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: 7497467
• 负责人: Yah-el Har-el
• 金额: $ 4.88万
• 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/7497467
• 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（由申请人提供）：卵巢癌转移通常仅限于腹膜腔。 α粒子发射放射性核素是对这种转移酶的有前途的疗法。它们的短路径长度将避免相邻的正常组织，而高局部能量沉积在对靶向细胞进行消毒时有效。该提案将开发纳米级输送载体，其中α发射体与质粒DNA（pDNA）/聚乙基苯胺（PEI）阳离子聚合物构建体结合在一起，将其封装在免疫染色体中，并用于将α颗粒递送到靶细胞的核心。该提案的目的是：1。在体外设计拟议的结构并评估稳定性； 2。在体外评估细胞内贩运，α递送和细胞毒性； 3。使用小型动物成像和伽马计数，评估递送车的生物分布，体内和ex vivo；和4。执行将结果转化为人类所需的数学建模和剂量法。由于通过大多数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靶向细胞的杀伤效率非常高，对邻近组织的毒性很小。提议的输送车预计将在将细胞毒性剂递送到靶向细胞核中具有更广泛的应用。