Ultrasound Molecular Imaging to Assess Therapeutic Response

 描述(申请人提供)：在过去的十年里，分子成像已经成为一种强大的新成像方法，通过在细胞水平上提供与疾病相关的生理评估来增强超声的能力。我们团队的目标是开发造影剂和超声技术，以显著提高诊断分子成像在临床翻译中的实用价值。到目前为止，我们的团队已经取得了几项非常重要的进展：(1)我们研制了一种新型的靶向造影剂，埋藏配体微泡，它是超声靶向的，非免疫原性的，减少了非特异性相互作用的可能性；(2)我们说明了定制造影剂的尺寸分布以提高成像对比度的效用；(3)我们证明了声辐射力在分子成像研究中的优势；(4)我们用未经改进的临床超声系统进行了声辐射力增强的分子成像；(5)我们说明了超声分子成像中需要三维；(6)我们肯定了超声分子成像在评估啮齿动物肿瘤对抗血管生成治疗的反应中的作用；以及(7)我们证明了声辐射力和埋藏配体微泡的组合具有更高的靶向性。与我们平行工作的其他几个小组已经证实了我们的结果，说明在啮齿动物身上，超声分子成像可以比传统方法(如肿瘤大小测量)更快地提供肿瘤治疗反应的指示。这一结果的意义在于，超声分子成像可以为监测肿瘤学中的个性化药物方法提供强大、低成本、安全的床边支持。随着这些技术的进步和啮齿动物模型的良好结果，现在是时候评估这项技术的临床应用的可译性了。到目前为止，美国所有报道的分子成像研究都是在小动物身上进行的。在这个项目中，我们将在一群患有自发性软组织肉瘤的客户拥有(宠物)犬身上验证超声分子成像技术。这一大型动物模型是验证超声分子成像临床应用的理想平台。狗接受与人类相似的放射和化疗治疗，其大小可以使用临床超声系统，并且可以使用原型分子靶向造影剂进行成像，而没有FDA和其他监管障碍。因此，该项目的目标是测试超声分子成像的能力，以检测犬患者肿瘤对治疗的早期反应。接受化疗的患者将受到监测，数据将与DCE-CT和免疫组织化学的黄金标准相关联。这项大型动物、多中心、临床前研究将得到一些研究的支持，以确保犬模型中分子成像的最佳性能，例如实现成像的3-D接口、对比剂和超声参数的优化，以及对专门饲养的狗的毒性的初步研究。我们目标的实现和超声分子成像作为具有临床价值的兽医肿瘤学治疗监测技术的验证将推动这项有前途的技术走向人类应用。

 DESCRIPTION (provided by applicant): Over the past decade, molecular imaging has gained traction as a powerful new imaging method to enhance the capabilities of ultrasound by providing assessment of physiology associated with disease on the cellular level. Our team has set out with the goal of developing contrast agents and ultrasound technology to substantially improve the utility of diagnostic molecular imaging for clinical translation. Thus far, our team ha achieved several highly significant advances: (1) we formulated a new type of targeted contrast agent, the buried-ligand microbubble, which is ultrasound-targeted, non-immunogenic and reduces the potential for nonspecific interactions; (2) we illustrated the utility of tailoring thesize distribution of contrast agents to improve imaging contrast; (3) we demonstrated the advantage of acoustic radiation force to enhance sensitivity in molecular imaging studies; (4) we performed acoustic radiation force-enhanced molecular imaging with an unmodified clinical ultrasound system; (5) we illustrated the need for 3-D in ultrasound molecular imaging; (6) we affirmed the utility of ultrasound molecular imaging in assessing tumor response to anti-angiogenic therapy in rodents; and (7) we demonstrated increased targeting specificity with the combination of acoustic radiation force and buried-ligand microbubbles. Several other groups working parallel to ours have corroborated our results, illustrating in rodents that ultrasound molecular imaging can provide an indication of tumor response to therapy significantly sooner than traditional methods, such as tumor size measurements. The significance of this result is that ultrasound molecular imaging can provide robust, low-cost, safe, bedside support for monitoring personalized medicine approaches in oncology. With these technological advances and promising results in rodent models, it is now time to evaluate the translatability of this technology for clinical application. To date, all reported molecular imaging studies in the US have been in small animals. In this project, we will validate the technology of ultrasound molecular imaging in a population of client-owned (pet) dogs with spontaneous soft tissue sarcomas. This large animal model is an ideal platform for validation of the clinical utility of ultrasound molecular imaging. Dogs receive similar radiation and chemotherapeutic treatments as humans, are of a size where clinical ultrasound systems can be utilized, and can be imaged with prototype molecularly targeted contrast agents without FDA and other regulatory hurdles. Thus, the goal of this project is to test the ability of ultrasound molecular imaging to detect eary response of tumors to therapy in canine patients. Patients undergoing chemotherapy will be monitored, and data will be correlated with the gold standards of DCE-CT and immunohistochemistry. This large animal, multi-center, pre-clinical study will be supported with studies to insure optimal performance of molecular imaging in the canine model, such as implementation of a 3-D interface for imaging, optimization of contrast agent and ultrasound parameters, and preliminary studies of toxicity in purpose-bred dogs. Accomplishment of our aims and validation of ultrasound molecular imaging as a treatment monitoring technique of clinical value for veterinary oncology will propel this promising technology toward human applications.