Dual function theranostic constructs for photoacoustic guided surgery and photodynamic therapy

项目摘要：口腔肿瘤患者的存活率几乎停滞不前。 在过去的十年中，有特殊的发病率，例如舌癌。这种学术和产业伙伴关系的目标是 (AIP)的应用是首次开发一种单一的治疗药物，即靶向双功能 靶向光动力学深部组织光声成像的抗体结合物 治疗(PDT)，以及用于手术指导的集成PAI-超声成像(USI)模块，从而使两个 口腔癌治疗结果的主要障碍已被克服。测量肿瘤侵袭深度的难度 手术切除和残留的显微疾病是导致高死亡率的两个主要障碍。 口腔肿瘤的局部复发率。谨慎切除多余的正常组织会导致功能性 损失和生活质量的降低。通过这个AIP，我们建立了一个合作框架， 哈桑博士在马萨诸塞州综合医院的学术研究实验室，临床耳鼻咽喉科 瓦瓦雷斯医生和奥古斯特医生在大众眼耳医院和MGH的外科团队，以及秋田创新 行业团队，以创建全面的治疗解决方案，使深部组织图像引导，正常 口腔内的保留组织手术和肿瘤靶向空间定位治疗。我们的协同科学 专业知识、各自的基础设施、临床翻译经验和地理位置接近，使我们能够 实现我们的目标。该提案包括三个部分，将实现深层组织图像引导手术和治疗残留 一次手术中的疾病。1.DFAC，通过靶向表皮实现成像和治疗 生长因子受体(EGFR)，口腔肿瘤中公认的生物标记物，2.定制的、整合的PAI 用于手术指导的临床USI模块。3.靶向PDT。DFAC由FDA批准的西妥昔单抗组成 EGFR靶向抗体，与一种用于深层组织PAI的新的近红外(&gt；850 nm)萘酞菁染料偶联 以及FDA批准的光敏剂苯并卟啉衍生物(BPD)。我们假设启用了DFAC 深部组织PAI引导手术和术中残余病变的PDT将实现局部肿瘤控制， 减少复发，提高口腔癌患者的无病生存率和生活质量。这一概念 将在临床前和临床上验证4个特定的目标：AIM-1的开发和体外优化 DFAC用于光声对比剂和治疗效果。通过以下途径优化临床口腔内USI系统以实现PAI 定制的光传输策略和光谱算法。AIM-2。进行啮齿动物毒理学研究， DFAC的GMP生产，并获得EIND批准。AIM-3。小鼠模型治疗效果的评价 口腔癌。AIM-4。利用DFAC引导的PAI能力实施首个人类0期临床试验 勾画出深部肿瘤边缘。相关性：该研究提供深层组织成像和靶向治疗 术中疗程，复发率低，费用低，总存活率高，质量提高 生活。DFAC和集成PAI-US的模块化设计使该平台能够适应其他癌症。

PROJECT SUMMARY: Survival rates in patients with oral cavity tumors have remained nearly stagnant in the past decade with exceptional morbidity e.g., tongue cancers. The goal of this Academic-Industry Partnership (AIP) application is to develop, for the first time, a single theranostic agent namely targeted Dual Function Antibody Conjugate (DFAC) amenable to deep tissue photoacoustic imaging (PAI) with targeted photodynamic therapy (PDT), and an integrated PAI-ultrasound imaging (USI) module for surgery guidance such that the two main barriers to oral cancer treatment outcomes are overcome. Difficulty in gauging the depth of tumor invasion during surgical resection and residual microscopic disease are the two main barriers responsible for the high loco-regional recurrence rates in oral cavity tumors. Cautionary removal of extra normal tissue leads to functional loss and a compromised quality of life. Through this AIP, we establish a collaborative framework between the academic research lab of Dr. Hasan at Massachusetts General Hospital (MGH), the clinical Otolaryngology surgical team of Drs. Varvares and August at Mass Eye and Ear Infirmary and MGH, and the Akita Innovations industry team, to create a comprehensive theranostic solution that enables deep tissue image-guided, normal tissue-sparing surgery and tumor-targeted spatially-localized therapy in the oral cavity. Our synergistic scientific expertise, respective infrastructures, clinical translation experience and geographic proximity position us well to achieve our goals. The proposal has 3 parts that will enable deep tissue image-guided surgery and treat residual disease in one intraoperative setting. 1. A DFAC, that enables both imaging and therapy by targeting Epidermal growth factor receptor (EGFR), an established biomarker in oral cavity tumors, 2. A custom-built, PAI integrated clinical USI module for surgical guidance. 3. Targeted PDT. DFAC is composed of cetuximab, an FDA-approved EGFR targeting antibody, conjugated to a new near-infrared (>850 nm) napthalocyanine dye for deep-tissue PAI and an FDA-approved photosensitizer Benzoporphyrin Derivative (BPD). We postulate that DFAC-enabled deep-tissue PAI- guided surgery and intraoperative PDT of residual disease will achieve local tumor control, reduce recurrence, increase disease-free survival and improve quality of life in oral cancer patients. The concept will be validated pre-clinically and clinically in 4 specific aims: Aim-1 Development and in vitro optimization of DFACs for photoacoustic contrast and therapeutic efficacy. Optimize clinical intra-oral USI systems to PAI via customized light delivery strategies and spectroscopic algorithms. Aim-2. Perform rodent toxicology studies, GMP production of DFAC and obtain eIND approvals. Aim-3. Evaluation of therapeutic efficacy in mouse models of oral cancer. Aim-4. Implementation of first-in-human Phase 0 clinical trial with DFAC-guided PAI ability to delineate deep tumor margins. Relevance: The study offers deep tissue imaging and targeted therapy in a single intraoperative session, resulting in lower recurrence, lower cost, higher overall survival and improved quality of life. The modular design of DFAC and integrated PAI-US, enables adaptation of the platform to other cancers.