Nerve-Specific Near-Infrared Fluorescent Contrast Agents for Image-Guided Surgery

描述（由申请人提供）：在外科手术过程中保留神经的能力仍然是一个令人烦恼的问题，因为周围组织经常掩盖它们。事实上，对于大多数外科手术，神经损伤是主要的发病率。例如，在根治性直肠癌切除术中，保留下腹下丛和海绵体神经至关重要。男性的能力和排尿能力取决于这些神经的正常功能。目前，保留神经的根治性前列腺切除术是基于外科医生对一般前列腺神经解剖学的了解，而不是单个男性的神经可视化。 理想的神经特异性造影剂应满足以下标准：1）在pH 7.4下具有0.5至3的LogD以最大化血神经屏障（BNB）渗透，2）具有500 Da的MW d以最大化BNB渗透，3）结合神经特异性靶标并在神经中保留数小时，以及4）是近红外（NIR）荧光团，其激发和发射波长在700 nm和900 nm之间的NIR“窗口”中。NIR荧光团是图像引导手术的特别令人兴奋的试剂，因为光子穿透最大，组织自发荧光最小，并且由导师实验室开发的FLARE（辅助切除和探索）成像系统已经可用，并正在三个独立的临床试验中使用。尽管FLARE系统具有为神经可视化保留的波长通道，但目前不存在神经特异性NIR荧光团。 在申请人进行的初步研究中，已经合成了两种神经特异性试剂，并发现其突出小鼠、大鼠和猪中的多种神经结构。虽然是一个积极的开始，但这些试剂在吸收波长、发射波长、量子产率和图像引导手术的溶解度特性方面远非理想。该K01奖项的目标将是1）系统地修改现有的药物以实现NIR激发和发射，2）开发可行的体内制剂以量化药物的生物分布和清除，以及3）在图像引导手术中进行动物验证研究。 此K01应用程序是专为具有强大的光学成像技术背景的博士候选人设计的培训工具。我在达特茅斯与Brian Pogue博士一起工作，但在光学造影剂的开发或光学技术的临床转化方面经验有限。通过K01奖项申请，候选人要求接受造影剂化学和体内光学成像方面的强化培训。Mentor的实验室在近红外荧光造影剂的开发和光学技术的临床转化方面拥有专业知识。共同导师的实验室在荧光团化学方面拥有超过20年的经验。在这种学术环境中，K01申请描述了职业发展计划和机构承诺，这将允许候选人在五年内过渡到独立，而她同时有助于研究具有深远临床意义的领域。

DESCRIPTION (provided by applicant): The ability to spare nerves during surgical procedures has remained a vexing problem because surrounding tissue often obscures them. Indeed, for a majority of surgical procedures, nerve damage is the major morbidity. For example, sparing of the inferior hypogastric plexus and cavernous nerve is of paramount importance during radical prostatectomy. Male potency and urinary continence is dependent on proper functioning of these nerves. At the present time, nerve-sparing radical prostatectomies are based on the surgeon's knowledge of general prostate nerve anatomy, rather than nerve visualization in individual men. The ideal nerve-specific contrast agent should fulfill the following criteria: 1) have a LogD at pH 7.4 between 0.5 to 3 to maximize blood-nerve-barrier (BNB) penetration, 2) have a MW d 500 Da to maximize BNB penetration, 3) bind to a nerve-specific target and be retained in nerve for several hours, and 4) be a near-infrared (NIR) fluorophore having excitation and emission wavelengths in the NIR "window" between 700 nm and 900 nm. NIR fluorophores are particularly exciting agents for image-guided surgery since photon penetration is maximal, tissue autofluorescence is minimal, and the FLARE (Fluorescence-Assisted Resection and Exploration) imaging system, developed by the mentor's laboratory, is already available and is being used in three separate clinical trials. Although the FLARE system has a wavelength channel reserved for nerve visualization, no nerve-specific NIR fluorophore presently exists. In preliminary studies conducted by the applicant, two nerve-specific agents have been synthesized and found to highlight a multitude of nervous structures in mice, rats and pigs. Although a positive start, these agents are far from ideal in absorption wavelength, emission wavelength, quantum yield, and solubility properties for image-guided surgery. The goals of this K01 award will be 1) to systematically modify the existing agents to achieve NIR excitation and emission, 2) to develop a viable in vivo formulation to quantify the agent's biodistribution and clearance and 3) to perform animal validation studies in image-guided surgery. This K01 application is designed as a training vehicle for a candidate with a strong background in optical imaging technology from her Ph.D. work with Dr. Brian Pogue at Dartmouth, but limited experience in the development of optical contrast agents or clinical translation of optical technology. Through the K01 award application, the candidate requests intensive training in contrast agent chemistry and in vivo optical imaging. The Mentor's laboratory has expertise in the development of NIR fluorescent contrast agents and the clinical translation of optical technology. The Co-Mentor's laboratory has over 20 years of experience in fluorophore chemistry. Within this academic environment, the K01 application describes a career development plan and institutional commitment that will permit the transition of the candidate to independence over a period of five years, while she simultaneously contributes to an area of investigation with profound clinical significance.