Great effort has been made in developing tumor-targeted gene delivery, but no attention has been given to targeting the therapeutic gene products that are transcribed and translated from genes transfected in normal tissues into tumors. Targeting gene product in tumors is very important for systemic gene delivery because only a portion of genes are successfully delivered into tumors by using the most successful systemic tumor-targeted gene delivery technology. Targeting gene product in tumors is also important for intratumoral gene delivery because the most commonly used therapeutic genes like TRAIL yield soluble proteins that are secreted into the blood circulation and are harmful to normal cells. Moreover, some gene products such as IL-12 are more effective when co-localized with tumors, compared to systemic localization (Li, S., JNCI, 2002; Li, S., Mol Therapy, 2005). In this application, the applicant will select the effective tumor vessel-targeted peptides to target or anchor the therapeutic gene product transcribed and translated from the injected gene into tumors. Specifically, tumor vessel- anchored IL-12 gene encoding the selected tumor vessel-anchored mini-peptide and IL-12 will be generated and will be administered into tumors via electric pulses to achieve the tumor-targeted gene delivery and the tumor-targeted gene-product auto-delivery. The hypothesis is that the increased IL-12 accumulation in tumor and reduction of IL-12 circulation in serum by using tumor vessel-anchored IL-12 electrogenetherapy will greatly reduce systemic toxicity and enhance tumor eradication. To test this hypothesis, we will 1) select the most effective peptides for anchoring gene product that are transcribed and translated from the injected gene into tumors using our high throughput in vivo screening system; 2) Determine the therapeutic efficacy of tumor vessel-anchoring IL-12 electrogenetherapy for treating tumors in immunocompetent tumor-bearing mice and spontaneous tumor bearing felines; and 3) test a novel mechanism by which IL-12 inhibits tumor angiogenesis and by shich tumor vessel-anchored IL-12 enhances the inhibition of tumor angiogenesis. The experiments that we propose have a high probality of success because we have an excellent model system in place, the access to spontaneous tumor- bearing large animals, and all the resources necessary to complete the task. ? ? ?
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