Stimulus-Responsive Microbubbles for Site-Specific Imaging of Thrombosis

描述（由申请人提供）：本提案描述了首个生化反应超声造影剂的合成和验证，这可能是血管内疾病深层组织成像的突破性进展。通过提高超声的功率，这一多学科建议的完成将为一种廉价、广泛的技术增加价值和功率，因此具有良好的临床转化潜力。此外，这种激活机制可能被转化为其他应用，如直接增强超声治疗或治疗药物的部位特异性释放。在本提案中，本提案描述了首个生化反应超声造影剂的合成和验证，这可能是血管内疾病深层组织成像的突破性进展。关心这个国家。急性血栓可能迅速形成并发展成更严重的情况，如果不及时治疗，可能导致患者死亡。最好使用压缩超声进行检测，这是一种无痛、无创的门诊手术，对症状性近端静脉血栓形成具有良好的预测价值。然而，超声不能区分不应治疗的旧血栓和必须立即治疗的急性血栓。pi团队已经开发出一种新型的微泡，在正常条件下超声波是看不见的，但只有在暴露于某些化学刺激后才会被检测到。在激活之前，微泡被一层刚性的交联聚合物外壳包裹，以抑制微泡对超声波的反应。用特定的刺激去除交联，留下一个灵活的，自由振荡的微泡。由此产生的微泡可以通过其谐波振荡检测，具有优异的特异性。微泡将被设计成对凝血酶（一种参与凝血级联反应的蛋白酶）敏感。微泡将被聚合物外壳包裹，聚合物外壳由对凝血酶敏感的DNA适体交联而成。接下来，它们在超声中的行为将通过PI先前设计的特殊设备在单泡水平上实时检查，以创建超声脉冲程序，以优化信噪比成像。这些对凝血酶敏感的超声造影剂将在离体血流模型和兔体内血栓形成模型中进行验证，以检测实际的急性血栓。因此，一种新型的微泡将被调整到医学相关的系统，并在体内验证，具有极好的翻译机会。

DESCRIPTION (provided by applicant): This proposal describes the synthesis and validation of the first example of a biochemical- responsive ultrasound contrast agent, a potentially groundbreaking advance for deep-tissue imaging of intravascular disease. By improving the power of ultrasound, completion of this multidisciplinary proposal would add value and power to an inexpensive, widespread technique and thus has excellent potential for clinical translation. In addition, this mechanism of activation may be translated to other applications like direct enhancement of sonolytic therapy or site- specific release of therapeutic agents. In this proposal, This proposal describes the synthesis and validation of the first example of a biochemical- responsive ultrasound contrast agent, a potentially groundbreaking advance for deep-tissue imaging of intravascular disease. concern for this country. Acute thrombi may form quickly and develop into worse conditions, potentially leading to patient death if left untreated. Detection is preferably performed using compression ultrasound, a painless, non-invasive outpatient procedure that has good predictive value for symptomatic, proximal vein thrombosis. However, ultrasound cannot differentiate between older clots that should not be treated and acute thrombi that must be treated immediately. The team of PIs has developed a new type of microbubble that remains invisible to ultrasound under normal conditions but becomes detectable only after exposure to certain chemical stimuli. Prior to activation, the microbubble is coated by a rigid, crosslinked polymer shell that dampens the microbubble's response to ultrasound. Treatment with a specific stimulus removes the crosslinks, leaving a flexible, freely oscillating microbubble. The resultant microbubble can be detected via its harmonic oscillations with excellent specificity. Microbubbles will be designed to exhibit sensitivity to thrombin, a protease involved in the coagulation cascade. The microbubbles will be coated with polymer shells crosslinked by DNA aptmaters sensitive to thrombin. Next, their behavior in ultrasound will be examined in real-time on the single bubble level through special equipment previously designed by the PI to create ultrasound pulse programs for optimized signal-to-noise imaging. These thrombin-sensitive ultrasound contrast agents will then be validated in an ex vivo flow model and an in vivo rabbit thrombosis model to detect actual acute thrombi. Thus, a new type of microbubble will be tuned to a medically-relevant system and validated in vivo with excellent chance for translation. PUBLIC HEALTH RELEVANCE: Deep Venous Thrombosis is a rapidly developing, potentially fatal disease that is preferably diagnosed through ultrasound imaging, but current imaging techniques are unable to detect some of its forms. This proposal describes the fabrication and validation of a new type of contrast agent that lays dormant in healthy tissue but becomes strongly detectable by ultrasound in areas of thrombosis. Creation of these contrast agents would greatly improve patient prognosis through early detection and mitigate healthcare costs by empowering a quick and painless procedure that can be performed in operating rooms, clinics, and doctors' offices.