Cancer treatments have significantly advanced in recent years, marked by the development of highly potent chemotherapeutic drugs capable of targeting and eliminating cancer cells. However, significant challenges persist, such as limited stability, rapid intracellular degradation, and severe cytotoxicity towards healthy tissues. To address these issues, advanced drug delivery systems have been designed to enhance drug stability, improve target specificity, and reduce harmful side effects by selectively delivering therapeutic agents directly to cancer cells.
Peptide-based self-assemblies are particularly promising in this context due to their inherent biocompatibility, responsiveness, and ease of functionalization. Our project focuses on developing a drug delivery system capable of pH responsive dissociation near tumor sites, with in vitro tracking capabilities utilizing peptide self-assembly strategies. We have synthesized two rhodamine-B dipeptide conjugates, RhB-KK and RhB-KE, conjugated with the anticancer drug 5-fluorouracil via a succinic acid linker by using solid-phase peptide synthesis (SPPS) to get RhB-KK-Fu and RhB-KE-Fu. While RhB-KK and RhB-KE alone self-assemble into nanotubular structures, the RhB-KK-Fu and RhB-KE-Fu tend to form nanoparticles. Both RKK and RKE are pH sensitive as they exist in a nanotubular state at pH >4.6, and in a open-ring monomeric fluorescent state at pH<4.6, similar to the environment within tumor lysosomes (pH 4-4.5). This pH responsiveness allows the nanoparticle structures to selectively dissociate upon entering the cancer cell, thus enhancing the controlled and enzyme-mediated cleavage of the succinic acid linker and the targeted release of the therapeutic drug within cancer cells. Further extensions of our system are planned to explore the incorporation of arginine and tryptophan residues, which avoid lysosomal degradation, thereby significantly improving the efficiency of intracellular drug delivery within cancer cells.

Bingxun Li

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