Medical countermeasure after radiation exposure

放射线照射后的医疗对策

基本信息

批准号：
8800541
负责人：
Gerardo M. Castillo
金额：
$ 29.98万
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8800541
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）：迫切需要对GI造成的辐射损伤的新治疗方法，以确保暴露于因事故，核战或恐怖袭击（肮脏的炸弹）引起的电离辐射后生存。对造血系统和Gi tract的辐射射击是致命的，后者更严重致命。由于实用和技术挑战在提供持续有前途但不稳定的生长因子方面，肠道功能障碍的急性更高，因此无法获得肠道功能障碍的更严重的治疗方法，这些因素可能会大大阻止辐射损害造成损害，并加速肠道细胞功能的恢复，因此无法获得治疗。药剂开发了一种称为受保护的接枝共聚合物（PGC）的新药递送纳米技术，可用于单个皮下（S.C.）或静脉内（i.v.）注射PGC-Drug复合物，可作为药物储存剂，并在血液中释放出活性药物时，可折叠50倍的量，从而使50次折叠量增加了50倍的量。该络合物免受网状内皮系统和血清蛋白酶的消除屏蔽，并且足够大，可以摆脱肾小球清除率。该络合物还积聚在血管通透性增加（例如肠子受损的位置），从而有可能最大化其功效。该应用建议将两种有前途的药物FGF-4和FGF-7制定为各种PGC，并将在体外测试这些配方。当致死辐射暴露后24-72小时给药时，将在体内测试所选的配方，以提高其增加生存率。 AIM 1将集中于FGF4和FGF7的候选PGC的设计，合成和纯化。 AIM 2将集中于确定各种PGC和FGF之间的复杂配方效率（离解常数或KD），并选择最合适的PGC。 AIM 3将重点介绍：3a）PGC-FGF4和PGC-FGF7的药代动力学特征，以及3B）它们在C57BL/6小鼠中的相应最大耐受性MTD剂量，以及在AIM 4中产生足够数量的AIM 4。辐射剂量后24至72小时给药。药品的长期目标之一是生产有效的自我管理的注射构成，用于用于民用紧急情况下。药品公司机密