Molecular tumor targeting of gelonin by fusion with F3 peptide  

作　　者：Song-Hee HAM Kyoung Ah MIN Meong Cheol SHIN 

机构地区：[1]College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam 660- 701, Republic of Korea [2]College of Pharmacy, Inje University, Gimhae, Gyeongnam 621- 749, Republic of Korea

出　　处：《Acta Pharmacologica Sinica》2017年第6期897-906,共10页中国药理学报（英文版）

摘　　要：Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs. But tumor cell-selective intracelluiar delivery of the macromolecules remains a major hurdle for their successful clinical application. To overcome this challenge, we engineered a novel genetic fusion protein （F3-Gel） that composed of F3 peptide, a tumor- homing peptide, and gelonin, a plant-derived ribosome-inactivating protein （RIP）, and then evaluated its anti-cancer activity in vitro and in vivo. The F3-Gel-encoding gene was synthesized by genetic recombination, and F3-Gel was successfully expressed in E coil The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays, which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity （IC5o=11 pmol/L） as unmodified gelonin （10~o=10 pmol/L）. Furthermore, F3-Gel displayed enhanced cellular uptake into cancer cells （U87 MG, HeLa, LnCaP and 9L） than noncancerous cells （293 HEK and SVGp12）. Compared with gelonin, F3-Gel exerted significantly higher cytotoxicity against these cancer cells. F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells： F3-Gel （0.5 pmol/L） was able to reduce the protein level to less than 50%, while gelonin （1 pmol/L） did not affect the intracellular protein level. In a U87 MG xenograft tumor-bearing mouse model, F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with geionin. Administration of F3-Gel （0.5, 0.75 mol/kg, iv） caused 36% and 66%, respectively, inhibition of tumor growth in U87 MG xenograft mice, suggesting that it is a promising candidate drug for cancer treatment. Furthermore, this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs. But tumor cell-selective intracelluiar delivery of the macromolecules remains a major hurdle for their successful clinical application. To overcome this challenge, we engineered a novel genetic fusion protein （F3-Gel） that composed of F3 peptide, a tumor- homing peptide, and gelonin, a plant-derived ribosome-inactivating protein （RIP）, and then evaluated its anti-cancer activity in vitro and in vivo. The F3-Gel-encoding gene was synthesized by genetic recombination, and F3-Gel was successfully expressed in E coil The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays, which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity （IC5o=11 pmol/L） as unmodified gelonin （10~o=10 pmol/L）. Furthermore, F3-Gel displayed enhanced cellular uptake into cancer cells （U87 MG, HeLa, LnCaP and 9L） than noncancerous cells （293 HEK and SVGp12）. Compared with gelonin, F3-Gel exerted significantly higher cytotoxicity against these cancer cells. F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells： F3-Gel （0.5 pmol/L） was able to reduce the protein level to less than 50%, while gelonin （1 pmol/L） did not affect the intracellular protein level. In a U87 MG xenograft tumor-bearing mouse model, F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with geionin. Administration of F3-Gel （0.5, 0.75 mol/kg, iv） caused 36% and 66%, respectively, inhibition of tumor growth in U87 MG xenograft mice, suggesting that it is a promising candidate drug for cancer treatment. Furthermore, this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.

关 键 词：GELONIN TOXIN F3 peptide selective tumor targeting GLIOBLASTOMA 

分 类 号：Q279[生物学—细胞生物学] O631.6[理学—高分子化学]