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: 7501508
• 负责人: Yah-el Har-el
• 金额: $ 5.04万
• 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/7501508
• 关键词: Acids; Adherent Culture; Alpha Particles; Anhydrides; Animals; Antigens; Autoradiography; B-Cell Neoplasm; Binding; Biodistribution; Biological Assay; Breast Cancer Cell; Butylamines; Caliber; Cancer Model; Cell Death; Cell Line; Cell Nucleus; Cell Survival; Cell membrane; Cells; Chelating Agents; Cholesterol; Choline; Confocal Microscopy; Count; Cytosol; Cytotoxic agent; DNA; Data; Deposition; Dose; Drug Kinetics; Electron Microscopy; Encapsulated; Engineering; Ensure; Exposure to; Fellowship; Future; Gamma counter; Greater sac of peritoneum; Hour; Human; Image; Immunoliposome; In Vitro; Incubated; Individual; Injection of therapeutic agent; Kinetics; Label; Lecithin; Length; Lethal Dose 50; Linear Energy Transfer; Lipids; Liposomes; Lysosomes; Magnetic Resonance Spectroscopy; Maleimides; Malignant neoplasm of ovary; Measures; Monoclonal Antibodies; Mus; Myeloid Leukemia; Names; Neoplasm Metastasis; Normal tissue morphology; Nude Mice; Organ; Ovarian Carcinoma; Pathway interactions; Pentetic Acid; Phospholipase; Phosphorylcholine; Polymers; Protein Overexpression; Radioactivity; Radioisotopes; Roche brand of trastuzumab; Staining method; Stains; Time; Tissues; Toxic effect; Translating; Travel; Work; base; cancer cell; cell killing; cytotoxic; cytotoxicity; dioleoylphosphatidylcholine; dosimetry; endosome membrane; in vivo; intraperitoneal; killings; mathematical model; monolayer; nanoscale; particle; photoactivation; plasmid DNA; research study; response; trafficking; tumor

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。发射α粒子的放射性核素是一种很有前途的治疗此类转移的方法；它们的短路径长度将节省邻近的正常组织，而高局部能量沉积在杀菌目标细胞方面是有效的。这项提议将开发一种纳米级的递送载体，其中连接到质粒DNA(PDNA)/聚乙烯亚胺(PEI)阳离子聚合物构建的α发射体被包裹在免疫脂质体中，用于将α粒子递送到靶细胞的核。该建议的目的是：1.设计所建议的结构并在体外评估稳定性；2.在体外评估细胞内的转运、α-递送和细胞毒性；3.使用小动物成像和伽马计数，评估递送载体在体内和体外的生物分布；以及4.执行将结果转化为人体所需的数学建模和剂量测定。由于穿过大多数细胞细胞核的一个或两个阿尔法轨迹是致命的，这种方法将确保对目标细胞的非常高的杀伤率，同时对邻近组织的毒性最小。所提出的递送载体有望在向靶细胞核递送细胞毒剂方面有更广泛的应用。