Stimulus-Responsive Microbubbles for Site-Specific Imaging of Thrombosis

描述（由申请人提供）：该提案描述了生化响应超声造影剂的第一个实例的合成和验证，这是血管内疾病的深层组织成像的潜在突破性进展。通过提高超声波的功率，完成这一多学科的建议将增加价值和功率的廉价，广泛的技术，因此具有良好的潜力，临床翻译。此外，这种激活机制可以转化为其他应用，如直接增强超声治疗或治疗剂的位点特异性释放。 在该提案中，该提案描述了生化响应超声造影剂的第一个示例的合成和验证，这是血管内疾病的深层组织成像的潜在突破性进展。关心这个国家。急性血栓可能迅速形成并发展为更严重的疾病，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、非侵入性的门诊程序，对有症状的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团队开发了一种新型的微泡，在正常条件下对超声保持不可见，但只有在暴露于某些化学刺激后才能检测到。在激活之前，微泡被刚性交联聚合物壳包覆，该壳抑制微泡对超声的响应。用特定刺激物处理去除交联，留下柔性的、自由振荡的微泡。所得的微泡可以通过其具有优异特异性的谐波振荡来检测。 微泡将被设计为对凝血酶（一种参与凝血级联反应的蛋白酶）表现出敏感性。微泡将被对凝血酶敏感的DNA适配体交联的聚合物壳包覆。接下来，将通过PI先前设计的特殊设备在单个气泡水平上实时检查它们在超声中的行为，以创建用于优化信噪比成像的超声脉冲程序。这些凝血酶敏感的超声造影剂将在体外血流模型和体内兔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，并在体内验证具有良好的翻译机会。

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.