Liposomal Delivery of High LET Emitters to Cell Nuclei

高 LET 发射体的脂质体递送至细胞核

• 批准号: 7150751
• 负责人: Yah-el Har-el
• 金额: $ 4.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150751
• 关键词: DNA; birth; cell nucleus; liposomes; particle; radionuclides

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.

描述（申请人提供）：卵巢癌转移通常局限于腹膜腔。释放α粒子的放射性核素是一种很有希望的治疗这种转移的方法；它们的短路径长度将不影响邻近的正常组织，而高局部能量沉积对靶细胞的消毒是有效的。该方案将开发一种纳米级的递送载体，其中α -发射器与质粒DNA (pDNA)/聚乙烯亚胺（PEI）阳离子聚合物结构结合，被包裹在免疫脂质体中，用于将α -颗粒递送到靶细胞的细胞核。该提案的目的是：1。设计所提出的构建并评估体外稳定性；2. 体外评估细胞内运输、α传递和细胞毒性；3. 利用小动物成像和伽马计数，评估给药载体在体内和离体的生物分布；和4。进行数学建模和剂量测定，将结果转化为人类。由于通过大多数细胞核的一个或两个α轨道是致命的，这种方法将确保对目标细胞的高杀伤效率，同时对邻近组织的毒性最小。所提出的递送载体有望在将细胞毒性药物递送到靶向细胞核方面有更广泛的应用。