Ultrabright Theranostic SERRS Nanoparticles for Gastrointestinal Endoscopy

总结 食道癌、胃癌和结直肠癌等胃肠道癌症是最常见的癌症之一 具有挑战性和致命性的癌症类型。仅结直肠癌是男性癌症的第三大常见原因 和美国妇女，尽管实施结肠镜检查以早期发现。食管和 胃癌虽然不常见，但若不及早发现，预后极差。 目前的临床实践标准使用传统的白色光内窥镜，其局限性在于， 仅提供形态学信息，难以检测显微病变， 依赖。如果依靠以下方法，上消化道和下消化道内窥镜检查的受益将更大 特定的分子信号。为此，我们开发了新一代超灵敏拉曼 纳米粒子信标-第四代SERRS-纳米星（4G Nanostars）-静脉注射后 专门针对癌前病变和癌性病变。它们发出独特的拉曼光谱 特征（“拉曼指纹”），其清楚地识别肠道病变。因为它的灵敏度很高 （检测限在阿摩尔范围内），甚至可以检测到100 µm大小的显微病变。4G-- Nanostars是以一种特殊的眼光开发的，用于临床转化，由惰性材料组成。 重要的是，已经开发出了可以检测4G纳米星的临床拉曼内窥镜。 我们将首先在NIH纳米技术表征的帮助下表征4G纳米星 实验室确保最佳配方，并在体内研究之前排除任何意外的不良反应。 然后我们将确定小鼠的最佳剂量，并使用非侵入性动态正电子发射断层扫描 成像以量化4G-Nanostars在器官和肠道病变中的生物分布。4G-Nanostar摄取 食管、胃和结肠病变将根据组织学 每个病变的分类，以确定它们是否可以用于非侵入性地区分不同的 病变类型随后，我们将确定4G-Nanostars可以检测肠道的准确性。 在小鼠和大型动物模型的食管癌、胃癌和结肠癌中的病变。我们将测试 使用我们的合作者开发的临床拉曼内窥镜进行4G-Nanostar成像的准确性。我们将 还使用光热消融评估SERRS-Nanostars作为治疗诊断剂的用途。总的来说， 该提案旨在建立一种全新的、高度可翻译的方法， 敏感和特异性地检测和消融食管、胃、结肠的（前）恶性病变 和直肠实验设计彻底和严格，以便在资助期结束时，所有 已获取数据以提交临床试验IND。

Summary Gastrointestinal cancers such as esophageal, gastric, and colorectal cancers represent some of the most challenging and lethal cancer types. Colorectal cancer alone is the third most common cause of cancer in men and women in the United States, despite implementation of colonoscopy for early detection. Esophageal and gastric cancers are less common, but their prognosis is dire if not detected early. The current standard of clinical practice uses conventional white light endoscopy, which is limited in that it offers only morphological information, has difficulties detecting microscopic lesions, and is highly operator dependent. Much greater benefits of upper and lower endoscopy would be anticipated if it would rely on specific molecular signals. To this end, we have developed a new generation of ultra-sensitive Raman nanoparticle beacons – 4th generation SERRS-Nanostars (4G Nanostars) – that after intravenous injection home specifically to both precancerous and cancerous lesions. They emit a unique Raman spectroscopic signature (“Raman fingerprint”) that clearly identifies the intestinal lesion. Because of the very high sensitivity (limit of detection in the attomolar range), even microscopic lesions of 100 µm in size can be detected. The 4G- Nanostars were developed with a special eye towards clinical translation, and consist of inert materials. Importantly, a clinical Raman endoscope that can detect the 4G-Nanostars has already been developed. We will first characterize the 4G-Nanostars with the assistance of the NIH Nanotechnology Characterization Laboratory to ensure optimal formulation and exclude any unexpected adverse effects ahead of in vivo studies. We will then determine optimal dosage in mice, and use non-invasive dynamic positron emission tomography imaging to quantify the biodistribution of 4G-Nanostars in organs and intestinal lesions. 4G-Nanostar uptake into esophageal, gastric and colonic lesions will be quantified and ranked according to the histological classification of each lesion, in order to determine if they can be used to noninvasively discriminate different lesion types. Subsequently, we will determine the accuracy with which 4G-Nanostars can detect the intestinal lesions in both mouse and large animal models of esophageal, gastric and colon cancer. We will test the accuracy of 4G-Nanostar imaging using a clinical Raman endoscope developed by our collaborators. We will also evaluate the use of SERRS-Nanostars as a theranostic agent using photothermal ablation. In summary, this proposal aims to establish a fundamentally new and highly translatable method that will allow more sensitive and specific detection and ablation of both (pre-)malignant lesions of the esophagus, stomach, colon and rectum. The experiments are designed thoroughly and rigorously so that at the end of the grant period all data has been acquired to file an IND for a clinical trial.