Radioprotective / Radiomitigating Efficacy of Rx100 in the Gastrointestinal Tract

Rx100 在胃肠道中的辐射防护/辐射缓解功效

• 批准号: 7472935
• 负责人: Wenlin Deng
• 金额: $ 50万
• 依托单位: RXBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472935
• 关键词: Acute; Amifostine; Androstenediol; Androstenediols; Bacterial Translocation; Biological Assay; Bioshield; Bone Marrow; Cancer Patient; DL-alpha-Difluoromethylornithine; Development; Drug Formulations; Drug Kinetics; Evaluation; Exposure to; Gastrointestinal Agents; Gastrointestinal Injury; Gastrointestinal tract structure; Glucose; Goals; Government; Label; Lethal Dose 50; Life; Measures; Medical; Methods; Modeling; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Natural regeneration; Nuclear; Performance; Permeability; Pharmaceutical Preparations; Public Health; Radiation; Radiation Injuries; Radio; Recovery; Request for Applications; Route; Source; Stem cells; Structure; Tissues; Toxic effect; Tracer; Treatment Protocols; Villus; absorption; day; gastrointestinal; gastrointestinal function; liquid chromatography mass spectrometry; pre-clinical; response; small molecule; synergism

DESCRIPTION (provided by applicant): Gastrointestinal (GI) mucosa is one of the most radiosensitive tissues and radiation-associated GI injury could be fatal. We have developed a small molecule (Rx100) with potent radioprotecting/radiomitigating efficacy in GI tract. In response to Request For Application (RFA-AI-07-013) "Medical Countermeasures to Restore Gastrointestinal Function after Radiation Exposure: Project Bioshield (RC1)" issued by NIAID, we submit this application focusing on preclinical development of Rx100 as a radioprotector/radiomitigator against radiation-associated GI damage. We propose four specific aims with the ultimate goal to provide the U.S. government and mankind with a product effective in protecting life from radiation injury. 1. Optimize the formulation and delivery route of Rx100 to provide maximum efficacy in mice. Rx100 will be formulated using different carriers, and an optimal formulation will be chosen for further evaluation. 2. Explore synergisms between Rx100 and three existing radioprotectors/radiomitigators: alphadifluoromethylornithine (DFMO), amifostine (WR-2721) and 5-androstenediol (5-AED). 3. Evaluate the capacity of optimal Rx100 regimens, either alone or in combinations, to restore the GI barrier function after radiation exposure: Glucose absorption, mucosal permeability and bacterial invasion. 4. Acute toxicity study and pharmacokinetic profile of Rx100 Methods: (1) Microcolony Assay measures the capacity of GI stem cells to survive radiation injury. Mice are sacrificed 3.5 days after whole-body exposure to a Cs137 source. (2) Bone-Marrow-Shielding Model to select GI responses reflects mouse survival attributed to drugs' GI protection. (3) Analysis of recovery of villus structure up to 10 days postirradiation reflects the crypt regeneration dynamics. (4) GI glucose absorption and permeability will be measured in mice using radio-labeled tracers. Bacterial translocation will be evaluated by appropriate microbiological methods. (5) LD50 of Rx100 will be determined in acute toxicity study. (6) PK study using high-performance liquid chromatography mass spectrometry (LC/MS/MS). Relevance to public health: Exposure to radiation could result in fatal damage to the gut. No satisfactory radioprotectors/radiomitigators are available yet. We propose to develop Rx100 into a highly efficient medical countermeasure against radiological and nuclear threats, and a potent drug for cancer patients.

描述（由申请方提供）：胃肠道（GI）粘膜是最敏感的放射组织之一，放射相关GI损伤可能是致命的。我们已经开发了一种小分子（Rx100），在胃肠道中具有有效的放射保护/放射抑制功效。为响应NIAID发布的申请请求（RFA-AI-07-013）“辐射暴露后恢复胃肠道功能的医疗对策：Bioshield项目（RC 1）”，我们提交了本申请，重点关注Rx100作为辐射防护剂/辐射引发剂对辐射相关胃肠道损伤的临床前开发。我们提出了四个具体目标，最终目标是为美国政府和人类提供有效保护生命免受辐射伤害的产品。 1.优化Rx100的制剂和给药途径，以在小鼠中提供最大功效。Rx100将使用不同的载体配制，并将选择最佳制剂进行进一步评价。 2.探索Rx100和三种现有的辐射保护剂/辐射抑制剂之间的协同作用：α-二氟甲基鸟氨酸（DFMO），氨磷汀（WR-2721）和5-雄烯二醇（5-AED）。 3.评价最佳Rx100方案（单独或组合）在辐射暴露后恢复GI屏障功能的能力：葡萄糖吸收、粘膜渗透性和细菌侵入。 4. Rx100的急性毒性研究和药代动力学特征 方法：（1）微集落法检测胃肠道干细胞在放射损伤后的存活能力。在全身暴露于Cs 137源后3.5天处死小鼠。(2)选择GI反应的骨髓屏蔽模型反映了归因于药物GI保护的小鼠存活率。(3)绒毛结构的恢复分析，直到10天postirradiation反映隐窝再生动力学。(4)将使用放射性标记的示踪剂在小鼠中测量GI葡萄糖吸收和渗透性。将通过适当的微生物学方法评价细菌移位。(5)在急性毒性研究中确定Rx100的LD 50。(6)使用高效液相色谱质谱法（LC/MS/MS）进行PK研究。 与公共卫生的相关性：暴露于辐射可能对肠道造成致命损害。目前还没有令人满意的辐射防护剂/辐射抑制剂。我们建议将Rx100开发成一种针对放射性和核威胁的高效医疗对策，以及一种针对癌症患者的强效药物。