Intracellular trafficking and gene expression of pH-sensitive, artificially enveloped adenoviruses in vitro and in vivo

Van den Bossche, Jeroen, Al-Jamal, Wafa' T, Yilmazer, Açelya, Bizzarri, Elisabetta, Tian, Bowen and Kostarelos, Kostas (2011) Intracellular trafficking and gene expression of pH-sensitive, artificially enveloped adenoviruses in vitro and in vivo. Biomaterials, 32 (11). pp. 3085-3093. ISSN 1878-5905

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Abstract

Recombinant adenovirus (Ad) has shown great promise in gene therapy. Artificial envelopment of adenovirus within lipid bilayers has previously been shown to decrease the immunogenicity and hepatic affinity of naked Ad in vivo. Unfortunately, this also resulted in a significant reduction of gene expression, which we attributed to poor endosomal release of the Ad from its artificial lipid envelope. In this work, we explored the artificial envelopment of Ad within pH-sensitive DOPE:CHEMS bilayers and characterized this vector by TEM, AFM, dot blot, dynamic light scattering and zeta potential measurements. The artificially enveloped viral vectors exhibited good stability at physiological pH but immediately collapsed and released naked Ad virions at pH 5.5. Intracellular trafficking using confocal laser scanning microscopy (CLSM) revealed that Cy3-labelled Ad enveloped in DOPE:CHEMS bilayers exhibited the characteristic Ad distribution within the cytoplasm that led to virion accumulation around the nuclear membrane, indicating endosomal release of Ad. We obtained equivalent levels of gene expression as those of naked Ad in a series of CAR-positive (CAR+) and CAR-negative (CAR-) cell lines. This suggested that the mechanism of infection for the artificially enveloped Ad remained dependent on the presence of CAR receptors. Finally, the pH-sensitive enveloped Ad were injected intratumorally in human cervical carcinoma xenograft-bearing nude mice, also illustrating their capacity for efficient in vivo marker gene expression. This study is a step forward toward the engineering of functional, artificially enveloped adenovirus vectors for gene transfer applications.

Item Type: Article
Additional Information: Copyright © 2011 Elsevier Ltd. All rights reserved.
Uncontrolled Keywords: adenoviridae,animals,humans,hydrogen-ion concentration,gene expression,coxsackie and adenovirus receptor-like membrane protein,genetic therapy,mice,mice, nude,uterine cervical neoplasms,receptors, virus,phosphatidylethanolamines,female
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Pure Connector
Date Deposited: 05 Oct 2013 00:55
Last Modified: 21 Apr 2020 21:57
URI: https://ueaeprints.uea.ac.uk/id/eprint/43577
DOI: 10.1016/j.biomaterials.2010.12.043

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