Development of contrast agents to facilitate image-guided surgery

开发造影剂以促进图像引导手术

• 批准号: 10810184
• 负责人: Ajay Jain
• 金额: $ 60.7万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810184
• 关键词: Address; Adjuvant Chemotherapy; Adverse effects; Area; Benchmarking; Benign; Binding; Biodistribution; Biological Markers; Blood; Blood Proteins; Blood Vessels; Clinical; Clinical Trials; Contrast Media; Data; Desmoplastic; Detection; Development; Devices; Dose; Drug Kinetics; Dyes; Excision; Fibrosis; Fluorescence; Formulation; Freezing; Future; Generations; Goals; Head; Heterogeneity; Human; Image-Guided Surgery; Imaging technology; Inflammation; Label; Laboratories; Maleimides; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Measures; Methods; Microscopic; Modeling; Molecular; Molecular Probes; Monoclonal Antibodies; Mus; Near-infrared optical imaging; Neoadjuvant Therapy; No-Observed-Adverse-Effect Level; Non-Malignant; Oncopig; Operative Surgical Procedures; Oxyhemoglobin; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Pathology; Patient Care; Patients; Peptides; Peripheral; Pharmacodynamics; Phase; Positive Lymph Node; Procedures; Radiation therapy; Reporter; Reporting; Resectable; Resolution; Risk; Safety; Sampling; Sensitivity and Specificity; Signal Transduction; Specificity; Tail; Testing; Tissues; Toxic effect; Toxicology; Translating; Tumor Tissue; Work; chemotherapy; clinical translation; deoxyhemoglobin; extracellular; fluorescence imaging; image guided; imaging modality; imaging probe; improved; in vivo; innovation; meter; optoacoustic tomography; pancreatic cancer patients; phase II trial; pre-clinical; preclinical development; receptor expression; safety assessment; safety testing; scale up; surgical risk; targeted imaging; time use; tumor

Presently, surgical resection offers the only chance of cure for patients with pancreatic adenocarcinoma. While the goal of resection is to obtain R0 (negative) margins, the reported R1 (positive tumor within 1 mm) margin resection rates of patients undergoing pancreatic resection range up to 75% resulting in an unmet need to intraoperatively identify live PDAC tumor. The extent of vascular involvement of tumor, potential surrounding inflammation, desmoplastic reaction, and dense tissue abutting these critical vessels may impact successful resections in potentially patients with borderline resectable tumors. While recent advances in fluorescent-guided surgery and on-going active clinical trials that utilize NIR-fluorescent labeled monoclonal antibodies to target PDAC have demonstrated PDAC tumor enhancement in some cases where tumors were positive/upregulated expression of the receptor, these trials also highlight the need for additional molecular probes to address biomarker heterogeneity in pancreatic cancer. These NIR-fluorescent imaging trials also highlight the need to overcome potential fluorescent signal quenching by blood and adjacent blood vessels to improve resection accuracy. To address these limitations, we have investigated extracellular acidic pH as a biomarker for pancreatic cancer and conducted a Phase I safety assessment of intraoperative Multispectral Optoacoustic Tomography (IIT trial NCT04365413). Clinical MSOT study indicated safety of the MSOT device in a human surgical setting and our murine in vivo results suggest that tumor-specific contrast agents improve tumor identification, our objective to develop VD-ZW800C contrast agent to facilitate image-guided surgery of PDAC. We have developed a second generation optoacoustically detectable pancreatic cancer specific probe, VD- ZW800C to facilitate MSOT- or NIR-fluorescent- guided resection of pancreatic cancer. The overarching hypothesis is that VD-ZW800C will have an acceptable safety profile and use of VD-ZW800C will improve the separation of PDAC tumor tissue from benign or fibrosis (resulting from chemo- or radiation therapy) tissues in real-time using clinical MSOT or NIR fluorescent imaging with greater specificity than frozen pathology. Based upon this hypothesis, we propose the following objectives: 1) Develop VD-ZW800C that is detectable using MSOT and NIR fluorescence; 2) Evaluate preclinical toxicology and pharmacokinetics; and 3) Assess optimized VD-ZW800C to facilitate detection of PDAC in Oncopig using MSOT and NIR-guided surgery and assess VD- ZW800C microdose 1st-in human. Successful completion of these specific aims will produce VD-ZW800C as a pancreatic cancer-specific probe detectable by MSOT or NIR fluorescence. We will test our VD-ZW800C probe as both an MSOT and NIR-fluorescent detectable imaging probe in the Oncopig and 1st in human. Our long-term impact will be in demonstrating the feasibility of VD-ZW800C as a PDAC specific targeted image guided surgical agent for future trials.

目前，手术切除为胰腺腺癌患者提供了唯一的治疗机会。尽管 切除的目的是获得R0（负）边缘，报告的R1（1 mm范围内的阳性肿瘤） 接受胰腺切除术的患者切除率最高75％，导致未满足的需求 术中识别活PDAC肿瘤。肿瘤的血管参与程度，周围的潜力 炎症，脱糖反应和邻接这些关键血管的密集组织可能会影响成功 潜在的可切除肿瘤患者的切除术。虽然荧光引导的最新进展 手术和正在进行的活跃临床试验，利用NIR荧光标记为单克隆抗体的手术 在某些情况下，PDAC已证明PDAC肿瘤的增强，肿瘤是阳性/上调的 受体的表达，这些试验还强调了需要附加分子探针来解决的。 胰腺癌生物标志物异质性。这些NIR荧光成像试验也强调了 克服潜在的荧光信号通过血液和邻近的血管淬灭以改善切除 准确性。为了解决这些局限性，我们研究了细胞外酸性pH作为生物标志物 胰腺癌并进行了I期术中多光谱光声的安全评估 断层扫描（IIT试验NCT04365413）。临床MSOT研究表明，MSOT设备在人类中的安全性 手术环境和我们的鼠体内结果表明肿瘤特异性对比剂改善肿瘤 识别，我们开发VD-ZW800C对比剂以促进PDAC的图像引导手术的目标。 我们已经开发了第二代光学检测到的胰腺癌特异性探针VD- ZW800C促进胰腺癌的MSOT或NIR荧光引导切除术。总体 假设是VD-ZW800C具有可接受的安全性，使用VD-ZW800C将改善 PDAC肿瘤组织与良性或纤维化（由化学疗法或放射治疗）组织的分离 实时使用临床MSOT或NIR荧光成像具有比冷冻病理更特异性的实时。基于 通过此假设，我们提出以下目标：1）开发可检测的VD-ZW800C MSOT和NIR荧光； 2）评估临床前毒理学和药代动力学； 3）评估优化 VD-ZW800C使用MSOT和NIR引导的手术促进PDAC在Oncopig中检测并评估VD- ZW800C Microdose 1st-in Human。这些特定目标的成功完成将产生VD-ZW800C作为一个 通过MSOT或NIR荧光检测到胰腺癌特异性探针。我们将测试我们的VD-ZW800C探针 作为MSOT和NIR荧光的可检测成像探针，在人类中也是第一个。我们的长期 影响将在证明VD-ZW800C作为PDAC特异性图像指导外科手术的可行性上 未来试验的代理商。