Polylactide-tethered SN38 prodrugs in polymeric nanoparticles as reliable nanomedicines for the treatment of cervical cancer

Background Cervical cancer remains a major global health burden, and current chemotherapeutic options are limited by poor efficacy and severe toxicity. Irinotecan (CPT-11) exerts its antitumor activity via its active metabolite, SN38, a topoisomerase I inhibitor that disrupts DNA synthesis. However, the clinical utility of CPT-11 is compromised by its poor aqueous solubility, low in vivo conversion efficiency to SN38, and significant systemic toxicity. Although nanotechnology has been used to improve the delivery of SN38, the existing nanocartors still have the defects of insufficient tumor targeting and low cellular uptake, highlighting the need to optimize the drug delivery system. This study aims to develop 2SN38-PLA@PEG1 _0k -PLA _20k nanodrugs and evaluate their in vitro and in vivo antitumor efficacy against cervical cancer, in order to provide new insights into optimizing drug delivery systems and improving clinical outcomes in cervical cancer therapy. Methods We synthesized and characterized 2SN38-PLA prodrugs, then prepared three poly(ethylene glycol)-polylactic acid (PEG-PLA) copolymers with varying chain lengths (PEG _2k -PLA _2k , PEG _5k -PLA _8k , and PEG10k-PLA _20k ) via nanoprecipitation to screen the optimal formulation. We then determined the physicochemical properties of these nanodrugs. In vitro evaluations were carried out to assess cellular uptake, cytotoxicity, apoptosis, and cell cycle distribution, while in vivo therapeutic efficacy and biosafety were evaluated using a TC-1 cell-derived subcutaneous xenograft model established in C57BL/6 mice. Results 2SN38-PLA@PEG _10k -PLA _20k nanoparticles exhibited stable physicochemical stability. In vitro, the nanodrugs were efficiently internalized by cervical cancer cells, showing lower IC ₅₀ values against cervical cancer cell lines and reduced toxicity compared to CPT11. Mechanistically, the nanodrugs induced DNA damage, which in turn triggered cell cycle arrest and apoptotic cell death. In vivo experiments, the nanodrugs significantly inhibited xenograft tumor growth, prolonged the mouse survival, and showed no obvious systemic toxicity, confirming the favorable biosafety. Conclusion 2SN38-PLA@PEG _10k -PLA _20k nanoparticles emerge as a highly efficient and biocompatible nanodrug with robust antitumor activity against cervical cancer, validated both in vitro and in vivo. This study provides a solid preclinical foundation for the translational application of the nanodrug, thereby facilitating the optimization of cervical cancer therapeutic outcomes.