Stimulus-Responsive Nano-Prodrug Strategies for Cancer Therapy: A Focus on Camptothecin Delivery

Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug-based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus-responsive CPT nano-prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus-responsive CPT nano-prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus-responsive CPT nano-prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano-prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected.