Development of contrast agents to facilitate image-guided surgery

目前，手术切除为胰腺癌患者提供了唯一的治愈机会。而 切除的目标是获得R 0（阴性）边缘，报告的R1（1 mm内的阳性肿瘤）边缘 接受胰腺切除术的患者的切除率高达75%，导致未满足的需求， 术中识别肝PDAC肿瘤。肿瘤血管受累的程度、潜在的周围环境 炎症、促结缔组织增生反应和致密组织邻接这些关键血管可能影响成功的血管重建。 在潜在的边缘可切除肿瘤患者中进行切除。虽然荧光引导的最新进展 手术和正在进行的积极临床试验，利用近红外荧光标记的单克隆抗体靶向 PDAC已经证明，在肿瘤阳性/上调的某些病例中，PDAC肿瘤增强 这些试验还强调了需要额外的分子探针来解决 胰腺癌的生物标志物异质性。这些近红外荧光成像试验也强调了需要 克服血液和邻近血管对潜在荧光信号的猝灭，以改善切除 精度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，并进行了术中多光谱光声的I期安全性评估 断层扫描（IIT试验NCT 04365413）。临床MSOT研究表明MSOT器械在人体中的安全性 手术设置和我们的小鼠体内结果表明，肿瘤特异性造影剂改善肿瘤 本研究的目的是研制VD-ZW 800 C造影剂，以促进PDAC的图像引导手术。 我们已经开发了第二代光声检测胰腺癌特异性探针，VD- ZW 800 C有助于MSOT或NIR荧光引导下的胰腺癌切除术。总体 假设VD-ZW 800 C具有可接受的安全性，使用VD-ZW 800 C将改善 将PDAC肿瘤组织与良性或纤维化（由化疗或放疗引起）组织分离， 实时使用临床MSOT或NIR荧光成像，比冷冻病理学具有更高的特异性。基于 基于这一假设，我们提出了以下目标：1）开发VD-ZW 800 C， MSOT和NIR荧光; 2）评价临床前毒理学和药代动力学; 3）评估优化的 VD-ZW 800 C使用MSOT和NIR引导手术促进Oncopig中PDAC的检测，并评估VD- ZW 800 C微剂量首次用于人体。成功完成这些具体目标将使VD-ZW 800 C成为 胰腺癌特异性探针可通过MSOT或NIR荧光检测。我们将测试我们的VD-ZW 800 C探头 在Oncopig中作为MSOT和NIR荧光可检测成像探针，在人体中作为第一种。我们的长期 其影响将是证明VD-ZW 800 C作为PDAC特定靶向图像引导手术的可行性 代理未来的审判。

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.