Larotaxel (LTX), a next-generation taxane chemotherapeutic agent, demonstrates broad-spectrum antitumor activity and enhanced efficacy against resistant cancers compared to paclitaxel in clinical studies. To overcome delivery challenges and exploit the tumor microenvironment, LTX was conjugated via disulfide bonds to 2-hydroxy-1,3-bis(alkanoyl) glyceride to form prodrugs with different fatty acid chain lengths of triglyceride, LTX-SS-TG(C8) and LTX-SS-TG(C16). These dual-stimuli responsive prodrugs were designed for rapid, complete LTX release triggered by elevated glutathione (GSH) and lipase activity within tumors. Albumin is considered as an ideal drug carrier due to its biocompatibility and ligand-binding domains. We co-assembled the prodrugs with albumin and optimized the nanoparticle formation. Our findings revealed that alkanoyl chain length critically governed prodrug-albumin binding affinity, and improved the in vivo pharmacokinetic profile of nanoparticles. Specifically, the LTX-SS-TG(C16) NPs demonstrated superior albumin assembly, resulting in nanoparticles with an area under the curve (AUC) 12.99 times higher than that of the LTX solution. And these nanoparticles achieved improved tumor-specific distribution, potent antitumor efficacy, and significantly improved safety. This study provides a novel strategy for optimizing LTX delivery via albumin-based prodrug nanoparticles, broadening its potential for clinical application.

The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells. However, the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions. Supplementing with an additional reductant is a promising strategy to further boost drug release. Herein, inspired by the specific absorption mechanism of triglyceride fat, structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin (SN38) were designed to improve intestinal permeability and bypass the first-pass effect. SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract. Surprisingly, we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38, indicating an effective oral delivery. In addition, the reduction-responsive disulfide bond was used as a linker, and ascorbic acid (ASC) was coadministrated to further promote the efficient release of SN38 from the prodrug. ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety. In summary, the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.