Stimulus-Responsive Microbubbles for Site-Specific Imaging of Thrombosis

用于血栓形成特定部位成像的刺激响应微泡

• 批准号: 8299530
• 负责人: Jennifer N Cha
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299530
• 关键词: Acoustics; Acute; Area; Behavior; Biochemical; Biological; Biological Markers; Blood Clot; Blood coagulation; Cessation of life; Chemicals; Chronic; Clinic; Clinical; Coagulation Process; Contrast Media; Country; DNA; Data; Deep Vein Thrombosis; Detection; Diagnosis; Dimensions; Disease; Early Diagnosis; Engineering; Environment; Enzymes; Equipment; Equipment Design; Evaluation; Excision; Exhibits; Exposure to; Fluorocarbons; Generations; Goals; Health Care Costs; Image; Imaging Techniques; Inferior vena cava structure; Knowledge; Lead; Left; Measures; Microbubbles; Microscopic; Modeling; New Zealand; Noise; Operating Rooms; Oryctolagus cuniculus; Outpatients; Painless; Patients; Peptide Hydrolases; Phlebography; Physiologic pulse; Polymers; Predictive Value; Procedures; Process; Property; Proteinase-Activated Receptors; Protocols documentation; Radiology Specialty; Signal Transduction; Site; Special Equipment; Specificity; Stimulus; System; Techniques; Therapeutic Agents; Thrombin; Thrombosis; Thrombus; Time; Tissues; Translating; Translations; Ultrasonography; Validation; Veins; Work; clinically relevant; crosslink; design; empowered; engineering design; experience; flexibility; improved; in vivo; in vivo Model; interdisciplinary approach; multidisciplinary; novel; outcome forecast; programs; radiologist; research study; response

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.

描述（由申请人提供）：该提案描述了生化反应性超声对比剂的第一个例子的综合和验证，这是对血管内疾病的深度组织成像的潜在突破性进步。通过提高超声波的功能，该多学科建议的完成将为廉价，广泛的技术增添价值和力量，因此具有巨大的临床翻译潜力。此外，这种激活机制可以转化为其他应用，例如直接增强Sonolosic Therapy或特定部位的治疗剂。 在该提案中，该提案描述了生化反应性超声对比剂的第一个例子的综合和验证，这是对血管内疾病的深度组织成像的潜在突破性进步。对这个国家的关注。急性血栓可能会迅速形成并发展为较差的疾病，如果未治疗，可能会导致患者死亡。优选使用压缩超声（一种无痛的，无创的门诊手术）进行检测，对于有症状的，近端的静脉血栓形成具有良好的预测价值。但是，超声无法区分不应治疗的旧凝块和必须立即处理的急性血栓。 PIS团队已经开发了一种新型的微泡，该微泡在正常条件下仍然是超声不可见的，但仅在暴露于某些化学刺激后才能检测到。在激活之前，微泡是通过刚性的交联聚合物壳覆盖的，该壳会抑制微泡对超声的响应。用特定的刺激治疗可以去除交联，从而留下柔性，自由振荡的微泡。可以通过其特异性出色的谐波振荡来检测所得的微泡。 微泡将设计成对凝血蛋白的敏感性，这是凝血级联反应的蛋白酶。微泡将与DNA Aptmaters对凝血酶敏感的聚合物壳涂覆。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波中的行为，以创建超声脉冲程序，以优化信号到噪声成像。然后将在离体流模型和体内兔血栓形成模型中验证这些凝血酶敏感的超声对比剂，以检测实际的急性血栓。因此，一种新型的微泡将调整为与医学相关的系统，并在体内验证，并具有极好的翻译机会。