Retargeting Adenoviral Vectors to Improve Gene Transfer into Tumors

摘要

Gene targeting to tumors using adenoviral 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 adenoviral 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 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 adenoviral delivery, and the use of vascular disrupting agents such as combretastatin can help elucidate these contributions. In this investigation, we evaluate a variety of these methods for retargeting adenoviral vectors to tumor cells in vitro and in vivo, and assess the contributions of specific molecular and tissue interactions that affect adenoviral transgene delivery.