Contrast Enhanced Ultrasound with Therapeutic Modality

描述（由申请人提供）： 造影剂（CA）开发的最新进展扩大了诊断超声（US）的范围，超声是一种成像方式，具有安全、实时、廉价和便携的优点。现在的挑战是区分器官（如肝脏和乳腺）中的软组织转移，对实际和潜在疾病状态（如动脉粥样硬化斑块或缺血区域）进行成像，以及区分恶性和良性。此外，超声的治疗作用的潜力，使用成像来引导和触发药物输送提出了令人兴奋的新的研究领域。长期目标是开发一种具有治疗能力的聚合物超声造影剂。目标是使用相同的US能量对药物从CA的释放进行成像和靶向。聚合物CA应增强诊断图像，并帮助医生定位病变组织。该试剂必须是无毒的、生物相容的、可生物降解的并且在注射后在成像期间是稳定的。它必须不受阻碍地通过毛细血管床（直径小于-6 pm）。第一个目标是开发一种CA，其在医学成像范围（1-10 MHz）内具有回声，并且在体内稳定，提供清晰的诊断图像，并且具有递送药物的潜力。第二种是将药物附着在CA的表面上，并使用聚焦US在所需的时间和位置可视化并释放精确剂量的药物。具体目标1：开发、优化和表征生物可降解聚合物CA，其特性使其能够用作药物载体和递送系统。具体目标2：在使用和不使用不同频率的US的情况下，表征中空聚合物微胶囊的降解模式。具体目标3：研究生物活性化合物掺入聚合物胶囊壳中。将确定产生生物活性化合物的最大有效载荷并减少任何初始突释效应的方法。具体目标4：确定超声能量对造影剂中生物活性化合物释放速率和模式的影响、超声对化合物活性的影响以及有效载荷对声学特性的影响。了解超声参数、频率、压力和能量对药物释放曲线的影响，探讨药物释放的机理，以便更好地控制药物的释放曲线。具体目标5：使用组织培养的乳腺癌细胞系研究体外声触发药物递送。通过评估组织培养物中的细胞损伤，与空白胶囊和单独US相比，将测试优化的载药胶囊的生物活性化合物释放功效。这些研究是在体内研究之前显示可行性的前奏。

DESCRIPTION (provided by applicant): Recent advances in contrast agent (CA) development have expanded the range of diagnostic ultrasound (US), an imaging modality that has the advantage of being safe, real-time, inexpensive and portable. The challenge now becomes the differentiation of soft tissue metastases in organs such as the liver and breast, imaging of actual and potential disease states such as atherosclerotic plaque or regions of ischemia, and discrimination between malignant and benign. Moreover the potential of a therapeutic role for US, using imaging to guide and trigger drug delivery presents exciting new areas of research. The long-term objective is to develop a polymer-based US contrast agent with therapeutic capabilities. The goal is to both image and target release of a drug from the CA using the same US energy. The polymer CA should enhance the diagnostic image and aid the physician in locating diseased tissue. The agent must be non toxic, biocompatible, biodegradable and stable after injection for the duration of imaging. It must pass unimpeded through the capillary bed, (be less than -6 pm in diameter). The first aim is to develop a CA that is echogenic in the medical imaging range, (1-10 MHz) and stable in vivo giving a clear diagnostic image and have the potential to deliver a drug. The second is to attach a drug onto the surface of the CA and to use focused US to visualize and release the exact dose of drug at the time and location required. Specific Aim 1: To develop, optimize and characterize a biodegradable polymer CA with characteristics that enable it to function as a drug carrier and delivery system. Specific Aim 2: To characterize the degradation pattern of the hollow polymer microcapsules, with and without US of different frequencies. Specific Aim 3: To investigate incorporation of bioactive compounds into the polymer capsule shell. Determination will be made of the method which yields the greatest payload of the bioactive compound and which reduces any initial burst effect. Specific Aim 4: To determine the effects of ultrasound energy on the bioactive compound release rate and pattern from the contrast agent, the effect of ultrasound on the compound activity and the effect of payload on acoustic properties. To understand the effects of the ultrasound parameters, frequency, pressure and energy on the drug release profile, and investigate the mechanism of drug release, in order to better control the release profile. Specific Aim 5: Investigate acoustically-triggered drug delivery in vitro using tissue cultured breast cancer cell lines. Optimized drug-loaded capsules will be tested for efficacy of bioactive compound release by assessing cell damage in tissue cultures, compared with blank capsules and with US alone. These studies are a prelude to show feasibility prior to in vivo studies.