Prodrug-Based Cascade Self-Assembly Strategy for Precisely Controlled Combination Drug Therapy

The development of codelivery systems for combination therapy that can load different drugs in a single carrier and precisely deliver payloads (ratio and administration time) via programmable administration has proven to be challenging. By taking advantage of the increased dimension or space from particle self-assembly approach, we have developed a prodrug-based cascade self-assembly strategy to construct a supramolecular hydrogel that can load different drugs in stages yet temporally/spatially release drugs by cascade disassembly of supramolecular hydrogel under different microenvironments. The cascade self-assembly mechanism has been investigated in detail by morphology evolution of prodrug micelles. Using tumor cell uptake, cytotoxicity assay, and a tumor-bearing animal model, the effectiveness of the prodrug micelle-based cascade self-assembly system was studied, such as loading, controlling the drug ratio, and the administration time for possible therapeutic applications. These studies fully demonstrate the proof of concept and open up an attractive new way to construct multidrug-loaded carriers for combination therapy.