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Retargeting adenoviral vectors to improve gene transfer into tumors.

ABSTRACT: Gene targeting to tumors using adenoviral (Ad) vectors holds great potential for cancer imaging and therapy, but the limited efficacy of current methods used to improve delivery to target tissues and reduce unwanted interactions remain substantial barriers to further development. Progress in characterizing the set of molecular interactions used by Ad vectors to infect particular tissues has aided the development of novel strategies for retargeting vectors to tumor cells. One method is chemical retargeting of adenovirus using bispecific antibodies (bsAbs) against both viral capsid proteins and tumor-specific cell surface molecules. This approach can be combined either with competitive inhibitors designed to reduce viral tropism in undesired tissues, or with traditional therapeutics to increase the expression of surface molecules for improved tumor targeting. Ablating liver cell-specific interactions through mutation of capsid proteins or chemical means are promising strategies for reducing adenovirus-induced liver toxicity. The nature of tumor neovasculature also influences Ad delivery, and the use of vascular disrupting agents (VDAs) such as combretastatin can help elucidate these contributions. In this investigation, we evaluate a variety of these methods for retargeting Ad vectors to tumor cells in vitro and in vivo, and assess the contributions of specific molecular and tissue interactions that affect Ad transgene delivery.

SUBMITTER: Hogg RT

PROVIDER: S-EPMC3060954 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Retargeting adenoviral vectors to improve gene transfer into tumors.

Hogg R T RT Thorpe P P Gerard R D RD

Cancer gene therapy 20101224 4

Gene targeting to tumors using adenoviral (Ad) vectors holds great potential for cancer imaging and therapy, but the limited efficacy of current methods used to improve delivery to target tissues and reduce unwanted interactions remain substantial barriers to further development. Progress in characterizing the set of molecular interactions used by Ad vectors to infect particular tissues has aided the development of novel strategies for retargeting vectors to tumor cells. One method is chemical r ...[more]

PMID: 21183946

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Project description:Adenovirus serotype 5 remains one of the most promising vectors for delivering genetic material to cancer cells for imaging or therapy, but optimization of these agents to selectively promote tumor cell infection is needed to further their clinical development. Peptide sequences that bind to specific cell surface receptors have been inserted into adenoviral capsid proteins to improve tumor targeting, often in the background of mutations designed to ablate normal ligand:receptor interactions and thereby reduce off target effects and toxicities in non-target tissues. Different tumor types also express highly variable complements of cell surface receptors, so a customized targeting strategy using a particular peptide in the context of specific adenoviral mutations may be needed to achieve optimal efficacy. To further investigate peptide targeting strategies in adenoviral vectors, we used a set of peptide motifs originally isolated using phage display technology that evince tumor specificity in vivo. To demonstrate their abilities as targeting motifs, we genetically incorporated these peptides into a surface loop of the fiber capsid protein to construct targeted adenovirus vectors. We then systematically evaluated the ability of these peptide targeted vectors to infect several tumor cell types, both in vitro and in vivo, in a variety of mutational backgrounds designed to reduce CAR and/or HSG-mediated binding. Results from this study support previous observations that peptide insertions in the HI loop of the fiber knob domain are generally ineffective when used in combination with HSG detargeting mutations. The evidence also suggests that this strategy can attenuate other fiber knob interactions, such as CAR-mediated binding, and reduce overall viral infectivity. The insertion of peptides into fiber proved more effective for targeting tumor cell types expressing low levels of CAR receptor, as this strategy can partially compensate for the very low infectivity of wild-type adenovirus in those cells. Nevertheless, the incorporation of relatively low affinity peptide ligands into the fiber knob, while effective in vitro, has only minimal targeting efficacy in vivo and highlights the importance of high affinity ligand:receptor interactions to achieve tumor targeting.

Dataset Information

Retargeting adenoviral vectors to improve gene transfer into tumors.

Publications

Retargeting adenoviral vectors to improve gene transfer into tumors.

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