Synthesis and Antitumor Mechanism of a Fluorescent Cyclic Peptide Selectively Targeting Integrin αvβ3 on...

The cyclic peptide GG-8-6: cyclo-(VLLLIPLVL) isolated from Goniothalamus griffithii (Annonaceae family), exhibited significant antihepatocellular carcinoma (HCC) activity. To enhance its tumor targeting and bioavailability, we designed and synthesized a fluorescent RGD-modified cyclic peptide, CP38 (cyclo-(VLLLIPLVRGDK)-5Fam), which selectively recognized the αvβ3 integrin. CP38 preferentially accumulated in αvβ3-overexpressing HCC cells (MHCC97H and HCCLM3) and showed significant cytotoxicity with IC₅₀ values of 6.39 and 10.78 μM, respectively, while sparing αvβ3-low HEK293T normal cells. In vivo, CP38 achieved a remarkable tumor inhibition rate of 80.5%, comparable to that of sorafenib. Mechanistic studies revealed that CP38 induced 97H cell apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway. Furthermore, transcriptomic analysis indicated that CP38 probably exerted its effects by regulating genes associated with the cancer proteoglycans and the TNF signaling pathway. These findings indicate that CP38 is a promising targeted therapeutic candidate for HCC with favorable selectivity and biosafety.