Cancer is one of the leading causes of death in the US. Chemotherapy remains an important cancertreatment modality. Traditionally, cytotoxic molecules that activate only a single tumor-killing mechanismare used. Combination chemotherapy is now a common practice, which involves treating patients withseveral drugs that differ in their killing mechanisms. Gemcitabine is approved for the treatment of variouscarcinomas: pancreatic, breast, lung, and bladder cancers. Although it is extremely potent in tumor cellsin culture, the clinical outcomes of gemcitabine in patients is rather modest, and recent pre-clinical dataindicated that a gemcitabine-in-liposome formulation helped improve the efficacy of gemcitabine. Arecent new development is the use of synthetic macromolecular double-stranded RNA (dsRNA) as apotential chemotherapy agent. Certain dsRNA molecules have multiple direct and indirect pro-apoptotic,anti-proliferative, and anti-angiogenic activities. Interestingly, our recent data showed that the anti-tumoractivity of an intratumorally injected synthetic dsRNA was significantly enhanced when it was dosed incombination with gemcitabine, indicating that a combination therapy using gemcitabine and dsRNArepresents a promising tumor therapy approach. In previous studies, the synthetic dsRNA was injecteddirectly into (or around) the tumor tissues in order to increase the internalization of the dsRNA by thetumor cells, because many dsRNA receptors or dsRNA-binding proteins are intracellular. However, directintratumoral injection is clinically impractical for the majority of tumors. We propose to develop epidermalgrowth factor (EGF)-conjugated, long-circulating, nanometer-scale liposomal formulations for dsRNA andgemcitabine to target them into EGF receptor-over-expressing tumor cells after intravenous injection, andto validate the resultant anti-tumor activity in murine models of mouse or human cancers. To accomplishour overall goal, we propose the following three specific aims: (i) to engineer EGF-coated, long-circulating liposomal carriers for a synthetic dsRNA and gemcitabine and to validate their activities invitro, (ii) to evaluate the extent to which the liposomal carriers will deliver the dsRNA and gemcitabineinto model tumors in mice after intravenous injection, and (iii) to evaluate the extent to which acombination therapy using tumor-targeting liposomal dsRNA and gemcitabine will inhibit the tumorgrowth in vivo. The completion of this application will lay a solid scientific foundation to improve theclinical outcome of cancers sensitive to dsRNA and gemcitabine in the future. A similar strategy can alsobe adopted to combine dsRNA with other chemotherapy agents to fight other tumors. Many tumor cells over-express EGF receptor. The successful engineering of EGF-conjugated, long-circulating liposomal carriers for synthetic dsRNA and gemcitabine, and the validation of their anti-tumoractivities when given in combination will lay a sound scientific foundation for future improvement of theclinical outcomes of tumors sensitive to both gemcitabine and dsRNA. A similar strategy can also beutilized to fight other cancers by combining dsRNA with other chemotherapy agents.
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