pH/reduction dual-responsive hyaluronic acid-podophyllotoxin prodrug micelles for tumor targeted delivery

Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are in great demand for enhanced cancer treatment. Hyaluronic acid (HA), which has excellent biocompatibility and targeting ability for cluster determinant 44 (CD44), has been proposed for delivering drugs that have poor solubility and high toxicity. Herein, podophyllotoxin (PPT) was conjugated to HA via ester and disulfide linkages to construct a pHand reduction-responsive prodrug (HA-S-S-PPT). The micelles self-assembled from HA-S-S-PPT prodrug efficiently accumulated at tumor site due to HA receptor-mediated endocytosis. HA-S-S-PPT micelles exhibited 33.1% higher cumulative release than HA-NH-CO-PPT micelles (sensitive only to pH) owing to their dual responsiveness to pH and reduction. HA-S-S-PPT micelles achieved excellent antitumor activity in vivo, with the tumor inhibition rate reaching 92%, significantly higher than that of HA-NH-CO-PPT micelles (65%), and negligible systemic toxicity. This controllable-targeting nanoparticle system provides a potential platform for clinical application of PPT.

Automated summary

Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are highly desirable for improving cancer treatment. Hyaluronic acid (HA), known for its excellent biocompatibility and targeting ability for CD44, has been suggested as a carrier for delivering drugs with poor solubility and high toxicity. In this study, podophyllotoxin (PPT) was conjugated to HA through ester and disulfide linkages to create a pH and reduction-responsive prodrug (HA-S-S-PPT). Micelles self-assembled from HA-S-S-PPT efficiently accumulated at the tumor site due to HA receptor-mediated endocytosis. These micelles exhibited 33.1% higher cumulative release compared to HA-NH-CO-PPT micelles, which were only sensitive to pH. HA-S-S-PPT micelles demonstrated excellent antitumor activity in vivo, with a tumor inhibition rate of 92%, significantly higher than that of HA-NH-CO-PPT micelles (65%), and minimal systemic toxicity. This controllable-targeting nanoparticle system presents a potential platform for the clinical application of PPT.