title: Efficient Inhibition of Ovarian Cancer by Gelonin Toxin Gene Delivered by Biodegradable Cationic Heparin-polyethyleneimine Nanogels.
abstract: The use of toxins for cancer therapy has great promise. Gelonin, a potent plant toxin, causes cell death by inactivating the 60S ribosomal subunit. Recently, we developed a novel gene delivery system using biodegradable cationic heparin-polyethyleneimine (HPEI) nanogels. In the current study, the antitumor activity of a recombinant plasmid expressing gelonin (pGelonin) on human ovarian cancer was assessed. The application of HPEI nanogels, was also evaluated. Gelonin-cDNA was cloned into the pVAX1 plasmid vector and transfected into SKOV3 human ovarian cancer cells using biodegradable cationic HPEI nanogels. The expression of gelonin in vitro and in vivo was confirmed using RT-PCR and western blot analysis. Cell viability and apoptosis were examined using an MTT assay and flow cytometric analysis. For the in vivo study, an SKOV3 intraperitoneal ovarian carcinomatosis model was established, and nude mice were randomly assigned into four groups receiving i.p. administration of pGelonin/HPEI complexes, pVAX/HPEI complexes, HPEI alone and 5% glucose solution. The tumor weight was monitored, and a TUNEL assay and Ki-67 immunohistochemistry were performed to evaluate apoptosis and cell proliferation in the tumor tissue sections, respectively. Gelonin was efficiently expressed in SKOV3 cancer cells in vitro and in vivo using pGelonin incorporated with HPEI nanogels. The pGelonin/HPEI complexes inhibited cell viability and induced apoptosis in the cell culture. Treatment for intraperitoneal carcinomatosis with pGelonin/HPEI complexes reduced the tumor weight by ~58.55% compared to the control groups (P<0.05). The antitumor effect was accompanied by increased apoptosis and reduced cell proliferation (P<0.05). No significant side effects were observed with i.p. administration of the pGelonin/HPEI complexes. Our data indicate that HPEI nanogel-delivered pGelonin may have promising applications against human ovarian cancer.
authors.affiliation: 1. 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, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.affiliation: 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Maling
authors.initials: M
authors.lastname: Gou
authors.affiliation: 1. 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, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yi
authors.affiliation: 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: 1. 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, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.affiliation: 1. 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, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Lin
authors.affiliation: 1. 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, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.affiliation: 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: 1. 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, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001672:Biocompatible Materials; D002412:Cations; D002460:Cell Line; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006493:Heparin / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000080385:Nanogels; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D054789:Ribosome Inactivating Proteins, Type 1 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001672:Biocompatible Materials; D002412:Cations; D000080385:Nanogels; D054789:Ribosome Inactivating Proteins, Type 1; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; C025674:GEL protein, Gelonium multiflorum; D011094:Polyethyleneimine; D006493:Heparin
keywords: cationic nanogels; gelonin toxin; gene therapy; heparin-polyethyleneimine (HPEI); ovarian cancer