Development of contrast agents to facilitate image-guided surgery

目前，手术切除是治疗胰腺癌的唯一途径。而当 切除的目标是获得R0(阴性)边缘，报告的R1(阳性肿瘤在1毫米内)边缘 接受胰腺切除的患者的切除率高达75%，导致未得到满足的需求 术中发现活体PDAC肿瘤。肿瘤血管受累程度、周围潜伏期 炎症、促结缔组织反应和与这些关键血管毗邻的致密组织可能会影响成功 可能患有交界性可切除肿瘤的患者的切除。虽然荧光引导技术的最新进展 利用近红外荧光标记的单抗靶向的外科手术和正在进行的积极临床试验 PDAC在某些肿瘤阳性/上调的病例中显示了PDAC的肿瘤增强 受体的表达，这些试验也强调了需要额外的分子探针来解决 胰腺癌中生物标记物的异质性。这些近红外荧光成像试验也突显了 克服血管和邻近血管潜在的荧光信号猝灭，提高切除率 精确度。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 并进行了术中多光谱光声治疗的I期安全性评估 断层扫描(IIT试验NCT04365413)。临床MSOT研究表明MSOT装置在人体内是安全的 手术环境和我们的小鼠体内实验结果表明，肿瘤特异性造影剂可以改善肿瘤 识别，我们的目标是开发VD-ZW800C造影剂，以促进图像引导下的PDAC手术。 我们已经开发出第二代可光声检测的胰腺癌特异性探针--VD- ZW800C促进MSOT或近红外荧光引导下胰腺癌切除。最重要的是 假设VD-ZW800C将具有可接受的安全性，并且使用VD-ZW800C将改善 从良性或纤维化(化疗或放射治疗所致)组织中分离PDAC肿瘤组织 实时使用临床MSOT或近红外荧光成像，比冰冻病理具有更强的特异性。基座 基于这一假设，我们提出了以下目标：1)开发可用来检测的VD-ZW800C MSOT和NIR荧光；2)评估临床前毒理学和药代动力学；以及3)评估优化 VD-ZW800C便于使用MSOT和近红外引导手术检测OnCopig中的PDAC，并评估VD- ZW800C微剂人体首例。这些具体目标的成功完成将使VD-ZW800C成为一种 可通过MSOT或近红外荧光检测到的胰腺癌特异性探针。我们将测试我们的VD-ZW800C探头 作为一种MSOT和近红外荧光成像探针，在OnCopig和人类中都是第一种。我们的长期合作 其影响将在于论证VD-ZW800C作为PDAC特定靶向图像引导手术的可行性 未来试验的代理人。

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.