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

pH 响应型晶体管纳米探针，用于灵敏检测头颈部未知原发性癌症

• 批准号: 10631041
• 负责人: Baran D Sumer
• 金额: $ 56.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631041
• 关键词: Acidosis; Address; Adjuvant Therapy; Aerodigestive Tract; Avidity; Basement membrane; Biopsy; Blood Vessels; Cancer Detection; Cancer Patient; Caring; Cells; Chemotherapy and/or radiation; Clinical; Darkness; Data; Detection; Endoscopes; Epithelium; Excision; FDA approved; Fluorescence; Freezing; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histologic; Histology; Histopathology; Human Papillomavirus; Image; Impairment; Indocyanine Green; Inflammatory; Intravenous; Libraries; Light; Lymphatic; Lymphoid Tissue; Malignant Neoplasms; Malignant neoplasm of pharynx; Mediating; Micelles; Modality; Mucous Membrane; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathology; Patient-Focused Outcomes; Patients; Pharyngeal structure; Phase; Phase II Clinical Trials; Phase Transition; Physical Examination; Polymers; Positron-Emission Tomography; Primary Neoplasm; Prognosis; Quality-Adjusted Life Years; Sensitivity and Specificity; Serious Adverse Event; Staging; Stains; Surface; Tail; Testing; Time; Tissues; Tonsil; Tonsillar Tissue; Tonsillectomy; Transistors; Validation; Veins; X-Ray Computed Tomography; amphiphilicity; aqueous; cancer diagnosis; detection sensitivity; fluorodeoxyglucose; functional improvement; head and neck cancer patient; human tissue; improved; in vivo fluorescence; intravenous administration; intravenous injection; invention; lymph nodes; lymphocyte proliferation; meter; millimeter; nanoprobe; optimal treatments; overtreatment; standard of care; targeted treatment; tumor; tumor microenvironment; viral detection

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.

一种pH响应型晶体管纳米探针用于未知底物的灵敏检测 头颈癌 项目总结/摘要 大约有65，000例头颈部鳞状细胞癌（HNSCC）， 在美国每年都有诊断，并出现在上呼吸消化道的粘膜内层 并扩散到局部淋巴结。在某些情况下，原发性肿瘤太小而无法检测， 淋巴结肿大是HNSCC的唯一表现。这些未知的原发性癌症 人乳头状瘤病毒（HPV）感染引起的UPCs通常发生在Waldeyer's淋巴结的粘膜中， 环，咽部的淋巴扁桃体组织。发现UPC意义重大且有影响力 解决未满足的需求，通过定位改善长期肿瘤和功能结局 并删除UPC。然而，它们的检测受到波纹状的隐蔽表面的损害， 淋巴组织的结节化降低了体检的敏感性， 淋巴组织的血管和氟脱氧葡萄糖（FDG）亲和力掩盖了小肿瘤， 计算机断层扫描（CT）和正电子发射断层扫描（PET）。 我们已经发明了超pH敏感（UPS）纳米探针库，其共价缀合至 吲哚菁绿色（ICG）对酸性肿瘤微环境有反应， 一种这样的纳米探针，ONM-100，已经被用于检测它们的荧光状态从OFF到ON的变化。 在1期和正在进行的FDA批准的2期临床试验中开发和研究。已经 显示耐受性良好，无严重不良事件，与外科内窥镜兼容， 并且能够真实的实时检测包括HNSCC在内的多种癌症。根据这些数据，我们 假设ONM-100作为SOC全景内窥镜检查的辅助手段可以改善 刚果爱国者联盟。为了验证我们的假设，我们将（1）比较可激活的敏感性和特异性 用于癌症检测的探针ONM-100到用于Waldeyer环中的肿瘤的始终开启探针;（2） ONM-100全身给药后检测HPV介导的HNSCC， （3）在全身施用后检测患者中的UPC ONM-100该项目的成功实施将提供UPC的精确切除和避免 UPC患者的强化辅助治疗显著改善了这些患者的护理和结局， 患者在肿瘤学上效果较差，过度治疗不精确。