Alkanoyl-chain of glyceride modifications in Larotaxel to enhance albumin binding for improved safety and antitumor efficacy

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.