Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus.

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  • Author(s): Zeng Q;Zeng Q; Han J; Zhao D; Gong T; Zhang Z; Sun X
  • Source:
    International journal of nanomedicine [Int J Nanomedicine] 2012; Vol. 7, pp. 985-97. Date of Electronic Publication: 2012 Feb 27.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: DOVE Medical Press Country of Publication: New Zealand NLM ID: 101263847 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1178-2013 (Electronic) Linking ISSN: 11769114 NLM ISO Abbreviation: Int J Nanomedicine Subsets: MEDLINE
    • Publication Information:
      Original Publication: Auckland : DOVE Medical Press,
    • Subject Terms:
      Adenoviridae/*chemistry ; Antibodies, Neutralizing/*immunology ; Polyethylene Glycols/*chemistry ; Transfection/*methods; Adenoviridae/immunology ; Adenoviridae/metabolism ; Antibodies, Neutralizing/metabolism ; Cations/chemistry ; Cations/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; HEK293 Cells ; Humans ; Neutralization Tests ; Polyethylene Glycols/pharmacology ; Polyethyleneimine/chemistry ; Polyethyleneimine/pharmacology
    • Abstract:
      Background: The generation of anti-adenovirus neutralizing antibody (NAb) in humans severely restricts the utilization of recombinant adenovirus serotype 5 (Ad5) vectors in gene therapy for a wide range of clinical trials. To overcome this limitation, we ionically complexed Ad5 with a newly synthesized copolymer, which we called APC, making an adenovirus shielded from NAb.
      Methods: APC, a cationic polyethylene glycol derivative, was synthesized via two steps of ring-opening copolymerization of ethylene oxide and allyl glycidyl ether, followed by the addition of 2-mercaptoethylamine. The copolymer or the control PEI-2k was ionically complexed to anionic Ad5 in 5% glucose, and in vitro transduction assays were carried out in coxsackievirus and adenovirus receptor-positive cells (A549) and coxsackievirus and adenovirus receptor-negative cells (B16 and SKOV3). The physical properties and morphology of adenovirus alone or the complexes were investigated respectively by zeta potential, size distribution, and transmission electron microscopy image. Then cytotoxicity of APC was examined using 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Finally, the ability of APC to protect adenovirus from NAb was evaluated by transfection assays after a neutralizing effect.
      Results: APC was successfully synthesized and showed a low cytotoxicity. Positively charged Ad5/APC exhibited slightly increased diameter (130.2 ± 0.60 nm) than naked Ad5 (115.6 ± 5.46 nm) while Ad5/PEI-2k showed severe aggregation (1382 ± 79.9 nm). Ad5/APC achieved a gene transfection level as high as Ad5/PEI-2k in A549 or B16 cells, and significantly higher than Ad5/PEI-2k in SKOV3 cells. Most importantly, after the exposure to the neutralizing antibody, naked Ad5 and Ad5/PEI-2k exhibited poor gene expression while Ad5/APC still showed significantly efficient gene expression.
      Conclusion: Our results demonstrated that Ad5/APC complex offered good protection for Ad5 against NAb in vitro and suggested a potential strategy of resistance to NAb in vivo.
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    • Contributed Indexing:
      Keywords: adenovirus; anti-adenovirus neutralizing antibody; cationic PEG derivative
    • Accession Number:
      0 (Antibodies, Neutralizing)
      0 (Cations)
      3WJQ0SDW1A (Polyethylene Glycols)
      9002-98-6 (Polyethyleneimine)
    • Publication Date:
      Date Created: 20120314 Date Completed: 20120619 Latest Revision: 20211021
    • Publication Date:
      20221213
    • Accession Number:
      PMC3299205
    • Accession Number:
      10.2147/IJN.S27526
    • Accession Number:
      22412299