A pH Responsive Transistor-like Nanoprobe for Sensitive Detection of Unknown Primary Cancers of the Head and Neck

一种灵敏检测未知基团的pH响应型管状纳米探针 头颈部癌症 项目摘要/摘要 大约65,000例头颈部鳞状细胞癌(HNSCC)患者 每年在美国确诊，出现在上呼吸道的粘膜衬里 并扩散到局部淋巴结。在某些情况下，原发肿瘤太小而无法检测到， 结节增大是HNSCC的唯一表现。这些未知的原发癌症 常由人乳头瘤病毒(HPV)诱发，常发生于Waldeyer‘s粘膜。 咽部的扁桃体淋巴组织。寻找UPC意义重大且影响深远 解决未得到满足的需求，并通过定位改善长期肿瘤和功能结果 以及移除UPC。然而，它们的检测受到波纹、隐蔽表面和 淋巴组织结节，降低体检的敏感性，而 淋巴组织的血管密度和氟脱氧葡萄糖亲和力通过 计算机断层扫描(CT)和正电子发射断层扫描(PET)。 我们已经发明了一个超pH敏感(UPS)纳米探针库，共价连接到 对酸性肿瘤微环境有反应的吲哚青绿(ICG)，伴随着尖锐的 它们的荧光状态从关闭变为打开。其中一个这样的纳米探针ONM-100已经被 在FDA批准的第一阶段和正在进行的第二阶段临床试验中开发和研究。一直以来都是这样 显示出良好的耐受性，没有严重的不良反应，与手术内窥镜兼容， 并能够实时检测包括HNSCC在内的各种癌症。基于这些数据，我们 假设ONM-100用作SOC全胃镜检查的辅助设备可以提高对 UPC。为了检验我们的假设，我们将(1)比较Actiatable的敏感性和特异性 用于癌症检测的ONM-100探头对Waldeyer环肿瘤的探头始终在用；(2) 全身应用ONM-100后检测HPV介导的HNSCC的比较 对真阳性肿瘤的荧光；(3)全身给药后检测患者的UPC ONM-100。该项目的成功执行将提供UPC的精确切除和避免 对UPC患者的强化辅助治疗显著改善了这些患者的护理和预后 因肿瘤效果不佳而遭受严重痛苦的患者。

A pH Responsive Transistor-like Nanoprobe for Sensitive Detection of Unknown Primary Cancers of the Head and Neck Project Summary/Abstract Approximately 65,000 cases of Head and Neck Squamous Cell Cancer (HNSCC) are diagnosed each year in the US and arise in the mucosal lining of the upper aerodigestive tract and spread to local lymph nodes. In some cases, the primary tumor is too small to be detected, with enlarged nodes being the only manifestation of HNSCC. These unknown primary cancers (UPCs), often induced by human papilloma virus (HPV), usually arise in the mucosa of Waldeyer's ring, the lymphatic tonsillar tissues of the pharynx. Finding UPC is significant and impactful addressing an unmet need with long term oncologic and functional outcomes improved by locating and removing UPC. However, their detection is impaired by the corrugated, cryptic surface, and nodularity of lymphatic tissue which decreases the sensitivity of physical examination while the vascularity and fluorodeoxyglucose (FDG) avidity of the lymphoid tissue obscure small tumors by computerized tomography (CT) and positron emission tomography (PET). We have invented a library of ultra pH sensitive (UPS) nanoprobes, covalently conjugated to indocyanine green (ICG) that respond to acidic tumor microenvironment, with a concomitant sharp change in their fluorescence state from OFF to ON. One such nanoprobe, ONM-100, has been developed and studied in a Phase 1 and ongoing FDA approved Phase 2 clinical trial. it has been shown to be well tolerated with no serious adverse events, compatible with surgical endoscopes, and able to detect a variety of cancers including HNSCC in real time. Based on these data we hypothesize that ONM-100 used as an adjunct to SOC panendoscopy can improve detection of UPC. To test our hypothesis, we will (1) Compare the sensitivity and specificity of activatable probe ONM-100 for cancer detection to always ON probes for tumors in Waldeyer's ring; (2) Detect HPV-mediated HNSCC in patients after systemic administration of ONM-100 comparing fluorescence to true-positive cancers; (3) Detect UPC in patients after systemic administration of ONM-100. Successful execution of this project will provide precise excision of UPC and avoidance of intense adjuvant therapy for UPC patients significantly improving care and outcomes for these patients who suffer greatly from less oncologically effective imprecise overtreatment.