Transarterial administration of integrin inhibitor loaded nanoparticles combined with transarterial chemoembolization for treating hepatocellular carcinoma in a rat model.
OBJECTIVE
To compare the effect of transarterial chemoembolization (TACE) plus GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro, integrin-inhibitor) loaded nanoparticles with TACE alone or TACE + GRGDSP in a rat model of liver tumor.


METHODS
Morris hepatoma 3924A tumors were implanted in the livers of 30 ACI rats. The ACI rats were divided randomly into three groups (10 animals each). Tumor volume before treatment (V1) was examined by magnetic resonance imaging (MRI), and then, after laparotomy and placement of a PE-10 catheter into the hepatic artery, the following interventional protocols were performed: TACE (mitomycin C + lipiodol + degradable starch microspheres) + GRGDSP loaded nanoparticles for group A; TACE + GRGDSP for group B (control group 1); TACE alone for group C (control group 2). Tumor volume (V2) was assessed by MRI and the mean ratio of the post-treatment to pretreatment tumor volumes (V2/V1) was calculated. Immunohistochemical analysis was performed to assess the quantification of matrix metalloprotein 9 (MMP-9) and vascular endothelial growth factor (VEGF) positive tumor cells in each treatment group.


RESULTS
The mean tumor growth ratios (V2/V1) were 1.3649 ± 0.1194 in group A, 2.0770 ± 0.1595 in group B, and 3.2148 ± 0.1075 in group C. Compared with groups B and C, group A showed a significant reduction in tumor volume. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C. The angiogenesis of tumor was evaluated using anti-VEGF antibodies, and the metastasis of tumor was assessed using anti-MMP-9 antibody. MMP-9 and VEGF were expressed in all specimens. The immunoexpression of these proteins was confirmed by the presence of red cytoplasmic staining in tumor cells. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C.


CONCLUSIONS
Transarterial administration of integrin inhibitor loaded nanoparticles combined with TACE evidently retards tumor growth and intrahepatic metastases compared with TACE alone or TACE plus integrin inhibitor in an animal model of hepatocellular carcinoma.
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Jun
J
Qian
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Elsie
E
Oppermann
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Andreas
A
Tran
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Ulli
U
Imlau
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Kun
K
Qian
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Thomas Josef
TJ
Vogl
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D004998:Ethiodized Oil / Q000008:administration & dosage; D006499:Hepatic Artery; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles; D009842:Oligopeptides / Q000008:administration & dosage*; D011912:Rats, Inbred ACI; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A
D000970:Antineoplastic Agents; D016023:Integrins; D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D004998:Ethiodized Oil; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
ACI rats; Hepatocellular carcinoma; Integrin inhibitor; Matrix metalloprotein 9; Nanoparticles; Transarterial chemoembolization; Vascular endothelial growth factor