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; 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.

项目摘要：口腔肿瘤患者的存活率几乎停滞不前 过去的十年，发病率异常，例如舌癌。这个学术与行业伙伴关系的目标 （AIP）应用是首次开发单个静脉剂，即靶向双功能 抗体结合物（DFAC）与深层组织光声成像（PAI）具有靶向光动力学 治疗（PDT）和用于手术指导的综合PAI-Ultrasound Imaging（USI）模块，以使两者 克服了口腔癌治疗结果的主要障碍。衡量肿瘤侵袭深度的困难 在手术切除和残留微观疾病期间，是两个主要障碍 口腔肿瘤中的机车区域复发率。警示去除额外的正常组织会导致功能性 损失和折衷的生活质量。通过此AIP，我们在 马萨诸塞州综合医院（MGH）哈桑博士的学术研究实验室，临床耳鼻喉科学 DRS外科团队。 Varvares和Mass Eye and Ear医院和MGH的八月以及Akita Innovations 行业团队，创建一个综合的疗法解决方案，以实现深层组织图像引导，正常 在口腔中，组织的手术和针对肿瘤的空间定位疗法。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接近地位 实现我们的目标。该提案有3个部分，可实现深层组织图像引导的手术并治疗残留 术中疾病。 1。dFAC，可以通过靶向表皮实现成像和治疗 生长因子受体（EGFR），一种口腔肿瘤中已建立的生物标志物，2。定制的PAI集成 用于手术指导的临床USI模块。 3。目标PDT。 DFAC由Cetuximab组成，是FDA批准的 EGFR靶向抗体，与新的近红外（> 850 nm）的午睡酸苯胺染料相结合，用于深组织PAI 以及由FDA批准的光敏剂苯并核苷衍生物（BPD）。我们假设启用了DFAC 深部组织的手术和残留疾病的术中PDT将获得局部肿瘤控制， 减少复发，增加无病生存率并改善口腔癌患者的生活质量。这个概念 将在4个特定目标中进行临床和临床验证：AIM-1开发和体外优化 光声对比和治疗功效的DFAC。优化临床内部USI系统到PAI通过 定制的轻型输送策略和光谱算法。 AIM-2。进行啮齿动物毒理学研究， GMP生产DFAC并获得EIND批准。 AIM-3。评估鼠标模型中治疗功效 口腔癌。 AIM-4。以DFAC引导的PAI能力实施第一阶段0阶段0临床试验 描绘深肿瘤边缘。相关性：该研究提供了深层组织成像和靶向治疗 术中会议，导致较低的复发，较低的成本，较高的总生存率和提高的质量 生活。 DFAC和集成的PAI-US的模块化设计使平台适应其他癌症。