Systemic virus dissemination during local gene delivery in solid tumors and its control with an alginate solution

摘要

Intratumoral infusion, a routine method for local gene delivery in solid tumors, may cause a systemic dissemination of gene vectors. This is because tumor vessels are intrinsically leaky and intratumoral injection can also result in damage of tumor vessels. To this end, we investigated the extent of virus dissemination during and after local infusion of adenoviral vectors into a murine adenocarcinoma (4T1) transplanted in mice. Three different vectors were used in this study, they contained genes encoding either mouse interleukin-12 (IL-12), luciferase, or enhanced green fluorescence protein (EGFP). The virus distribution in the body was determined as the transgene expression in normal and tumor tissues. Our data demonstrated that a large fraction of injected viral vectors disseminated into liver tissues. To reduce the dissemination problem, we developed a novel method for viral vector delivery based on an alginate solution. We observed that this vehicle could significantly reduce virus dissemination without compromising the therapeutic efficacy of adenoviral vectors. Taken together, the data suggests that systemic virus dissemination is a serious problem in local gene therapy in tumors and that the dissemination can be significantly reduced by an alginate-based polymeric vehicle.