent 10-HCPT dose, HH-2 achieved a tumor inhibition rate of 46.31%, compared with 19.70% for free 10-HCPT. Histological analysis further suggested a favorable preliminary safety profile. Overall, this HES-based polymer prodrug micelle system provides a promising strategy for improving the stability, therapeutic efficacy, and safety of 10-HCPT and may serve as a potential platform for cancer chemotherapy. Download: Download high-res image (67KB) Download: Download full-size image