Instantaneous Tumor Spray for Real-Time Surgical Guidance

早期卵巢癌通常是无症状的。直到疾病达到 晚期，疾病表现为广泛的腹腔内腹膜转移。 标准护理治疗包括手术细胞减灭术以去除肿瘤块，然后使用铂类药物 化疗或原发性新辅助化疗，然后在肿瘤缩小后进行间隔细胞减灭术。 尽管成功的初步治疗，80-90%的晚期癌症女性经历肿瘤复发。 手术结果可能会有很大的不同，因为有些癌性病变是肉眼不可见的 监视或触诊，这是外科医生实时可用的唯一工具。有重要证据表明， 延长的无病期或甚至治愈与切除多少癌组织有因果关系。 一种敏感、特异、易于可视化的染料，可精确突出小颗粒（<5 mm）和其他隐藏颗粒 病变将更好地区分健康组织和癌组织，能够更好地做出明智的手术决策， 为卵巢癌患者带来更好的结果。 在分子靶向技术公司（Molecular Targeting Technologies，Inc.）威尔康奈尔医学院， 开发一种新型的肿瘤特异性药物，用于术中近红外荧光成像， 实时的癌症手术。在初步的可行性研究中，我们已经确定了优化的pH敏感 近红外荧光染料（CypH-11），在正常组织中不发荧光，但立即发荧光 当喷到微环境呈微酸性的癌组织上时，我们假设癌症 CypH-11的选择性染色将使外科减瘤手术精确有效， 通常看不见的小而隐匿的病变，实现更好的手术效果。这种方法可能预示着一个 外科肿瘤学的范式转变。 在直接进行第二阶段SBIR研究时，我们将扩大CypH-11的合成和生产， 符合cGMP的配制小瓶;对CypH-11进行临床前优化和验证 在皮下小鼠模型中测定制剂的活性，并在原位模型中验证其灵敏度和特异性 模拟临床环境;并获得药代动力学、生物分布和毒性数据， 探索性IND备案。该申请将提交给FDA，预计将进行0期首次人体研究。

Early stage ovarian cancer is typically asymptomatic. Undiagnosed until the disease has reached an advanced stage, the disease presents extensive intra-abdominal peritoneal metastases. Standard of care treatment includes either a surgical cytoreduction to remove tumor bulk, then platinum-based chemotherapy or primary neoadjuvant chemotherapy followed by interval cytoreduction after tumor shrinkage. Despite successful initial treatments, 80–90% of women with advanced cancer experience tumor recurrence. Surgical outcomes can vary considerably since some cancerous lesions are not visible to naked-eye surveillance or palpation, the only tools available to the surgeon in real-time. There is significant evidence that an extended disease-free period or even a cure are causally related to how much cancerous tissue is excised. A sensitive, specific, easy to visualize dye which precisely highlights small (< 5mm) and otherwise hidden lesions would better differentiate healthy from cancerous tissue, enable better informed surgical decisions and lead to better outcomes for ovarian cancer patients. In this collaboration between Molecular Targeting Technologies, Inc. and Weill Cornell Medical School we are developing a novel, tumor-specific agent for intraoperative near-infrared fluorescence imaging to guide ovarian cancer surgeries in real-time. In preliminary feasibility studies we have identified an optimized pH-sensitive near-infrared fluorogenic dye (CypH-11) which is non-fluorescent in normal tissues, but fluoresces immediately when sprayed onto cancer tissue, whose microenvironment is slightly acidic. We hypothesize that the cancer selective staining by CypH-11 will make the surgical debulking procedure precise and effective by locating normally unseen small and occult lesions, achieving a better surgical outcome. This approach could herald a paradigm shift in surgical oncology. In direct to Phase II SBIR studies we will scale-up synthesis and manufacture of CypH-11 and the final formulated vial in compliance with cGMP; perform preclinical optimization and validation of the CypH-11 formulation in a subcutaneous murine model and validate its sensitivity and specificity in an orthotopic model that simulates the clinical setting; and obtain pharmacokinetic, biodistribution and toxicity data to support an exploratory IND filing. The application will be submitted to the FDA anticipating a Phase 0 first-in-human study.