Medical countermeasure after radiation exposure

描述（由申请人提供）：迫切需要新的gi束辐射损伤治疗方法，以确保在事故，核战争或恐怖袭击（脏弹）引起的电离辐射暴露后的生存。对造血系统和胃肠道的辐射损伤是致命的，后者更严重致命。由于实际和技术上的挑战，无法提供持续剂量的有希望但不稳定的生长因子，这些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，因此没有治疗肠道功能障碍的更急性致命性的方法。PharmaIN开发了一种新的药物递送纳米技术，称为保护性移植物共聚物（PGC），可用于单次皮下（s.c）或静脉（i.v）注射PGC-药物复合物，作为药物储存库，当血液中游离药物量减少时释放活性药物，提供50- 600倍的明显半衰期。该复合物不被网状内皮系统和血清蛋白酶消除，并且足够大，可以从肾小球清除中逃脱。该复合物也在血管通透性增加的部位积聚，如受损的肠，从而可能最大化其功效。本申请建议将两种有前景的制剂FGF-4和FGF-7配制成各种pgc，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小时使用时提高生存率的能力。目的1将重点关注FGF4和FGF7候选PGCs的设计、合成和纯化。目标2将侧重于确定各种PGCs和FGFs之间的复杂配方效率（解离常数或Kd），并选择最合适的PGCs。目标3将侧重于确定：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，以及为目标4的动物研究生产足够数量的选定制剂。Aim 4将测试pgc - fgf在放射剂量后24至72小时给予LD50/6放射剂量后延长生存期的功效。PharmaIN的长期目标之一是制造一种有效的自我给药注射组合物，可用于民用紧急情况下的辐射损伤。PharmaIN公司机密

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