Source Datas.xlsx

BackgroundSurface engineering emerges as a promising strategy to enhance the performance of nanomedicines. In particular, the level of PEGylation in prodrug nanoassemblies plays a crucial role in determining their stability, drug release kinetics, cytotoxicity, cellular uptake, <i>in vivo</i> pharmacokinetics, biodistribution and antitumor efficacy.MethodsWe systematically evaluated the effect of surface engineering ratios (0% NPs, 5%, 20%, 40%, 60% 80%, 100%, 150%, 200%, W_DSPE-mPEG2k/W_prodrug) on the SN38 prodrug nanoassemblies. Drug release kinetics were measured using high-performance liquid chromatography (HPLC), while cytotoxicity was assessed via the MTT assay. Cellular uptake was accurately quantified using an HPLC-MS-8060 system. In vivo pharmacokinetics were evaluated in Sprague-Dawley (SD) rats, and the biodistribution and antitumor efficacy were assessed using a CT26 colon tumor model established in Balb/c mice. Additionally, we examined intestinal toxicity to evaluate the safety profile.ResultsAlthough all of these ratios could form nanoparticles, 80% NPs showed excellent stability, cytotoxicity, and cellular uptake. However, 80% NPs were quickly cleared by the mononuclear phagocyte system (MPS) <i>in vivo</i>, causing SN38 leakage and intestinal toxicity. In comparison, 150% NPs maintained structural integrity in systemic circulation due to their sufficient PEGylation level, which allowed for significant accumulation at the tumor site through the enhanced permeability and retention (EPR) effect.Conclusions150% NPs exhibited the best antitumor effect and the lowest intestinal toxicity. Our findings underscore the critical impact of PEGylation levels to enhance the performance and safety of SN38 prodrug nanoassemblies.