Acoustic Nanobeacons for Targeted Detection and Treatment of Tumor Angiogenesis

该项目的统一和长期假设是使用新型超声造影剂成像 试剂可以描绘与血管生成、炎症和炎症相关的选定分子表位， 在肿瘤扩张过程中的非常早期阶段的肿瘤转移（“血管生成开关”）， 使用配体靶向的全氟化碳纳米颗粒乳剂造影剂。靶向配体，如 血管整联蛋白α v β 3或ASFA和跨膜糖蛋白如“组织因子”存在于 肿瘤生长和转移所需的血管生成新血管系统的阶段。其它表位 例如纤维蛋白作为肿瘤的临时基质并允许植入。我们已经开发出一种 液体全氟化碳纳米颗粒造影剂，其用作各种 病理学我们建议使用这个平台来定义所选分子表位的表达， 将单克隆Ab或小分子肽模拟物与纳米颗粒缀合， 靶向配体： 由于超声技术在临床上遍及世界各地，并且是一种相对较好的超声技术， 便宜，便携，简单的成像方式，可在大多数医疗中心，它提供了一个 有机会实施具有全球渗透性和广泛基础的相关性的临床分子成像 疾病片段因此，我们将定义靶向纳米颗粒在表征癌症中的作用 与临床和研究（高频）超声成像仪。我们将演示应用 用于局部递送可通过超声监测的抗血管生成剂的载药纳米颗粒 成像作为药物递送和功效的替代终点。我们还将制定方法， 使用非空化的载药纳米颗粒的药物沉积和治疗功效 与商用成像仪一起应用的聚焦超声也可以提高诊断准确性 用于检测靶向载药纳米颗粒的结合。我们还将开发和实施新的 与飞利浦医疗的超声科学家一起， 用于某些类型的纳米颗粒的灵活和可调的热活化的系统， 可视化与新的“热闪光成像”技术，并为重点相转换的目标 液体全氟化碳纳米颗粒用于治疗。最后，我们将评估这些方法， 在临床前安全性测试中，预计将提交IND和51 OK申请， 纳米颗粒剂、方法和硬件。

The unifying and long-range HYPOTHESIS of this project is that imaging with novel ultrasound contrast agents can delineate selected molecular epitopes associated with angiogenesis, inflammation, and metastasis in tumors at very early stages in the process of tumor expansion (the "angiogenic switch") with the use of ligand-targeted, perfluorocarbon nanoparticle emulsion contrast agents. Targeting ligands such as vascular integrin alphavbeta3 or asfa and transmembrane glycoproteins such as "tissue factor" are present in early stages of angiogenic neo-vasculature that are required for tumor growth and metastases. Other epitopes such as fibrin serve as the provisional matrix of tumors and permit implantation. We have developed a liquid-perfluorocarbon nanoparticle contrast agent that serves as a targeting platform for a variety of pathologies. We propose to employ this platform to define the expression of selected molecular epitopes by conjugation of either monoclonal Ab or small molecule peptidomimetics to the nanoparticle for use as targeting ligands: Because ultrasound technology is clinically ubiquitous throughout the world, and is a comparatively cheap, portable, and straightforward imaging modality available at most medical centers, it offers an opportunity to implement clinical molecular imaging with global penetration and relevance to broad-based disease segments. Accordingly, we will define the role of targeted nanoparticles for characterizing cancer with both clinical and research (high frequency) ultrasound imagers. We will demonstrate the application of drug-carrying nanoparticles for local delivery of antiangiogenic agents that can be monitored with ultrasound imaging as a surrogate endpoint for drug delivery and efficacy. We also will develop approaches to enhance drug deposition and therapeutic efficacy from drug-carrying nanoparticles with the use of noncavitating focused ultrasound applied with commercially available imagers that also may improve diagnostic accuracy for detecting binding of targeted drug-carrying nanoparticles. We also will develop and implement new combined thermal and imaging probes ("TIPS") together with ultrasound scientists at Philips Medical Systems for flexible and tunable thermal activation of certain types of nanoparticles that are more easily visualized with novel "thermal flash imaging" techniques, and for focused phase conversion of targeted liquid perfluorocarbon nanoparticles for therapeutics. Finally, we will evaluate these methods and compositions in preclinical safety testing in anticipation of filing IND and 51 OK applications on new nanoparticulate agents, methods, and hardware.