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Abstract
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-α (TNF-α)-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-α-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.
Acknowledgements
We are greatly thankful for the Algerian Government for funding this research project.
Declaration of interest
K.D.F. and L.W.S are directors of Hybrid Systems Ltd., which owns the intellectual property on adenovirus coating using multivalent reactive pHPMA polymers. No competing financial interests exist for H.B., M.S. or V.Š.