(PQD5) imaging systemic tissue injuries induced by anticancer drugs

化疗药物是杀伤肿瘤细胞的毒素，但其疗效往往受到耐受性的限制 正常组织的上限。全身毒性的调查将为新药提供有价值的信息 药物开发候选人，以及现有药物组合的治疗方案 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一种新的 用于表征抗癌药物的全身毒性特征的方法。细胞凋亡是一个重要的 毒性引起的组织损伤的表现。全身扫描，我们称之为“ToxScan”， 就对药物的毒性反应而言，全身性损伤。我们用放射性药物， 99 mTc-Duramycin，检测死亡和垂死细胞中暴露的磷脂酰乙醇胺。成像 试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，它是独一无二的 适用于全身成像应用。我们的中心假设是，全身毒性特征反映了 个体对抗癌治疗的敏感性。扫描提供了药物耐受性的指标， 慢性不良影响指标。在初步研究中，我们证明了全身的敏感性， 99 mTc-Duramycin扫描，通过检测单次临床相关剂量后多个组织中的细胞死亡 阿霉素全身细胞凋亡扫描也显示了对同一治疗的个体化反应。 方案.组织损伤的单器官和多器官指数正被用于诊断和预后 目的以这种方式进行毒性评价将显著加速新药物的开发。 抗癌药物和新的联合治疗。最终，这种方法将使肿瘤患者受益， 在个性化的基础上优化治疗。

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 suited 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.