Tumor targeting by doxorubicin-RGD-4C peptide conjugate in an orthotopic mouse hepatoma model.
Vascular targeting is a novel strategy that directs endothelial toxins at tumor vessels expressing specific markers and kills tumor cells by vascular occlusion. Integrin-binding RGD motif has been reported to have a homing property to experimental tumor vasculature. In the present study, we evaluated the effect of vascular targeting by doxorubicin-RGD-4C conjugate in an orthotopic murine hepatoma model. MTT assay showed that dox-RGD-4C conjugates had lower cytotoxicity against MH134 mouse hepatoma cells than free dox. When given intravenously to mice with implanted orthotopic hepatoma, however, the dox-RGD-4C suppressed the growth of hepatoma more effectively than free dox (mean tumor volumes 24 mm(3) vs. 67 mm(3), respectively; p=0.047). Histologic analysis of the hepatoma tissue revealed prominent tumor cell death in the dox-RGD-4C treated group and complete tumor cell necrosis in 40% of cases. Immunochemical staining showed expression of integrin alphav mainly around the tumor nodule. These results show that dox-RGD-4C conjugate has a better antitumor effect in an orthotopic mouse hepatoma model by tumor targeting. Integrin alphav of hepatoma feeding vessels is suggested to be targeted by the dox-RGD-4C conjugate.
Kim
Jin-Wook
JW
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul 100-744, South Korea.
Lee
Hyo-Suk
HS
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C109961:doxorubucin cysteinyl-aspartyl-cysteinyl-arginyl-glycyl-aspartyl-cycsteinyl-phenylalanyl-cysteine conjugate; D004317:Doxorubicin