Liposomal Delivery of High LET Emitters to Cell Nuclei

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DESCRIPTION (provided by applicant): Ovarian cancer metastases are often confined to the peritoneal cavity. Alpha-particle-emitting radionuclides are a promising therapy against such metastases; their short path length will spare adjacent normal tissue while the high local energy deposition is effective at sterilizing targeted cells. This proposal will develop a nanoscale delivery vehicle in which alpha-emitters conjugated to a plasmid DNA (pDNA)/ polyethylenimine (PEI) cationic polymer construct are encapsulated within immunoliposomes and used to deliver alpha-particles to the nucleus of targeted cells. The aims of the proposal are to: 1. engineer the proposed construct and evaluate stability, in vitro; 2. assess intracellular trafficking, alpha delivery, and cytotoxicity, in vitro; 3. using small animal imaging and gamma counting, assess the biodistribution of the delivery vehicle, in vivo, and ex vivo; and 4. perform the mathematical modeling and dosimetry needed to translate results to the human. Since one or two alpha tracks through the nucleus of most cells is lethal, this approach will ensure a very high killing efficiency of targeted cells with minimal toxicity to adjacent tissue. The delivery vehicle proposed is expected to have a broader application in the delivery of cytotoxic agents to targeted cell nuclei.