Medical countermeasure after radiation exposure

放射线照射后的医疗对策

• 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
• 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

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(申请人提供)：迫切需要新的治疗胃肠道辐射损伤的方法，以确保因事故、核战争或恐怖袭击(脏弹)而暴露于电离辐射后的生存。对造血系统和胃肠道的辐射损伤是致命的，后者更为致命。由于在提供有希望但不稳定的持续剂量的生长因子方面存在实际和技术挑战，可以显著阻止辐射损伤级联反应并加速肠道细胞功能的恢复，因此对于更严重的致命性肠功能障碍尚无治疗方法。Pharmain开发了一种名为保护性接枝共聚合物(PGC)的新药物传递纳米技术，可用于单一皮下(S.C.)或静脉注射(静注)注射PGC-药物复合体，起到药物储存库的作用，当血液中游离药物的数量减少时释放活性药物，提供明显的50-600倍的半衰期。该复合体被网状内皮系统和血清蛋白水解酶屏蔽而不被清除，并且其大小足以逃脱肾小球清除。该复合体还聚集在血管通透性增加的部位，如受损的肠道，从而潜在地使其疗效最大化。这项申请建议将两种有希望的制剂，成纤维细胞生长因子-4和成纤维细胞生长因子-7，制成不同的原癌细胞，并将在体外测试这些制剂。选定的配方将在体内测试其在致命辐射暴露后24-72小时给药时提高存活率的能力。目标1将集中于FGF4和FGF7候选PGCs的设计、合成和纯化。目的2将着重于测定不同的PGCs和FGFs之间的复配效率(解离常数或Kd)，并选择最合适的PGCs。目标3将集中测定：3a)PGC-FGF4和PGC-Fgf7在C57BL/6小鼠体内的药代动力学特征，以及3b)它们在C57BL/6小鼠体内的相应最大耐受剂量，以及为Aim 4的动物研究提供足够量的选定制剂。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，可用于民事紧急情况。Pharmain公司机密