Journal
JOURNAL OF DRUG TARGETING
Volume 19, Issue 8, Pages 690-700Publisher
INFORMA HEALTHCARE
DOI: 10.3109/1061186X.2010.547585
Keywords
Polymer-coated virus; vascular targeting; inflammation; cancer
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Funding
- Algerian Government
- Biotechnology and Biological Sciences Research Council [BBS/B/03599] Funding Source: researchfish
- Cancer Research UK [11339] Funding Source: researchfish
- Medical Research Council [G0700166] Funding Source: researchfish
- MRC [G0700166] Funding Source: UKRI
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Background: E-selectin is an attractive endothelial cell surface marker in inflammation and cancer. Purpose: We sought to investigate retargeting of adenovirus via E-selectin as a viable pathway of infection in tumor necrosis factor-a (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). Methods: E1, E3-deleted Ad5 expressing cytomegalovirus immediate-early (CMV IE) promoter-driven luciferase (Adluc) was coated with an amino-reactive multivalent hydrophilic polymer based on poly [N-(2-hydroxypropyl) methacrylamide] to generate pHPMA-adenovirus (pcAdluc). This was then retargeted by covalent attachment of a mouse antihuman E-selectin monoclonal antibody (MHES mAb), purified from the H18/7 hybridoma cell line (MHESpcAdluc). Results: MHESpcAdluc was efficiently taken up into HUVECs, generating a high level of transduction in TNF-alpha-treated E-selectin positive cells but not in untreated receptor-negative cells. Specific retargeting of MHESpcAdluc was demonstrated through reduced transduction of stimulated HUVEC when incubated in the presence of free E-selectin antibodies. Discussion and conclusion: Our results suggest that E-selectin could be a valuable target for gene transfer strategies internalizing polymer-coated modified adenovirus particles through a viable receptor-mediated endocytosis pathway, generating adequate levels of transgene expression per virus genome copy without compromising the specific activity of the parental virus.
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