Medical countermeasure after radiation exposure

放射线照射后的医疗对策

基本信息

批准号：
8707174
负责人：
Gerardo M. Castillo
金额：
$ 29.99万
依托单位：
PHARMAIN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-05 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707174
关键词：
Accident and Emergency department Accidents Acute Address Adenovirus Vector Affect Animals Apoptosis Back Binding Biological Biological Markers Blood C57BL/6 Mouse Cell Death Cell division Cell physiology Cells Cessation of life Chronic Complex Data Development Dissociation Dose Drug Carriers Drug Delivery Systems Drug Formulations Drug Kinetics Effectiveness Electrolytes Emergency Situation Endothelial Cells Ensure Enzymes Epithelial Cells Event Exposure to FGF7 gene Fibroblast Growth Factor First Aid Frequencies Functional disorder Gastrointestinal tract structure Goals Growth Growth Factor Half-Life Health Hematopoietic Hematopoietic System Hemorrhage Hour In Vitro Infection Inflammation Injectable Injection of therapeutic agent Injury Intestines Intravenous infusion procedures Ionizing radiation Lead Lethal Dose 50 Maximum Tolerated Dose Mediating Medical Mucositis Nanotechnology Nuclear Warfare Organ Peptide Hydrolases Peptides Pharmaceutical Preparations Polyethylene Glycols Polymers Principal Investigator Production Proteins Radiation Radiation Injuries Radiation induced damage Radiation therapy Recovery Regimen Self Administration Self-Administered Sepsis Serum Site Stem cells Syndrome Syringes System Technology Testing Time Vascular Permeabilities Villus Viral Vector Weight Whole Organism Whole-Body Irradiation Work analog base copolymer crypt cell design dirty bomb efficacy testing functional restoration gastrointestinal improved in vitro testing in vivo intravenous injection keratinocyte growth factor nanocarrier nutrition portability prevent programs proto-oncogene protein kfgf repaired residence restoration subcutaneous success vector

项目摘要

DESCRIPTION (provided by applicant): New treatments for radiation injury to the GI-tract are desperately needed to ensure survival after exposure to ionizing radiation arising from accident, nuclear warfare, or terrorist attacks (dirty bombs). Radiation-injuries to the hematopoietic system and the GI-tract are fatal, with the latter more acutely fatal. No treatment is available fo the more acute lethality of intestinal dysfunction due to practical and technical challenges in delivering a sustain dose of promising, but unstable, growth factors that can significantly stop the radiation damage-cascade and accelerate recovery of the intestinal cell function. PharmaIN developed a new drug delivery nanotechnology called protected graft co-polymer (PGC) that can be used in a single subcutaneous (s.c.) or intravenous (i.v.) injection of PGC-drug complex that acts as a drug reservoir and releases active drugs when the amount of free drug in the blood decreases, providing an apparent half-life increase of 50- 600 fold. The complex is shielded from elimination by the reticulo-endothelial system and by serum proteases and is large enough to escape from glomerular clearance. The complex also accumulates at sites with increased vascular permeability such as damaged intestine, thus potentially maximizing their efficacy. This application proposes to formulate of two promising agents, FGF-4 and FGF-7, into various PGCs and will test these formulations in vitro. Selected formulations will be tested in vivo for their ability to increase survival when administered 24-72 hours after lethal radiation exposure. Aim 1 will focus on the design, synthesis, and purification of candidate PGCs for FGF4 and FGF7. Aim 2 will focus on the determination of complex formulation efficiency (dissociation constant or Kd) between various PGCs and FGFs and to pick the most suitable PGCs. Aim 3 will focus on the determination of: 3a) the pharmacokinetic profiles of PGC-FGF4 and PGC-FGF7, and 3b) their corresponding maximum tolerated MTD dose in C57BL/6 mice, and the production of sufficient amounts of selected formulations for the animal study in aim 4. Aim 4 will test the efficacy of PGC-FGFs in extending survival from an LD50/6 radiation dose when administered 24 to 72 hours after the radiation dose. One of the long term goals of PharmaIN is to manufacture a potent self-administered injectable composition for radiation injury that can be used in civil emergency situations. PharmaIN Corp Confidential

描述（由申请人提供）：迫切需要针对胃肠道辐射损伤的新疗法，以确保在暴露于因事故、核战争或恐怖袭击（脏弹）引起的电离辐射后的生存。造血系统和胃肠道的辐射损伤是致命的，后者的致命性更为严重。由于提供持续剂量的有前途但不稳定的生长因子（可以显着阻止辐射损伤级联并加速肠细胞功能的恢复）方面存在实际和技术挑战，因此无法治疗更严重的肠道功能障碍致死率。 PharmaIN 开发了一种称为受保护接枝共聚物 (PGC) 的新型药物输送纳米技术，可用于单次皮下 (s.c.) 或静脉 (i.v.) 注射 PGC-药物复合物，该复合物充当药物储库，并在血液中游离药物的量减少，半衰期明显增加 50-600 倍。该复合物免受网状内皮系统和血清蛋白酶的消除，并且足够大以逃避肾小球清除。该复合物还会在血管通透性增加的部位（例如受损肠道）积聚，从而有可能最大限度地发挥其功效。该申请建议将两种有前途的药物 FGF-4 和 FGF-7 配制到各种 PGC 中，并将在体外测试这些制剂。将在体内测试所选制剂在致命辐射暴露后 24-72 小时施用时提高存活率的能力。目标 1 将重点关注 FGF4 和 FGF7 候选 PGC 的设计、合成和纯化。目标 2 将重点确定各种 PGC 和 FGF 之间的复合制剂效率（解离常数或 Kd），并选择最合适的 PGC。目标 3 将重点确定：3a）PGC-FGF4 和 PGC-FGF7 的药代动力学特征，3b）它们在 C57BL/6 小鼠中相应的最大耐受 MTD 剂量，以及为动物生产足够量的选定制剂目标 4 中的研究。目标 4 将测试在辐射后 24 至 72 小时施用 PGC-FGF 在延长 LD50/6 辐射剂量生存期方面的功效剂量。 PharmaIN 的长期目标之一是制造一种有效的自我注射组合物，用于治疗辐射损伤，可用于民用紧急情况。 PharmaIN 公司机密