Construction Of Fusion Proteins Based On IRGD Peptides And Their Targeted Anti-tumor Effects

Tumor-penetrating Peptide Fused to a Proapoptotic Peptide Facilitates Effective Gastric Cancer TherapyBackground:KLAKLAKKLAKLAK(KLA)is a peptide which may lead to programmed cell death by disrupting the mitochondrial membrane.However,low penetration in tumors greatly limits its application and efficacy.Methods:To develop a KLA-based cancer therapy,KLA-iRGD,a recombinant protein was constructed.It consists of the KLA peptide and iRGD(CRGDKGPDC),a tumor-homing peptide with high penetration into tumor tissue and cells.Results:The conjugated KLA exhibits proapoptotic activity to prevent the growth of tumor once it is inside the cell.Once KLA-iRGD is internalized in cultured tumor cells,via the activation of the receptor neuropilin-1,it spreads extensively throughout the mass of tumor.The recombinant KLA-iRGD protein showed antitumor activity in vivo in mice and in vitro in tumor cell lines.The repeated treatment with KLA-iRGD greatly prevented the growth of tumor,resulting in a considerable reduction in the tumor volume.Conclusions:According to our data,KLA-iRGD serves as a potential anti-cancer agent with limited systemic toxicity and high selectivity to treat MKN45 gastric cancer,which might lead to the enhancement of new targeted anticancer agents.Tumor-specific peptide fused TRAIL is a promising therapeutic agent for gastric cancer treatmentBackground:Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)can selectively kill tumor cells and enhance therapy in vivo.However,concerns regarding its considerable liver toxicity limit its use in humans as a cancer therapy.Methods:To develop TRAIL into a cancer therapeutic,we constructed a recombinant protein named sTRAIL-iRGD consisting of the sTRAIL fused to iRGD(CRGDRGPDC),which is a tumor-homing peptide with high tumor penetrability and cell internalization.Results:sTRAIL-iRGD internalized into cultured tumor cells through a neuropilin-l-activated pathway,spreads extensively throughout both the multicellular spheroids and the tumor mass.The recombinant protein sTRAIL-iRGD also exhibited antitumor activity in tumor cell lines,multicellular spheroids,and mice.The repeated treatment with sTRAIL-iRGD greatly prevented the growth of tumor,resulting in a considerable reduction in the tumor volume.We demonstrated the therapeutic efficacy of sTRAIL-iRGD combined with Paclitaxel(PTX)could be further enhanced.These mice showed no sign of sTRAIL-iRGD-related liver toxicity.Conclusions:Our data suggest that sTRAIL-iRGD is a promising agent with high selectivity and limited systemic toxicity for gastric cancer treatment,which may lead to the development of novel,targeted anticancer agents.