Clinical Translation of Near Infrared Nerve-Specific Fluorophores for Nerve-sparing Prostatectomy

项目总结 医源性神经损伤是外科手术最可怕的并发症之一。神经是至关重要的 对大多数组织和神经的功能损伤可导致永久性残疾。外科手术是常见的 在美国，每年约有4000万例手术，造成多达60万例医源性神经损伤。 一种特别受神经损伤困扰的手术是根治性前列腺切除术(Rp)，它发生神经损伤。 在多达60%的患者中，尽管保留神经的外科手术方法已有30年的历史。目前在那里 没有临床批准的技术来改善手术中神经组织的视觉识别，留下 外科医生主要依靠解剖学知识来定位肉眼看不见的微小或被埋藏的神经。 荧光引导手术(FGS)是一个新兴的领域，已被证明在改善手术结果方面有效 用于肿瘤切除和正常解剖保存使用分子靶向荧光团和商业 FGS成像系统。我们已经开发了几个首创的、有针对性的近红外(NIR)荧光团， 具有高亲和力的神经组织标记-到目前为止最有希望的是IT01-08。IT01-08专门标记啮齿动物， 全身给药后的猪和狗的神经，并在体外的人身上表现出交叉反应 标本染色。值得注意的是，我们已经开发了一个IT01-08衍生品的库，其中几个已经展示 在初步测试中极大地改善了水的溶解度和毒性分布，增加了未观察到的有害物质 效应水平(NOAEL)剂量2-10倍。需要进行最终的溶解度、毒理学和药理学测试才能选择 来自IT01-08及其衍生物的铅化合物。在先导化合物选择之后，临床翻译 最佳的近红外神经特异性荧光体将在保留神经的RP中增强神经识别，从而导致 减少神经损伤，改善患者预后。这项研究的直接里程碑包括--第一阶段：(1) 选择临床上可行的近红外神经特异性荧光团进行翻译，(2)相关的药代动力学、剂量 包括药效学和生物分布量化，以及(3)初步毒理学分析 研究性新药(IND)-使研究成为可能。第二阶段：(4)综合良好实验室操作规范(GLP) 荧光团和制剂产品，(5)GLP两种药理和毒理学(PHARM/TOX)研究 协助(6)成功地向FDA提出IND申请。我们的长期战略计划是发展我们的近红外神经- 人用特定荧光团增强神经的识别和保存具有广泛的临床意义 对所有外科专科的影响。完成拟议的目标将建立这些项目的临床前测试 有望用于首次人体试验的神经增强剂，并为工业提供坚实的基础 临床翻译的合作伙伴关系和投资。

PROJECT SUMMARY Iatrogenic nerve injury is one of the most feared complications of surgery. Nerves are critically important to the function of most tissues and nerve injury can lead to permanent disability. Surgery is performed commonly in the U.S. with approximately 40 million operations annually, incurring up to 600,000 iatrogenic nerve injuries. One procedure particularly plagued by nerve damage is radical prostatectomy (RP), where nerve damage occurs in up to 60% of patients, despite the practice of nerve sparing surgical methods for >30 years. At present there is no clinically approved technology to improve visual recognition of nerve tissue during surgery, leaving surgeons to rely largely on anatomical knowledge to locate small or buried nerves invisible to the naked eye. Fluorescence-guided surgery (FGS) is a nascent field with demonstrated efficacy in improving surgical outcomes for cancer resection and normal anatomy preservation using molecularly-targeted fluorophores and commercial FGS imaging systems. We have developed several first-in-kind, targeted, near-infrared (NIR) fluorophores that label nerve tissue with high affinity—to date the most promising is IT01-08. IT01-08 specifically labels rodent, swine and canine nerves following systemic administration and demonstrates cross reactivity in ex vivo human specimen staining. Notably, we have developed a library of IT01-08 derivatives, several of which have displayed vastly improved water solubilities and toxicity profiles in preliminary testing, increasing the no observed adverse effect level (NOAEL) doses 2-10X. Final solubility, toxicology, and pharmacology testing is required to select a lead compound from IT01-08 and its derivatives. Following lead compound selection, clinical translation of the optimal NIR nerve-specific fluorophore will enhance nerve identification during nerve-sparing RP, resulting in reduced nerve injury and improved patient outcomes. This study’s immediate milestones include – Phase I: (1) selection of a clinically viable, NIR nerve-specific fluorophore for translation, (2) relevant pharmacokinetics, dose ranging pharmacodynamics, and biodistribution quantification, and (3) preliminary toxicology analysis to guide investigational new drug (IND)-enabling studies. Phase II: (4) good laboratory practice (GLP) synthesized fluorophore and formulation product for, (5) a GLP two-species pharmacology and toxicology (pharm/tox) study facilitating, (6) a successful IND application to the FDA. Our long-term strategic plan is to develop our NIR nerve- specific fluorophores for human use to enhance the identification and preservation of nerves with broad clinical impact for all surgical subspecialties. Completion of the proposed aims will establish pre-clinical testing of these promising nerve highlighting agents towards first-in-human trials and provide a strong foundation for industry partnerships and investment for clinical translation.