title: Adenoviral vectors modified by heparin-polyethyleneimine nanogels enhance targeting to the lung and show therapeutic potential for pulmonary metastasis in vivo.
abstract: Polyethyleneimine (PEI) is a well-known cationic polymer that has previously been shown to have significant potential to deliver genes in vitro and in vivo. However, PEI is non-degradable and exhibits a high cytotoxicity as its molecular weight increases. The clinical application for systemic administration of adenoviral (Ad) vectors is limited, as these vectors do not efficiently penetrate solid tumor masses due to a common deficiency of Coxsackie Adenovirus Receptor (CAR) on the tumor surface. In this study, we conjugated low molecular weight PEI (Mn = 1,800) to heparin (Mn = 4,000-6,000) to create a new type of cationic degradable nanogel (HPEI) that was then used to modify Ad vectors. The resulting HPEI-Ad complexes were used to infect CT26 and HeLa cells in vitro. Additionally, the HPEI-Ad complexes were administrated in vivo via intravenous injection, and tissue distribution was assessed using luciferase assays; the therapeutic potential of HPEI-Ad complexes for pulmonary metastasis mediated by CT26 cells was also investigated. In vitro, HPEI-Ad complexes enhanced the transfection efficiency in CT26 cells, reaching 36.3% compared with 0.1% of the native adenovirus. In vivo, HPEI-Ad complexes exhibited greater affinity for lung tissue than the native adenovirus and effectively inhibited the growth of pulmonary metastases mediated by CT26 cells. Our results indicate that Ad vectors modified by HPEI nanogels to form HPEI-Ad complexes enhanced transfection efficiency in CT26 cells that lacked CAR, targeted to the lung and demostrated a potential therapy for pulmonary metastasis.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Yandong
authors.initials: Y
authors.lastname: Mu
authors.forename: XiaoPeng
authors.initials: X
authors.lastname: Li
authors.forename: MaLing
authors.initials: M
authors.lastname: Gou
authors.forename: HaiLong
authors.initials: H
authors.lastname: Zhang
authors.forename: ShunTao
authors.initials: S
authors.lastname: Luo
authors.forename: Ke
authors.initials: K
authors.lastname: Men
authors.forename: YongQiu
authors.initials: Y
authors.lastname: Mao
authors.forename: ZhiYong
authors.initials: Z
authors.lastname: Qian
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D006367:HeLa Cells; D006493:Heparin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006651:Histocytochemistry; D006801:Humans; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D000080385:Nanogels; D009362:Neoplasm Metastasis; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006493:Heparin