A New Multimodal Molecular Imaging Approach to Guide Intra-Operative Tumor Resection and Post-Operative Treatment Planning

项目摘要 几个癌症患者的一线治疗方法是手术切除肿瘤，这可能会导致肿瘤变差。 本地化会导致冗长的不完整手术和重复就诊。我们的目标是为医生提供 一种全新的多模式分子成像策略，有可能提供术中手术 指导以确保肿瘤的完全切除，以及2)术后分子表达信息 改善治疗决策。口腔鳞状细胞癌(OSCC)是一种理想的治疗肿瘤。 开发我们新的多模式成像方法，因为它存在肿瘤分界不佳的问题，而且很容易获得 使用光学成像工具。我们打算开发一种全新的多模式纳米颗粒(NPs)来服务 作为我们的肿瘤靶向造影剂。这些新的NPs旨在提供实时荧光图像 肿瘤切除和拉曼多路成像中的指导以识别分子表达和药物 有效治疗的目标可获得性。这些多模式NPs有可能为医生提供 肿瘤的分子图谱具有更高的敏感性和特异性，这是现有的单一肿瘤图谱所不能达到的 模式分子成像技术。正在进行的开发新造影剂的尝试面临着 在获得监管批准方面存在的主要问题。我们的创新方法使用了已经通过FDA认证的染料 被批准用于我们的食品、药品和化妆品的着色。色彩无处不在，然而，我们常常误以为 当然，我们最喜欢的糖果、化妆品和服装中都有鲜艳的色彩。奇怪的是，之后 考虑到这些“五颜六色”的有机染料可以提供的不仅仅是美学，我们最近发现 它们实际上具有多种有用的光学特性(例如吸光度、荧光、拉曼散射)， 使其成为成像应用的理想之选。我们建议将这些染料及其多模式成像 将能力转化为专门设计的纳米颗粒结构，以提供有用的成像对比度 改进了癌症检测、定位和分子图谱。我们将从描述这些特征开始研究 这些新制造的纳米粒子的物理特征及其多模式成像能力。这将包括 多分子成像技术在体内评价药物的生物分布和渗出特性 工具。然后，我们将在细胞培养和人体组织上测试它们的肿瘤靶向效率。我们的纳米粒子将 通过化学共轭靶向配体主动靶向肿瘤和/或通过 增强了透气性和留着效果。我们将评估肿瘤靶向效率和手术 我们新开发的NPs与现有的临床前和临床分子成像工具的导航潜力。 这些研究将使这些美观的家用有机染料成为多式联用染料。 成像探头实现了一种全新的、临床上可翻译的范例。生成的图像来自 这些多模式纳米颗粒可以改进癌症检测和定位，以改进手术切除， 而且还帮助临床医生设计最适合个别患者的治疗方案。

Project Summary The first line of treatment for several cancer patients is surgical debulking which can suffer from poor tumor localization resulting in lengthy incomplete surgeries and repeat visits. Our objective is to provide physicians with an entirely new multimodal molecular imaging strategy that has the potential to offer 1) intra-operative surgical guidance to ensure complete resection of the tumor, and 2) post-operative molecular expression information to improve therapeutic decision-making. Oral squamous cell carcinoma (OSCC) is an ideal cancer on which to develop our new multimodal imaging approach as it suffers from poor tumor demarcation and is easy to access with optical imaging tools. We intend to develop an entirely new class of multimodal nanoparticles (NPs) to serve as our tumor targeting contrast agents. These new NPs are intended to provide real-time fluorescence image guidance during tumor resection and Raman multiplexed imaging to identify molecular expression and drug target availability for effective therapy. These multimodal NPs have the potential to provide physicians with a molecular map of the tumor with improved sensitivity and specificity not previously achievable with existing single mode molecular imaging technologies. Ongoing attempts toward developing new contrast agents have faced major problems in gaining regulatory approval. Our innovative approach utilizes the dyes that are already FDA approved for the coloring of our foods, drugs and cosmetics. Color is all around us, however, we often take for granted the sources of the vibrant colors we enjoy in our favorite candy, cosmetics and clothing. After curiously considering that these “colorful” organic dyes could offer more than just aesthetics, we recently discovered that they in fact have a multitude of useful optical properties (e.g. absorbance, fluorescence, Raman scattering) that make them ideal for imaging applications. We propose to integrate these dyes and their multimodal imaging capabilities into a nanoparticle construct specially designed to provide useful imaging contrast that enables improved cancer detection, localization and molecular profiling. We will begin our study by characterizing the physical characteristics of these newly fabricated NPs and their multimodal imaging capabilities. This will include in-vivo evaluation of their biodistribution and extravasation properties by utilizing multiple molecular imaging tools. We will then test their tumor targeting efficiency in cell culture and on human tissue. Our nanoparticles will actively target tumors through chemically conjugated targeting ligands and/or passively target the tumor through the enhanced permeability and retention effect. We will assess the tumor targeting efficiency and surgical navigation potential of our newly developed NPs with pre-existing preclinical and clinical molecular imaging tools. These studies will enable the repurposing of these aesthetically pleasing household organic dyes as multimodal imaging probes to enable an entirely new, and clinically translatable, paradigm. The images generated from these multimodal nanoparticles could improve cancer detection and localization for improved surgical resection, but also aid clinicians in the design of treatment protocols which are most suitable for the individual patient.