(PQD5) imaging systemic tissue injuries induced by anticancer drugs

产品描述（申请人提供）：化疗药物是一种杀伤肿瘤细胞的毒素，但其疗效往往受到正常组织耐受上限的限制。全身毒性的调查将提供有价值的信息，一个新的药物候选药物的药物开发，并对现有的药物组合的治疗方案，为每一个病人。该项目的总体目标是开发和验证全身细胞凋亡成像作为表征抗癌药物全身毒性的新方法。细胞凋亡是毒性诱导的组织损伤的重要表现。全身扫描，我们称之为“ToxScan”，根据对药物的毒性反应来检测全身组织损伤。我们使用一种放射性药物，99 mTc-Duramycin，它可以检测死亡和垂死细胞中暴露的磷脂酰乙醇胺。成像剂具有类似抗体的结合亲和力/特异性，但具有肽的清除动力学。因此，它是唯一适合全身成像应用。我们的中心假设是全身毒性反应反映了个体对抗癌治疗的敏感性。扫描提供了药物耐受性的指标，以及慢性不良反应的预后指标。在初步研究中，我们通过检测多个组织中的细胞死亡，证明了全身99 mTc-Duramycin扫描的灵敏度，在单次临床相关剂量的多柔比星后。全身细胞凋亡扫描也显示了对相同治疗方案的个体化反应。组织损伤的单器官和多器官指数正被用于诊断和预后目的。以这种方式评价毒性将显著加速新抗癌药物和新联合治疗的开发。最终，这种方法将通过在个性化的基础上优化治疗使肿瘤患者受益。

DESCRIPTION (provided by applicant): Chemotherapeutic drugs are toxins for killing tumor cells, but their efficacy is often limited by the tolerance ceiling of normal tissues. A survey of systemic toxicity will provide valuable information on a new drug candidate for pharmaceutical development, and on the therapeutic regimen for existing drug combinations for each patient. The overall goal of this project is to develop and validate whole-body apoptosis imaging as a new approach for characterizing the systemic toxicity profile of anticancer drugs. Apoptosis is an important manifestation of toxicity-induced tissue injuries. A whole-body scan, which we call "ToxScan", detects tissue injuries systemically, in terms of a toxicity profile in response to the drug. We use a radiopharmaceutical, 99mTc-Duramycin, which detects exposed phosphatidylethanolamine in dead and dying cells. The imaging agent has binding affinity/specificity like an antibody yet clearance kinetics of a peptide. It is thus uniquely suitd for whole-body imaging applications. Our central hypothesis is that a systemic toxicity profile reflects the individual susceptibility to anticancer treatment. The scan provides indices for drug tolerance, and a prognostic indicator for chronic adverse effects. In preliminary studies, we demonstrated the sensitivity of whole-body 99mTc-Duramycin scan by detecting cell death in multiple tissues after a single clinically relevant dose of Doxorubicin. Whole-body apoptosis scan also revealed individualized response to the same therapeutic regimen. Single-and multi-organ indices for tissue injury are being derived for diagnostic and prognostic purposes. The evaluation of toxicity in such fashion will significantly accelerate the development of new anticancer drugs and new combination treatments. Ultimately, this approach will benefit oncology patients by optimizing therapies on a personalized basis.