Ultrabright Theranostic SERRS Nanoparticles for Gastrointestinal Endoscopy

摘要 胃肠道癌症，如食道癌、胃癌和结直肠癌，是最常见的 具有挑战性且致命的癌症类型。仅结直肠癌就是导致男性癌症的第三大常见原因。 以及美国的女性，尽管实施了结肠镜检查以早期发现。食道和 胃癌不太常见，但如果不及早发现，其预后是可怕的。 目前的临床实践标准使用传统的白光内窥镜检查，其局限性在于它 仅提供形态信息，难以检测到显微损伤，并且高度可操作性 依附的。如果上下部内窥镜检查依赖于 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4代SerRS-纳米星(4G纳米星)-静脉注射后 既有癌前病变又有癌病变的地方。它们发出一种独特的拉曼光谱 签名(“拉曼指纹”)，清楚地识别肠道病变。因为它具有很高的灵敏度 (在大气压范围内的检测极限)，即使是100微米大小的微小病变也可以被检测到。4G- 纳米星是针对临床翻译而开发的，由惰性材料组成。 重要的是，可以检测4G纳米星的临床拉曼内窥镜已经开发出来。 我们将首先在NIH纳米技术表征的帮助下对4G-纳米星进行表征 实验室确保最佳配方，并在体内研究之前排除任何意想不到的不良影响。 然后我们将在小鼠身上确定最佳剂量，并使用非侵入性动态正电子发射断层扫描 成像，以量化4G-纳米星在器官和肠道病变中的生物分布。4G-NanSTAR吸收 将根据组织学对食道、胃和结肠病变进行量化和分级 对每个病变进行分类，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-Nanstar检测肠道的准确性 在食道癌、胃癌和结肠癌的小鼠和大型动物模型中的病变。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-NanSTAR成像的准确性。我们会 还评估了使用SERRS-纳米星作为光热消融剂的治疗效果。总而言之， 这项提议旨在建立一种全新的、高度可翻译的方法，将允许更多 敏感和特异地检测和消融食道、胃、结肠的(癌前)病变 还有直肠。这些实验都经过了周密和严谨的设计，因此在资助期结束时，所有 数据已经获得，可以提交IND进行临床试验。

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.