Transductional targeting involves the chemical or genetic modification of a vector, redirecting its tropism to a new target expressed preferentially on the target cell. This can be achieved either by direct targeting or indirect targeting. In direct targeting, the cell-specific targeting of the vector is mediated by a ligand that is directly inserted into the viral capsid (177). However, this direct, ligand-mediated targeting, has its prerequisites that have to be considered, as there should be a good internalization site, the ligand should be structure independent, not too large to avoid the destabilization of the entire capsid, the ligand should be cell-type specific, the ligand-receptor complex should be internalized in a way that allows an efficient transport of the virus and the release of the viral DNA in the cell nucleus (178). Recently, the arginine-glycine-aspar-tic acid (RGD) containing peptide ligands targeted to integrin receptors expressed on activated ECs have been studied (179).
In indirect targeting the interaction between the viral vector and the target cell is mediated by an associated molecule (e.g., a glycoside molecule or a bispecific antibody), which is bound to the viral surface and interacts with a specific cell surface molecule (178,180). A bispecific antibody containing Fab arms of aIIb^3 integrin and AAV capsid antibodies, could target AAV to cells, which are not normally permissive for AAV infection (181). Everts et al. used this targeting strategy to the selective delivery of dexamethasone to activated ECs, using an E-selectin-directed drug-Ab conjugate (182). Because E-selectin is not expressed in inactive EC the dexamethasone-Ab conjugate did not bind to resting ECs.
To achieve cell-specific transgene expression in pulmonary endothelium, Reynolds et al. used an adenoviral vector system that combined transductional and transcriptional targeting (183). The combination of transductional targeting to a pulmonary endothelial marker (angiotensin-converting enzyme [ACE]) and to an endothelial-specific promoter (VEGFR-1) resulted in a synergistic, 300,000-fold increased selectivity of transgene expression to lung tissue compared with non-targeted vectors, that, after systemic application usually sequestrate in the liver.
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