Xu_2025_Bioorg.Chem_160_108411

The combination of chemo- and gene-therapy for lung cancer therapy has attracted continuous attention due to its high synergistic therapeutic efficiency. Here, three novel esterase-responsive prodrug-based amphiphiles, SCN1 - SCN3, composed of 7-ethyl-10-hydroxycamptothecin (SN38, S) and di-(triazole-[12]aneN(3), N) moiety through different length of carbon chain (C, 5, 7, 11carbon alkyl chains, respectively) were designed and synthesized. The amphiphiles displayed excellent self-assembly capabilities and the ability to effectively condense and release siRNA, and SCN2 showed the most effective in inhibiting proliferation of A549 cells. Furthermore, SCN2, siRNA, DOPE (D) and DSPE-PEG(2000)-Biotin (B) were co-assembled into hybrid nanoparticles (SCN2-DB/siRNA) with an average size of 198 nm, outstanding serum tolerance, high targeting capability, and biocompatibility. Additionally, the release of SN38 (80 %) and siPLK1 (abundant) were observed clearly in the presence of esterase. In vitro experiments verified that SCN2-DB/siPLK1 NPs could efficiently suppress the proliferation, migration, and invasion of A549 cells. In vivo experiments demonstrated that SCN2-DB/siPLK1 NPs efficiently inhibited tumor growth (90 %) with negligible toxic side effects. The results showed that the combination of SN38 and siPLK1 through esterase-responsive amphiphile provided a strategy for lung cancer therapy that combined chemotherapy, gene therapy, and targeted delivery.