Efficient inhibition of ovarian cancer by recombinant CXC chemokine             ligand 10 delivered by novel biodegradable cationic heparin-polyethyleneimine             nanogels.
Currently, great interest is focused on the anti-neoplastic effects of CXC             chemokine ligand 10 (IP-10/CXCL10). IP-10 has shown significant antitumor and             anti-metastatic properties via immunological, antiangiogenic and anti-neoplastic             mechanisms. However, very few studies on the antitumor activity of IP-10 in human             ovarian cancer have been reported. The use of polymeric nanoparticles to deliver             functional genes intraperitoneally holds much promise as an effective therapy             for ovarian cancer. In our study, a recombinant plasmid expressing IP-10 (pVITRO-IP-10)             was constructed, and biodegradable cationic heparin-polyethyleneimine (HPEI) nanogels             were prepared to deliver pVITRO-IP-10 into SKOV3 human ovarian cancer cells. Transfection             efficiency was detected by expression profiling of green fluorescent protein.             The expression of IP-10 was determined using RT-PCR and western blot analysis.             In vitro, cell proliferation was evaluated by MTT assay. Apoptosis was examined             by Hoechst33258/PI staining and flow cytometry assays. The effect on the inhibition             of angiogenesis was evaluated by tube formation assay using human umbilical vein             endothelial cells (HUVECs). Moreover, a SKOV3 intraperitoneal ovarian carcinomatosis             model was established to investigate the antitumor activity of HPEI+pVITRO-IP-10             complexes in nude mice. Tumor weights were evaluated during the treatment course.             Cell proliferation and apoptosis were evaluated by Ki-67 immunochemical staining             and TUNEL assay, and the antiangiogenic effect of pVITRO-IP-10 was assessed by             CD31 immunochemical staining and alginate-encapsulated tumor cell assay. pVITRO-IP-10             was efficiently transfected into SKOV3 cells by HPEI nanogels. Intraperitoneal             administration of HPEI+pVITRO-IP-10 complexes led to effective growth inhibition             of ovarian cancer, in which tumor weight decreased by ~69.92% in the treatment             group compared with that in the empty vector control group. Meanwhile, decreased             cell proliferation, increased tumor cell apoptosis and reduction in angiogenesis             were observed in the HPEI+pVITRO-IP-10 group compared with those in the control             groups. These results indicated that HPEI nanogel delivery of pVITRO-IP-10 may             be of value in the treatment against human ovarian cancer.
Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, Sichuan, PR China.
Fan
F
Yang
Malin
M
Gou
Hongxin
H
Deng
Tao
T
Yi
Qian
Q
Zhong
Yuquan
Y
Wei
Xia
X
Zhao
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics*; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006493:Heparin / Q000008:administration & dosage / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000080385:Nanogels; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry; D014162:Transfection / Q000379:methods; D023041:Xenograft Model Antitumor Assays
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006493:Heparin