There are increased needs for effective radiation countermeasures that can protect bone marrow, promote the recovery of hematopoietic stem cells (HSCs), or even increase survival rate from radiation-induced damage in affected individuals. In general, radiation countermeasures may be divided into two areas: radioprotection and radiomitigation. The focus of this project is on broad-spectrum radioprotection. Currently, amifostine is the only broad-spectrum radioprotector approved by the FDA for clinical application. While amifostine effectively reduces normal organ damage caused by radiation, it does have serious adverse effects including nausea, vomiting, and pronounced hypotension, making it unacceptable for widespread use. At present, no other small-molecule agents have been approved by the FDA as a broad-spectrum radioprotector. Therefore, there is an urgent need to discover radioprotective agents with higher potency and/or fewer side effects. Previously, we synthesized a series of small-molecule immunomodulators (UTL compounds). In animal studies, we found that one of the compounds, UTL-5g, showed significant radioprotection against acute phase of radiation-induced liver injury. UTL-5g also significantly decreased the apoptosis of liver cells caused by irradiation. Subsequently, we showed that UTL-5g increased the survival of mice treated with lethal dose of total body irradiation (TBI). However, UTL- 5g is not water soluble, which makes it somewhat difficult for formulation development. To make further improvement, we recently used an SAR (structure activity relationship) approach and synthesized a new series of small molecules, UTS compounds, to further improve the radioprotective properties and water solubility. In a recent study, we found that three of the UTS compounds showed significant radioprotection. Among these three UTS compounds, UTS-1401 showed the best radioprotective activity; more strikingly, its radioprotective effect is significantly better than that of amifostine. This SBIR Phase 1 study is to show the feasibility of developing UTS- 1401 as a radioprotective agent. There are four specific aims for this Phase 1 SBIR study: (1) to determine the optimal drug dose of UTS-1401 and the optimal TBI dose for the animal studies; (2) to compare the radioprotective effects between UTS-1401 and amifostine; (3) to investigate the specific protective effects of UTS-1401 on TBI-induced toxicities; (4) to conduct a preliminary investigation on the mechanism of action (MOA) of UTS-1401. After the completion of this SBIR Phase 1 Study, we will have shown the feasibility of developing UTS-1401 as a broad-spectrum radioprotector for TBI. In the SBIR Phase 2 study, we will continue the pre- clinical development of UTS-1401 and to complete all essential studies required before an IND filing in order to get ready for clinical trials. The ultimate goal of this project is to develop UTS-1401 as a broad-spectrum radioprotector for clinical application and potential nuclear accidents including warfare and related events.
Project Terms: Acute; Adverse effects; Affect; Agonist; Amifostine; Animals; Apoptosis; Area; base; Biological; Blood Platelets; Bone Marrow; Bone Marrow Stem Cell; Cells; Chronic; clinical application; Clinical Trials; CSF3 gene; cytokine; Development; Dose; drug development; Drug Kinetics; Event; experimental study; FDA approved; Formulation; Goals; Grant; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic stem cells; Hematopoietic System; Hepatocyte; Hypotension; Immunomodulators; improved; Individual; Inflammatory; Injury; Investigation; irradiation; Kidney; Legal patent; Liver; liver injury; Luciferases; Lung; Mus; Nausea and Vomiting; Normal tissue morphology; novel; Nuclear Accidents; Occupational Exposure; Organ; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phase; phase 1 study; phase 2 study; physical property; Polysaccharides; pre-clinical; preclinical development; preclinical study; Production; Property; protective effect; Radiation; Radiation exposure; Radiation induced damage; Radiation Toxicity; Radiation-Protective Agents; Radioprotection; Recovery; Reporter; Series; Small Business Innovation Research Grant; small molecule; Structure-Activity Relationship; Sulfhydryl Compounds; Survival Rate; TNF gene; Toll-like receptors; Toxic effect; Water; water solubility; Whole-Body Irradiation;
