Medical countermeasure after radiation exposure

放射线照射后的医疗对策

• 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
• 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

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）：迫切需要新的胃肠道辐射损伤治疗方法，以确保暴露于事故、核战争或恐怖袭击（脏弹）引起的电离辐射后的生存。对造血系统和胃肠道的辐射损伤是致命的，后者更致命。由于在提供持续剂量的有希望但不稳定的生长因子方面的实际和技术挑战，没有治疗可用于肠功能障碍的更急性致死性，所述生长因子可以显著阻止辐射损伤级联并加速肠细胞功能的恢复。PharmaIN开发了一种新的药物递送纳米技术，称为受保护的接枝共聚物（PGC），可用于单次皮下（s.c.）或静脉内（i. v.）注射PGC-药物复合物，其充当药物储库并在血液中游离药物的量减少时释放活性药物，提供50- 600倍的表观半衰期增加。该复合物被网状内皮系统和血清蛋白酶屏蔽而不被消除，并且足够大以逃避肾小球清除。该复合物还在血管通透性增加的部位（如受损的肠）积聚，从而可能使其功效最大化。本申请提出将两种有前景的试剂FGF-4和FGF-7配制成各种PGC，并将在体外测试这些制剂。将在体内测试选定的制剂在致死辐射暴露后24-72小时施用时增加存活的能力。目标1将集中于设计、合成和纯化用于FGF 4和FGF 7的候选PGC。目的2将集中于确定各种PGC和FGF之间的复合物配制效率（解离常数或Kd），并挑选最合适的PGC。目的3将集中于确定：3a）PGC-FGF 4和PGC-FGF 7的药代动力学曲线，和3b）它们在C57 BL/6小鼠中的相应最大耐受MTD剂量，以及产生足够量的用于目的4中的动物研究的所选制剂。目的4将测试当在辐射剂量后24至72小时施用时，PGC-FGF在延长LD 50/6辐射剂量的存活中的功效。PharmaIN的长期目标之一是生产一种有效的自我管理的可注射组合物，用于辐射损伤，可用于民事紧急情况。PharmaIN Corp机密