Development of Novel Sensitizer to Improve Response of Hypoxic Tumors to Radiatio

描述（申请人提供）：组织探针测量和成像显示肿瘤缺氧在许多癌症中很常见，包括头颈癌、宫颈癌、前列腺癌和许多其他实体肿瘤。低氧浓度的肿瘤对放射治疗有抵抗力。新的影像学技术可用于诊断肿瘤缺氧。已经测试了许多方法来增加肿瘤的氧合，但通常没有很大的成功。目前还没有临床可用的增加肿瘤氧合的方法来改善对放射治疗的反应。这项第一阶段SBIR拨款申请的目的是开发一种基于十二全氟戊烷乳剂（DDFPe）的新型氧载体，其活性低于先前描述的载体剂量的1/ 1000，并且在放射治疗后不久就会从体内清除。具体目标是：1。开发优化的DDFPe辐射增敏剂配方；2. 体外表征该制剂；3. 研究细胞培养的毒性/生物相容性；4. 对小鼠进行毒性研究；5. 在细胞培养中进行辐射致敏研究。DDFPe之前在man进行了另一种应用研究，但用于稳定乳液的表面活性剂不纯。我们已经合成了用于稳定DDFPe的纯表面活性剂，在药学上应该是可以接受的。实验旨在测试和比较这些新的表面活性剂对DDFPe的稳定作用。从这些初步研究中，我们将确定DDFPe辐射致敏产品的原型，用于正式的临床前开发。在II期，我们将进行动物研究，我们将使用影像学来显示治疗前后肿瘤缺氧的改善，以及对缺氧肿瘤进行放射治疗后肿瘤反应的改善。

DESCRIPTION (provided by applicant): Tissue probe measurements and imaging show that tumor hypoxia is common in many cancers including head and neck cancer, cervical cancer, prostate cancer and many other solid tumors. Tumors with low oxygen concentrations are resistant to radiation treatment. New imaging techniques can be used to diagnose tumor hypoxia. A number of methods have been tested to increase tumor oxygenation, but in general without great success. There is as yet no clinically available method of increasing tumor oxygenation to improve response to radiation treatment. The purpose of this Phase I SBIR grant application is to develop a new oxygen carrier based upon dodecaperfluoropentane emulsion (DDFPe) that is active at less than 1/00th the dose of previously described carriers and that will clear from the body shortly after radiation treatment. The Specific Aims are: 1. Develop an optimized DDFPe radiation sensitizer formulation; 2. Characterize the formulation in vitro; 3. Study toxicity/biocompatibility in cell culture; 4. Conduct toxicity studies in mice; 5. Perform radiation sensitization studies in cell culture. DDFPe was previously studied in man for another application, but the surfactant used to stabilize the emulsion was not pure. We have synthesized pure surfactants for stabilizing DDFPe that should be pharmaceutically acceptable. The experiments are designed to test and compare these new surfactants for stabilizing DDFPe. From these preliminary studies we will define prototype DDFPe radiation sensitization product for formal preclinical development. In Phase II we shall conduct animal studies in which we will use imaging to show amelioration in tumor hypoxia pre and post treatment and improvement in tumor response with radiation therapy for hypoxic tumors. PUBLIC HEALTH RELEVANCE: Tumor hypoxia is common in many cancers including head and neck cancer, cervical cancer, prostate cancer and many other solid tumors. Tumors with low oxygen concentrations are resistant to radiation treatment. This NIH Phase I grant application is directed to development of a new sensitizer that may be much more effective than prior compounds in improving oxygenation of hypoxic cancer cells and improving response of cancer to treatment.