title: Efficient inhibition of ovarian cancer by truncation mutant of FILIP1L gene delivered by novel biodegradable cationic heparin-polyethyleneimine nanogels.
abstract: Filamin A interacting protein 1-like (FILIP1L), which was reported to be consistently absent in ovarian cancer cell lines, has been identified to hold therapeutic potential for inhibiting tumor growth, and its COOH-terminal truncation mutant (FILIP1LΔC103) was found to be more potent than the wild-type. The use of polymeric nanoparticles to deliver functional gene intraperitoneally holds much promise as an effective therapy for ovarian cancer. In this study, a recombinant plasmid expressing FILIP1LΔC103 (FILIP1LΔC103-p) was constructed, and biodegradable cationic heparin-polyethyleneimine (HPEI) nanogels were prepared to deliver FILIP1LΔC103-p into human ovarian cancer SKOV3 cells. The expression of FILIP1LΔC103 in vitro and in vivo was determined using RT-PCR and western blot analysis. Moreover, a SKOV3 intraperitoneal ovarian carcinomatosis model was established to investigate the antitumor activity of HPEI+FILIP1LΔC103-p 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, respectively, and the antiangiogenic effect of FILIP1LΔC103-p was assessed by CD31 immunochemical staining and alginate-encapsulated tumor cell assay. FILIP1LΔC103-p could be efficiently transfected into SKOV3 cells by HPEI nanogels. Intraperitoneal administration of HPEI+FILIP1LΔC103-p complexes led to effective growth inhibition of ovarian cancer, in which tumor weight decreased by almost 72% 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+FILIP1LΔC103-p group compared with those in the control groups. These results indicated that HPEI nanogels delivering FILIP1LΔC103-p might be of value in the treatment against human ovarian cancer.
authors.affiliation: Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Xie
authors.forename: Ma-ling
authors.initials: ML
authors.lastname: Gou
authors.forename: Tao
authors.initials: T
authors.lastname: Yi
authors.forename: Hongxin
authors.initials: H
authors.lastname: Deng
authors.forename: Zheng-yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Xiao-rong
authors.initials: XR
authors.lastname: Qi
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D005782:Gels; D015316:Genetic Therapy; D005822:Genetic Vectors; D006493:Heparin; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D053758:Nanoparticles; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011094:Polyethyleneimine
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C464562:FILIP1 protein, human; D005782:Gels; D011094:Polyethyleneimine; D006493:Heparin