Development and evaluation of gluconic acid-targeted liposomal doxorubicin for enhanced anti-tumor activity in colon cancer.

PEGylated liposomal doxorubicin (PLD) is widely used in cancer therapy, but its effectiveness is limited by poor tumor targeting. Given that glucose transporters are overexpressed in cancer cells, we explored gluconic acid (GA), a glucose derivative, as a novel targeting ligand for liposomal drug delivery. GA can be easily attached to liposomes, offering potential for improved cancer cell targeting. We created GA-modified PLD (PLD-GA) formulations with varying ligand densities (100, 200, and 400 GA molecules per liposome) and characterized their physicochemical properties, cellular uptake, and therapeutic efficacy. In BALB/c mice with C26 colon carcinoma, GA-modified liposomes showed enhanced cellular uptake and significantly better tumor growth inhibition compared to unmodified PLD, with PLD-GA200 achieving 99.1 % tumor growth delay versus 78.3 % for PLD. Biodistribution studies revealed that PLD-GA200 achieved enhanced tumor accumulation compared to unmodified PLD with minimal cardiac toxicity. Overall, GA-modified liposomes retained stability and size (∼110 nm) while significantly improving drug delivery to tumors. This study demonstrates GA as a promising new targeting ligand, providing a foundation for more effective liposomal drug delivery systems in cancer therapy.