Fluorophore-Conjugated Antibodies for Imaging and Resection of GI Tumors

我们建议在加州大学的研究人员之间建立一种独特的学术和产业合作关系 加州圣地亚哥(学术合作伙伴)和抗癌公司(工业合作伙伴)开发和验证 荧光团标记抗体在手术导航和腹腔镜定位中的应用 胃肠道肿瘤。拟议的研究将开发先进的成像技术、方法和工具 用于小鼠模型研究，这些研究将可移植到临床，以开发荧光引导的癌症手术。 假设荧光团标记的针对肿瘤特异性抗原的抗体将改善可视化， 原发癌和转移性胰腺癌和结肠癌的检测和切除。 特异性目的1荧光标记抗肿瘤抗原单抗的应用 CA19-9、CEA或两者的组合，以促进肿瘤边缘的成像和切除 胰腺癌和结肠癌的转移性病变。我们将使用荧光标记的单抗 抗肿瘤抗原CA19-9和CEA抗体或两者联合应用评价小鼠体内肿瘤负荷 建立人胰腺癌和结肠癌裸鼠原位转移模型 完全切除原位和转移性病变。毒性、剂量和组织分布研究将 用于荧光团偶联的单抗。 具体目标2我们将比较几种不同的荧光团在体内的剂量响应 在我们的小鼠模型中，信号持续时间、体内光漂白和体内信号背景比 人类胰腺癌。荧光团在体内的初始荧光强度可以有很大的不同 发射、荧光信号的持续时间、上覆组织的散射和吸收以及丢失的倾向 长时间暴露在强光下的荧光强度，这种现象称为光漂白。到期 对于这些荧光团之间的差异，选择一个稳定的荧光团是至关重要的 适合活体使用的波长和信号强度。我们将研究几个不同的荧光团 绿色(480-520 nm)、黄色(550-570 nm)、红色(610-650 nm)和远红(680-710 nm) 人胰腺癌裸鼠原位转移模型中最佳荧光团的确定 荧光引导的人类癌症手术的潜在临床应用的候选者。 具体目的3利用荧光腹腔镜术改善原发性和慢性盆腔炎的可视化 转移性胃肠道癌在正常的腹腔镜照射下是看不到的。有能力清楚地 术前通过腹腔镜术前区分所有荧光标记的癌组织可消除 不必要的剖腹手术和随后直接治疗胰腺癌和结肠癌的发病率。 我们将使用上述目标确定的抗体和荧光团的最佳组合来 比较荧光腹腔镜与传统腹腔镜对肿瘤的检出范围。

We propose a unique academic-industrial partnership between investigators at the University of California San Diego (Academic Partner) and AntiCancer, Inc. (Industrial Partner) to develop and validate the use of fluorophore-conjugated antibodies for surgical navigation and laparoscopic localization of gastrointestinal tumors. The proposed research will develop advanced imaging technology, methods and tools for mouse-model studies that will be translatable to the clinic to develop fluorescence-guided cancer surgery. Hypothesis Fluorophore-labeled antibodies against tumor-specific antigens will improve visualization, detection, and resection of primary and metastatic pancreatic and colon cancer. Specific Aim 1 Utilization of fluorophore-labeled monoclonal antibody specific for the tumor antigen CA19-9, CEA, or a combination of both to facilitate imaging and resection of tumor margins and metastatic lesions in pancreatic and colon cancer. We will use fluorescent-conjugated monoclonal antibodies against tumor antigen CA19-9 and CEA or a combination of both to evaluate tumor burden in vivo in an orthotopic metastatic nude mouse model of human pancreatic and colon cancer and to facilitate the complete resection of orthotopic and metastatic lesions. Toxicity, dosing, and tissue distribution studies will be performed for fluorophore-conjugated monoclonal antibodies. Specific Aim 2 We will compare several different fluorophores for in vivo dosing response, in vivo signal duration, in vivo photobleaching, and in vivo signal-to-background ratio in our mouse models of human pancreatic cancer. Fluorophores can vary greatly in their in vivo intensity of initial fluorescence emission, duration of fluorescence signal, scatter and absorption by overlying tissues and propensity for loss of fluorescence intensity with prolonged exposure to bright light, a phenomenon known as photobleaching. Due to these differences between fluorophores, it is of vital importance to choose a stable fluorophore with appropriate wavelength and signal intensity for in vivo use. We will examine several different fluorophores in the green (480-520 nm), yellow (550-570 nm), red (610-650 nm), and far-red (680-710 nm) ranges in our orthotopic metastastic nude mouse models of human pancreatic cancer to determine the optimal fluorophore candidates for potential clinical use for fluorescence guided cancer surgery in humans. Specific Aim 3 Utilization of fluorescence laparoscopy to improve visualization of primary and metastatic GI cancers not otherwise seen under normal laparoscopic lighting. The ability to clearly distinguish all fluorescently-labeled cancerous tissue pre-operatively via laparoscopy can eliminate the morbidity from an unnecessary laparotomy and direct subsequent treatment of pancreatic and colon cancer. We will use the optimal combination of antibodies and fluorophores as determined by the aims listed above to compare the extent of tumor detection during laparoscopy under fluorescence versus traditional laparoscopy.