Prodrug nanoassembly technology for colorectal cancer therapy

The clinical efficacy of Irinotecan is constrained by individual variability in its enzymatic conversion to the active metabolite, SN38. While direct administration of SN38 bypasses this enzymatic process and demonstrates potent anti-tumor activity, its clinical application remains hindered by poor physicochemical properties and off-target toxicity. These challenges highlight the necessity for efficient drug delivery strategies. Prodrug nanoassemblies combine the advantages of nano drug delivery technology and prodrug strategy, offering an effective approach to address these limitations. The modification module in prodrug design plays a critical role in imparting prodrugs self-assembly ability. Monomethyl branched-chain fatty acids (mmBCFAs), known for their biocompatibility and metabolite safety, show great potential as a worthy option. In this study, we designed and synthesized SN38-SS-BAc 18 by incorporating 16-methylheptanoic acid (BAc 18 ) as the modification module, and a disulfide bond as the responsive module for tumor-specific activation. The resulting SN38-SS-BAc 18 significantly improved the undesirable physicochemical properties of SN38 and exhibited enhanced self-assembly performance. Due to its prolonged circulation time, high tumor accumulation, and specific release profiles, the prodrug nanoassemblies (SN38-SS-BAc 18 NPs) exhibited superior anti-tumor efficacy and biosafety. This study addressed multiple therapeutic limitations of SN38 and Irinotecan, providing valuable insights for the rational design of efficient prodrug nanoassemblies for colorectal cancer treatment.