RGD-modified cyclic peptide CP38 achieves 80.5% tumor inhibition in αvβ3-positive hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths, with limited effective treatment options, especially for advanced stages. Current therapies like sorafenib often face challenges due to systemic toxicity and drug resistance. The αvβ3 integrin receptor is frequently overexpressed on the surface of HCC cells and tumor neovasculature, making it a promising target for selective drug delivery. Developing targeted agents that can specifically recognize and eliminate cancer cells while sparing healthy tissues is crucial for improving patient outcomes and reducing adverse effects.

Researchers designed and synthesized CP38 (cyclo-(VLLLIPLVRGDK)-5Fam), a fluorescent RGD-modified cyclic peptide, derived from the anti-HCC peptide GG-8-6. They evaluated its selectivity and cytotoxicity in αvβ3-overexpressing HCC cell lines (MHCC97H and HCCLM3) and αvβ3-low normal HEK293T cells using IC50 assays. In vivo, the antitumor efficacy of CP38 was assessed in a xenograft mouse model, comparing its tumor inhibition rate to that of sorafenib. Mechanistic studies involved apoptosis assays and transcriptomic analysis in 97H cells to elucidate underlying pathways.

The engineered cyclic peptide CP38 demonstrated selective recognition and preferential accumulation in αvβ3-overexpressing HCC cells. It exhibited significant cytotoxicity with IC50 values of 6.39 μM in MHCC97H cells and 10.78 μM in HCCLM3 cells, while showing minimal toxicity to αvβ3-low HEK293T normal cells. In an in vivo HCC model, CP38 achieved a remarkable tumor inhibition rate of 80.5%, which was comparable to the efficacy of sorafenib.

Mechanistic studies revealed that CP38 induced 97H cell apoptosis primarily through the suppression of the PI3K/Akt/mTOR signaling pathway. Furthermore, transcriptomic analysis indicated that CP38 likely exerts its effects by regulating genes associated with cancer proteoglycans and the TNF signaling pathway, suggesting a multi-faceted antitumor mechanism.