Use of Freshly Amputated Human Limbs for Pre-Clinical Evaluation of Molecular-Targeted Fluorescent Probes.
Use of Freshly Amputated Human Limbs for Pre-Clinical Evaluation of Molecular-Targeted Fluorescent Probes.
复制标题
使用刚截肢的人体肢体进行分子靶向荧光探针的临床前评估。
DOI：
10.1117/12.2650356
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Henderson,EricR
中科院分区：
文献类型：
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作者：
Bateman,LoganM;Hebert,KendraA;Streeter,SamuelS;Nunziata,JennaA;Barth,ConnorW;Wang,LeiG;Gibbs,SummerL;Henderson,EricR
我们共同开发了一种在新鲜截肢的人体肢体中进行荧光检测的同类第一模型。离体人体组织为在进行体内实验之前测试临床前荧光剂、收集成像数据和人体组织中的组织病理学检查提供了独特的机会。现有的临床前荧光剂研究主要依赖于动物模型，其不能直接预测荧光团在人体中的性能，并且如果药剂在早期人体试验中证明无效，则可能导致浪费资源和时间。由于荧光团没有预期的治疗效果，因此其临床实用性仅基于其安全性和突出感兴趣组织的能力。即使通过FDA的0期/微剂量途径推进人体试验，仍然需要大量的资源，单物种药代动力学测试和毒性测试。在最近结束的一项使用截肢人类下肢的研究中，我们能够在临床前开发中成功测试神经特异性荧光团。本研究通过血管插管和心脏灌注泵进行全身给药。我们设想，这种模型可以帮助早期的铅剂测试选择荧光团与各种目标和机制。
We have co-developed a first-in-kind model of fluorophore testing in freshly amputated human limbs. Ex vivo human tissue provides a unique opportunity for the testing of pre-clinical fluorescent agents, collection of imaging data, and histopathologic examination in human tissue prior to performing in vivo experiments. Existing pre-clinical fluorescent agent studies rely primarily on animal models, which do not directly predict fluorophore performance in humans and can result in wasted resources and time if an agent proves ineffective in early human trials. Because fluorophores have no desired therapeutic effect, their clinical utility is based solely on their safety and ability to highlight tissues of interest. Advancing to human trials even via the FDA’s phase 0/microdose pathway still requires substantial resources, single-species pharmacokinetic testing, and toxicity testing. In a recently concluded study using amputated human lower limbs, we were able to test successfully a nerve-specific fluorophore in pre-clinical development. This study used systemic administration via vascular cannulization and a cardiac perfusion pump. We envision that this model may assist with early lead agent testing selection for fluorophores with various targets and mechanisms.