Branched module-modified SN38 prodrug nanoassemblies for improved colorectal cancer therapy: Effectively balance efficacy and safety

The clinical utility of irinotecan is restricted by individual variability in carboxylesterase expression. Direct administration of its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN38), presents an appealing alternative due to its potent anti-tumor efficacy. However, the undesirable properties of SN38, such as poor water solubility and non-target toxicity, present significant hurdles to its clinical development. Prodrug nanoassemblies based on modular design strategy show promise in overcoming these challenges by enhancing drug delivery and selective activation. In modular design, the modification module plays a crucial role in improving the self-assembly capability of prodrugs. While current studies mainly focus on using straight aliphatic chains for prodrug design, branched aliphatic chains emerge as superior alternatives warranting further investigation. In this study, we selected 2-heptylundecanol (BAlc₁₈) as modification module to construct an SN38 prodrug. Through exquisite design, SN38-SS-BAlc₁₈ NPs integrated prominent properties in self-assembly capability, specific activation and biocompatibility, resolving the challenges of irinotecan and SN38, ultimately demonstrating excellent anti-tumor efficacy. This exploration enriched the design theory of prodrug nanoassemblies that can effectively balance safety and colorectal anti-tumor efficacy.