Image-guided Ultrasound-triggered Tumor Therapy

图像引导超声触发肿瘤治疗

• 批准号: 7665195
• 负责人: ALEXANDER L KLIBANOV
• 金额: $ 37.55万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665195
• 关键词: Acute; Aftercare; Animals; Apoptosis; Area; Behavior; Biodistribution; Blood; Blood Vessels; Blood flow; Characteristics; Complex; Contrast Media; Cultured Cells; Cytotoxic agent; Deposition; Drug Carriers; Drug Delivery Systems; Drug Formulations; Dyes; Encapsulated; Endothelial Cells; Endothelium; Enzymes; Evaluation; Fluorescence; Frequencies; Gel; Generations; Histology; Image; In Vitro; Label; Liposomes; Mediating; Membrane; Microbubbles; Modeling; Monitor; Pharmaceutical Preparations; Phase; Phase Transition; Physiologic pulse; Pulse taking; Radioactive; Radiolabeled; Solid Neoplasm; Structure; System; Therapeutic Agents; Thrombin; Thrombosis; Thrombus; Tissues; Toxic effect; Transition Temperature; Ultrasonic Therapy; Ultrasonography; antitumor agent; cytotoxic; design; fluorescence imaging; image guided therapy; in vivo; intravenous administration; intravital microscopy; mouse model; optical imaging; particle; radiotracer; subcutaneous; therapeutic enzyme; tumor; tumor growth

DESCRIPTION (provided by applicant): Ultrasound offers a unique approach to image-guided therapy. First, tumor vasculature is detected using echo contrast imaging. Next, focused, higher-intensity ultrasound pulse sequence is applied to activate contrast/drug carrier material and release the therapeutic agent in the insonated area. In this application we propose the design and evaluation of a new generation of ultrasound-triggered drug carrier materials. Drug carrier microbubbles and liposome constructs will be applied to release antitumor agents or thrombus-generating enzyme into tumor vasculature. Selective drug deposition in the tumor mass will be achieved. Targeted cytotoxic effect on the tumor and targeted thrombosis will result in restriction of tumor growth and apoptosis. Specific aims (R21 Phase): 1. Prepare targetable microbubble drug delivery constructs and perform ultrasound-mediated release of model dye markers from liposomes, liposomes attached to microbubbles, and microbubble carriers. Evaluate release efficacy as a function of liposome/particle membrane composition, structure, phase transition temperature and ultrasound intensity, frequency and pulse characteristics to achieve optimal release. 2. Evaluate targetability of microbubble/liposome/drug constructs to activated endothelium in cell culture, assess drug release, gel and endothelial cell culture deposition. 3. Study ultrasound-mediated "triggering" activation of microbubble/liposome/enzyme constructs in vitro; evaluate release and therapeutic enzyme availability to convert the substrate. 4. Assess the ability of ultrasound energy to destroy microbubble drug carrier systems in an in vivo subcutaneous tumor on demand with image-guided targeting of ultrasound application focus. Specific aims (R33 Phase): 1. Study acute toxicity, biodistribution, vascular behavior and targeting of microbubbles and microbubble-liposomes constructs in a mouse model after intravenous administration comparing echo imaging, fluorescence and radioactive labeling of shells and contents of drug carrier particles. 2. Investigate in vivo accumulation of microbubbles, liposomes/complexes, and encapsulated cytotoxic agents in the areas of insonation, by ultrasound imaging, biodistribution of radiolabeled and fluorescent markers, fluorescence in vivo optical imaging, and tissue histology, as well as longer-term survival animals studies. 3. Perform ultrasound activation of thrombin drug carrier constructs; release thrombin selectively in the areas of model vasculature during intravital microscopy. Monitor blood and microbubble flow through target tissue. 4. Demonstrate arrest of tumor growth by ultrasound-triggered release of thrombin from microbubble constructs selectively in the areas of tumor vasculature during insonation of a solid tumor, per se and in combination with cytotoxic drug-loaded particles. Monitor blood flow within the tumor after treatment. Perform final optimization of the drug carrier formulation and ultrasound activation parameters.

描述（由申请人提供）：超声提供了一种独特的图像引导治疗方法。首先，使用回声对比成像检测到肿瘤脉管系统。接下来，将聚焦，更高强度的超声脉冲序列应用于激活造影剂/药物载体材料并释放受宗修宗区的治疗剂。在此应用中，我们提出了新一代超声触发的药物载体材料的设计和评估。药物载体微泡和脂质体构建体将用于释放抗肿瘤剂或产生血栓形成酶为肿瘤脉管系统。将实现肿瘤质量中的选择性药物沉积。靶向细胞毒性对肿瘤和靶向血栓形成的作用将导致肿瘤生长和凋亡的限制。具体目的（R21期）：1。准备靶向微泡药物输送构建体，并从脂质体，附着在微泡中的脂质体和微泡载体进行超声介导的模型染料标记。评估释放功效是脂质体/颗粒膜组成，结构，相变温度和超声强度，频率和脉冲特性的函数，以实现最佳释放。 2。评估微泡/脂质体/药物构建体在细胞培养中活化的内皮，评估药物释放，凝胶和内皮细胞培养物沉积的目标。 3。研究超声介导的微泡/脂质体/酶构建体的“触发”激活；评估释放和治疗酶的可用性以转换底物。 4。评估超声能量在体内皮下肿瘤中销毁微泡药物载体系统的能力，并以图像引导的超声施用量的靶向超声靶向。具体目的（R33期）：1。研究急性毒性，生物分布，血管行为以及在静脉内给药后，在小鼠模型中，在小鼠模型中比较了Echo成像，荧光和壳壳的壳壳壳的荧光和放射性标记后，在小鼠模型中对微生物和微泡脂质体构建体进行了研究。 2。通过超声成像，放射性标记和荧光标记物的生物分布，体内光学成像中的荧光以及组织学成像以及组织学组织学和长期术语生存动物研究，研究微泡，脂质体/复合物以及封装的细胞毒性剂的体内积累。 3。执行凝血酶药物载体构建体的超声激活；在内部显微镜检查过程中，在模型脉管系统中有选择地释放凝血酶。监测血液和微泡流过靶组织。 4。证明，通过超声触发的凝血酶从微泡构建体中释放出肿瘤脉管造成的肿瘤脉络膜的释放，在实体肿瘤的致命期间，本身并结合细胞毒性药物载荷的颗粒，在肿瘤脉管系统中有选择性地释放了肿瘤生长。治疗后监测肿瘤内的血液流动。对药物载体配方和超声激活参数进行最终优化。