Lipid-assisted PEG-b-PLA nanoparticles with ultrahigh SN38 loading capability for efficient cancer therapy†

The topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin (SN38), has demonstrated potent anticancer activity. However, its clinical application is hindered by its low solubility and high crystallization propensity, which further complicates its encapsulation into nanoparticles for systemic delivery. Herein, we explore the utilization of lipid-assisted poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) nanoparticles to achieve ultrahigh loading capability for SN38. Through the introduction of cationic, anionic, or neutral lipids, the SN38 loading efficiency and loading capacity is elevated to >90% and >10% respectively. These lipids efficiently attenuate the intermolecular π–π stacking of SN38, thereby disrupting its crystalline structure. Moreover, we assess the therapeutic activity of SN38-loaded formulations in various tumor models and identify an anionic lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium salt (DOPG)-assisted formulation that exhibits the highest anticancer activity and has favorable biosafety. Overall, our findings present a simple and robust strategy to achieve ultrahigh loading efficiency of SN38 using commonly employed PEG-b-PLA nanoparticles, opening up a new avenue for the systemic delivery of SN38.