Optimization of an activatable photoacoustic agent to image thyroid cancer

 描述（由申请人提供）：甲状腺癌病例的数量在过去几十年中增加了一倍多。对于所有检测到的癌症，无论其大小或侵袭性如何，最常见的治疗方法是部分或全部甲状腺切除术。目前的临床成像技术不能区分良性和恶性结节或侵略性和惰性甲状腺恶性肿瘤。成像技术的特异性限制导致绝大多数结节活检以及患者过度治疗。光声成像具有良好的深度穿透性，结合高对比度和高分辨率，具有很大的潜力，可在临床上用于浅表器官（如甲状腺）的非侵入性、非电离可视化。在我们针对滤泡性甲状腺癌的初步研究中，我们成功地开发并利用了一种光声成像剂，该光声成像剂通过靶向甲状腺癌特异性生物标志物基质金属蛋白酶（MMP）赋予高肿瘤特异性。在本项目中，我们建议优化原始设计并充分表征新试剂，以开发一种用于甲状腺癌诊断的非侵入性，临床适用的分子光声成像策略。我们推测，分子信息的增加将赋予必要的特异性，已经敏感和广泛传播的甲状腺超声成像技术。我们将首先通过以下方式改善该试剂的信号传导、靶向和递送机制：选择最合适的小分子染料（信号传导）;增强MMP-9的底物特异性（靶向）;以及优化递送载体以实现最大细胞摄取（递送）。然后，通过研究全身和肿瘤生物分布，并进行详细的吸收、分布、代谢、排泄和毒性（ADME-Tox）研究，充分表征优化药物的体内行为。使用优化和药代动力学表征的试剂，我们将对小鼠原位甲状腺肿瘤进行详细的光声成像，并将体内信号强度与肿瘤中存在的MMP-9水平相关联。最后，为了促进临床翻译过程，我们将开发一种成像协议，利用代理与内部制造的临床光声/超声仪器。从该提案中获得的结果预计将显着加快翻译的分子光声成像从工作台到医生的房间。可以检测恶性甲状腺病变并识别需要治疗的患者的成像策略将为患者管理带来重大益处，并降低与大量活检和不必要手术相关的医疗保健成本。

 DESCRIPTION (provided by applicant): The number of thyroid cancer cases has more than doubled in the past few decades. Most common treatment for all detected cancers, regardless of their size or invasiveness, is a partial or full thyroidectomy. Current clinical imaging techniques cannot distinguish between benign and malignant nodules or between aggressive and indolent thyroid malignancy. The specificity limitations of the imaging techniques lead to the overwhelmingly high number of nodule biopsies as well as to the patient overtreatment. Photoacoustic imaging, with good depth penetration in combination with high contrast and high resolution has a great potential to be clinically utilized for non-invasive, non-ionizing visualization of a superficial organ such as the thyroid. In our preliminary studies focused on follicular thyroid cancer, we successfully developed and utilized a photoacoustic imaging agent that imparts high tumor specificity by targeting thyroid cancer specific biomarker, matrix metalloproteinases (MMP). In this project we propose to optimize the original design and fully characterize the novel agent to develop a non-invasive, clinically applicable molecular photoacoustic imaging strategy for diagnosis of thyroid cancer. We hypothesize that the addition of molecular information will impart necessary specificity to the already sensitive and widely spread technique of thyroid ultrasound imaging. We will first improve signaling, targeting and delivering mechanism of the agent by: selecting the most suitable small molecule dyes (signaling); enhancing substrate specificity for MMP-9 (targeting); and optimizing a delivering vehicle for maximum cellular uptake (delivery). The in vivo behavior of the optimized agent will then be fully characterized by investigating the whole-body and tumor biodistribution, and performing detailed Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) studies. Using the optimized and pharmacokinetically characterized agent we will perform detailed photoacoustic imaging of orthotopic thyroid tumors in mice and will correlate the intensity of signal in vivo with the level of the MMP-9 present in the tumors. Finally, to facilitae the clinical translation process, we will develop an imaging protocol utilizing the agent in conjunction with the in-house-made clinical photoacoustic/ultrasound instrument. The results obtained from this proposal are expected to significantly accelerate the translation of molecular photoacoustic imaging from the bench to the physician's room. The imaging strategy that can detect malignant thyroid lesions and identify patients that need treatment would bring major benefit to patient management and reduce the healthcare costs associated with high number of biopsies and unnecessary surgeries.