Anti-tumor effects of a novel cell penetrating peptide-based therapeutic approach to target Lactate Dehydrogenase C (LDHC) in triple negative breast cancer.

BackgroundLactate Dehydrogenase C (LDHC) is a promising candidate for therapeutic targeting thanks to its highly tumor-specific expression, immunogenicity, and pro-tumorigenic functions. Aberrant LDHC expression is associated with poor clinical outcomes in multiple cancers, including breast cancer. However, no specific LDHC inhibitors are currently available, highlighting the need for novel strategies to selectively target LDHC in tumor cells. This study explores the anti-tumor potential of cell-penetrating peptides (CPPs) to target LDHC in triple negative breast cancer (TNBC). MethodsFour CPPs were evaluated for their ability to deliver LDHC siRNA to tumor cells, including the positively charged 10R peptide (10R) and three bifunctional peptides containing the integrin v{beta}3 recognition motif Arg-Gly-Asp (RGD): 10R-RGD, cyclicRGD-10R (cRGD-10R), and internalizing RGD-10R (iRGD-10R). We characterized the physicochemical properties of all CPP:siRNA complexes, and determined their serum stability, cytotoxicity, cellular uptake, and LDHC silencing efficiency in vitro. The anti-tumor effects and cytotoxicity of cRGD-10R:siRNA and iRGD-10R:siRNA complexes were further assessed in a TNBC xenograft zebrafish model. ResultsAll four CPPs formed stable nanocomplexes with favorable safety profiles. The 10R-RGD and cRGD-10R peptides demonstrated the most efficient LDHC knockdown, reduced the clonogenic ability of TNBC cells and enhanced their treatment response to the chemotherapeutic drug olaparib in vitro. Treatment of TNBC xenograft zebrafish with 10R-RGD:siRNA and cRGD-10R:siRNA complexes significantly reduced tumor burden without inducing major toxicity. Conclusion Our findings demonstrate that CPP-based siRNA delivery provides a novel and safe approach to target LDHC, either as a monotherapy or in combination with common anti-cancer drugs, to enhance treatment outcomes.