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，使用回波对比成像检测肿瘤脉管系统。接下来，施加聚焦的、更高强度的超声脉冲序列以激活造影剂/药物载体材料并在受声波照射的区域中释放治疗剂。在此应用中，我们提出了新一代超声触发药物载体材料的设计和评价。药物载体微泡和脂质体构建体将用于将抗肿瘤剂或血栓生成酶释放到肿瘤血管系统中。将实现肿瘤块中的选择性药物沉积。靶向的细胞毒作用和靶向的血栓形成将导致肿瘤生长和凋亡的限制。具体目标（R21阶段）：1。制备可靶向的微泡药物递送结构，并进行模型染料标记物从脂质体、附着于微泡的脂质体和微泡载体的超声介导释放。根据脂质体/颗粒膜组成、结构、相变温度和超声强度、频率和脉冲特征评价释放功效，以实现最佳释放。2.评价微泡/脂质体/药物结构对细胞培养物中活化内皮的靶向性，评估药物释放、凝胶和内皮细胞培养物沉积。3.研究超声介导的“触发”激活微泡/脂质体/酶结构在体外;评价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破坏微泡药物载体系统的能力，并使用超声应用焦点的图像引导靶向。具体目标（R33阶段）：1。在小鼠模型中研究静脉给药后微泡和微泡-脂质体结构的急性毒性、生物分布、血管行为和靶向，比较药物载体颗粒外壳和内容物的回声成像、荧光和放射性标记。2.通过超声成像、放射性标记和荧光标记物的生物分布、荧光体内光学成像和组织学以及长期存活动物研究，研究微泡、脂质体/复合物和包封细胞毒性剂在超声辐照区域的体内蓄积。3.对凝血酶药物载体结构进行超声激活;在活体显微镜检查期间在模型血管系统区域选择性释放凝血酶。监测通过靶组织的血液和微泡流量。4.证明在实体瘤的超声辐照过程中，通过超声触发凝血酶从微泡结构中选择性地释放到肿瘤血管系统区域，本身以及与细胞毒性药物负载颗粒组合，抑制肿瘤生长。治疗后监测肿瘤内的血流。对药物载体配方和超声活化参数进行最终优化。