Locally advanced pancreatic cancer currently has no cure and the patients die within 5-11 months of diagnosis. Localized gene therapy could offer an attractive treatment modality. Many genes able to intervene with the path of pancreatic malignancy have already been developed and viral gene therapy showed efficacy in pancreatic tumor suppression. Yet, severe safety concerns undermine therapeutic prospects of the viral vectors and have ignited the search for non-viral alternatives. The non-viral systemic gene delivery to the tumor site and into the tumor cells is hampered by several formidable barriers. To facilitate efficacious, safe and minimally-invasive gene delivery to solid tumors following systemic administration, the delivery platform has to (i) selectively accumulate within the tumor, (ii) extravasate and distribue deep into the tumor mass to reach all viable tumor cells and, finally, (iii) mediate target cell transfection. The goal of the proposed research is to engineer a novel delivery platform for image-guided targeting of genetic material into tumors. The platform is designed such that it is responsive to the remote ultrasonic and magnetic physical stimuli and visible to a clinically-viable ultrasound imaging modality. In addition, lipid-like amphiphilic materials, termed lipidoids will be integrated into the platform. A large combinatorial library of lipidoid materials will be constructed and screened for their ability to incorporate into the platform, entrap genetic material and successfully mediate transfection. The platform containing the best performing lipidoid will be loaded with the plasmid DNA and tested in tumor-bearing mice for selectivity of gene expression in the tumor and distribution of the expressed genes deep within the tumor mass. Once tumor-selectivity and deep-intratumoral penetration are confirmed, the system will be further tested for therapeutic efficacy in a mouse model of human pancreatic cancer using interferon alpha plasmid DNA as a model gene therapeutic. Successful outcomes of this research will allow harnessing the value of a potent class of nucleotide-based therapeutics and providing a clinically viable way to realize gene therapy for locally advanced pancreatic cancer.
Locally advanced pancreatic cancer currently has no cure and the patients die within 5-11 months of diagnosis. The goal of this project is to engineer a new therapeutic modality for the treatment of this devastating disease.
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