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.