Liposomal Delivery of High LET Emitters to Cell Nuclei

描述（由申请人提供）：卵巢癌转移通常局限于腹膜腔。α粒子发射放射性核素是一种有前途的治疗这种转移;它们的短路径长度将节省相邻的正常组织，而高的局部能量沉积是有效的灭菌靶细胞。该提案将开发纳米级递送载体，其中与质粒DNA（pDNA）/聚乙烯亚胺（PEI）阳离子聚合物构建体缀合的α-发射体被封装在免疫脂质体内，并用于将α-颗粒递送至靶细胞的细胞核。该提案的目的是：1.工程化所提出的构建体并评估体外稳定性; 2.体外评估细胞内运输、α递送和细胞毒性; 3.使用小动物成像和γ计数，评估体内和离体递送载体的生物分布;和4.进行数学建模和剂量测定，以便将结果转化为人体。由于通过大多数细胞的细胞核的一个或两个α轨道是致命的，因此这种方法将确保对靶细胞的非常高的杀伤效率，同时对邻近组织的毒性最小。预期所提出的递送载体在将细胞毒性剂递送至靶向细胞核中具有更广泛的应用。

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.