Dual function theranostic constructs for photoacoustic guided surgery and photodynamic therapy

用于光声引导手术和光动力治疗的双功能治疗诊断结构

• 批准号: 10381460
• 负责人: Tayyaba Hasan
• 金额: $ 73.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381460
• 关键词: Adjuvant; Age; Algorithms; Biological Markers; Biology; Biomedical Engineering; Cancer Patient; Cetuximab; Chemicals; Clinic; Clinical; Clinical Research; Collaborations; Custom; Detection; Development; Diagnostic; Disease; Disease-Free Survival; Drug Kinetics; Dyes; Ear; Engineering; Ensure; Epidermal Growth Factor Receptor; Evaluation; Excision; Eye; FDA approved; Fluorescence; General Hospitals; Geography; Goals; Image; Image-Guided Surgery; In Vitro; Industrialization; Industry; Infrastructure; Investigational Drugs; Lesion; Light; Local Therapy; Macular degeneration; Malignant Neoplasms; Massachusetts; Methods; Microscopic; Modality; Morbidity - disease rate; Mouth Neoplasms; Mucous Membrane; New Drug Approvals; Noise; Normal tissue morphology; Operative Surgical Procedures; Optics; Oral; Oral cavity; Otolaryngology; Outcome; PUVA Photochemotherapy; Palpation; Patients; Phase; Phase 0 Clinical Trial; Photochemistry; Photosensitizing Agents; Positioning Attribute; Primary Neoplasm; Production; Quality of life; Radiation Tolerance; Rattus; Recurrence; Reporting; Research; Resected; Residual Tumors; Residual state; Resolution; Rodent; Salivary Glands; Sample Size; Signal Transduction; Structure; Surface; Surgeon; Survival Rate; Therapeutic; Time; Tissue imaging; Tissues; Tongue; Toxic effect; Toxicology; Treatment Efficacy; Treatment outcome; Tumor Burden; Tumor Cell Invasion; Tumor Tissue; Ultrasonography; antibody conjugate; base; bench to bedside; bench-to-bedside translation; cancer cell; chemoradiation; clinical translation; contrast imaging; cost; design; effective therapy; experience; first-in-human; fluorescence imaging; functional loss; healing; human tissue; hydrophilicity; image guided; imaging probe; imaging system; improved; industry partner; innovation; insight; interdisciplinary approach; malignant mouth neoplasm; malignant tongue neoplasm; mouse model; overexpression; photoacoustic imaging; physical property; pre-clinical; skills; standard of care; systemic toxicity; targeted treatment; theranostics; therapeutic evaluation; tumor; ultrasound

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.

项目总结：口腔肿瘤患者的生存率在2000年几乎停滞不前。 过去十年发病率异常，例如，舌癌这个学术-工业伙伴关系的目标 (AIP)应用是开发，第一次，一个单一的治疗诊断剂，即针对双功能 适用于具有靶向光动力学的深部组织光声成像（派）的抗体缀合物（DFAC） 治疗（PDT）和集成PAI-超声成像（USI）模块，用于手术指导， 口腔癌治疗结果的主要障碍被克服。难以测量肿瘤浸润深度 在手术切除和残留的显微镜下疾病是两个主要的障碍，负责高 口腔肿瘤的局部区域复发率。谨慎切除额外的正常组织导致功能性 损失和生活质量受损。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总医院（MGH）的学术研究实验室，临床耳鼻喉科 Mass Eye and Ear Infirmary和MGH以及秋田Innovations的Varvares博士和August博士的手术团队 行业团队，以创建一个全面的治疗诊断解决方案，使深部组织图像引导，正常 口腔中的组织保留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很好地 实现我们的目标。该提案有3个部分，将使深部组织图像引导手术和治疗残留 在一个术中设置疾病。1. DFAC，通过靶向表皮实现成像和治疗 生长因子受体（EGFR），口腔肿瘤中已确立的生物标志物，2.定制的派集成 用于手术指导的临床USI模块。3.靶向PDT。DFAC由西妥昔单抗（FDA批准的 EGFR靶向抗体，与新型近红外（>850 nm）萘酞菁染料偶联，用于深层组织派 和FDA批准的光敏剂苯并卟啉衍生物（BPD）。我们假设DFAC使能 深部组织派引导的手术和残余病变的术中PDT将实现局部肿瘤控制， 减少复发，提高无病生存率，改善口腔癌患者的生活质量。概念 将在4个特定目标中进行临床前和临床验证：Aim-1开发和体外优化 用于光声对比度和治疗功效的DFAC。优化临床口内USI系统，通过派 定制的光传输策略和光谱算法。目标二进行啮齿动物毒理学研究， DFAC的GMP生产并获得eIND批准。目标三在小鼠模型中的治疗有效性评价 口腔癌目标四实施具有DFAC指导的派能力的首次人体0期临床试验 描绘深部肿瘤边缘。相关性：该研究提供了一个单一的深层组织成像和靶向治疗。 术中会话，导致更低的复发率，更低的成本，更高的总生存率和改善的质量 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。