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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.

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  • Publisher Full Text

    • Authors

    Wei W, Mu Y, Li X, Gou M, Zhang H, Luo S, Men K, Mao Y, Qian Z, Yang L

    Institution

    State Key Laboratory of Biotherapy and Cancer Center West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China.

    Source

    Journal of biomedical nanotechnology 7:6 2011 Dec pg 768-75

    MeSH

    Adenoviridae
    Animals
    Cell Proliferation
    Drug Carriers
    Female
    Gene Therapy
    Genetic Vectors
    HeLa Cells
    Heparin
    Histocytochemistry
    Humans
    Lung
    Lung Neoplasms
    Mice
    Mice, Inbred BALB C
    Neoplasm Metastasis
    Polyethylene Glycols
    Polyethyleneimine
    Transfection
    Xenograft Model Antitumor Assays

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22416575