Image-guided Ultrasound-triggered Tumor Therapy

图像引导超声触发肿瘤治疗

基本信息

批准号：
8141399
负责人：
ALEXANDER L KLIBANOV
金额：
$ 37.77万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8141399
关键词：
Acute Adverse drug effect Adverse effects Aftercare Animals Antineoplastic Agents Apoptosis Area Behavior Biodistribution Biological Biological Models Blood Blood Circulation Blood Vessels Blood flow Cell Culture Techniques Characteristics Complex Contrast Media Cytotoxic agent Data Deposition Detection Development Devices Diagnostic Diagnostic Imaging Drug Carriers Drug Compounding Drug Delivery Systems Drug Formulations Drug resistance Dyes Effectiveness Elements Encapsulated Endothelial Cells Endothelium Enzymes Evaluation Event Fever Fluorescence Fluorescence Microscopy Frequencies Gel Generations Goals Histology Image Image Analysis In Vitro Ionizing radiation Label Lead Lipids Liposomes Malignant Neoplasms Mediating Membrane Methods Microbubbles Microscopy Modeling Molecular Target Monitor Morbidity - disease rate Mus Mutate Mutation Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures Optics Organ Outcome Patients Penetration Pharmaceutical Preparations Pharmacologic Substance Phase Phase Transition Photochemotherapy Physiologic pulse Proteins Radiation therapy Radioactive Radiolabeled Research Proposals Solid Neoplasm Specificity Staging Structure System Testing Therapeutic Agents Therapeutic Intervention Thrombin Thrombosis Thrombus Time Tissue Model Tissues Toxic effect Transducers Transition Temperature Tumor Tissue Ultrasonic Therapy Ultrasonography Work antitumor agent base cancer cell cancer therapy cytotoxic design effective therapy feeding fluorescence imaging image guided therapy improved in vivo intravenous administration intravital microscopy irradiation monolayer mortality mouse model neoplastic cell next generation novel novel strategies optical imaging particle pressure radiofrequency radiotracer response subcutaneous success therapeutic enzyme tumor tumor growth

项目摘要

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）：超声波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肿瘤脉管系统。接下来，应用聚焦的、更高强度的超声脉冲序列来激活造影剂/药物载体材料并在声波照射区域释放治疗剂。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估。药物载体微泡和脂质体结构将用于将抗肿瘤剂或血栓生成酶释放到肿瘤脉管系统中。将实现肿瘤块中的选择性药物沉积。对肿瘤的靶向细胞毒作用和靶向血栓形成将导致肿瘤生长和细胞凋亡的限制。具体目标（R21 阶段）： 1. 制备靶向微泡药物递送结构，并通过超声介导从脂质体、附着于微泡的脂质体和微泡载体中释放模型染料标记物。评估释放功效作为脂质体/颗粒膜组成、结构、相变温度和超声强度、频率和脉冲特征的函数，以实现最佳释放。 2. 评估微泡/脂质体/药物构建体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. 研究超声介导的体外“触发”微泡/脂质体/酶结构的激活；评估转化底物的释放和治疗酶的可用性。 4. 通过图像引导超声应用焦点的靶向，评估超声能量按需破坏体内皮下肿瘤中微泡药物载体系统的能力。具体目标（R33阶段）： 1.研究静脉注射后小鼠模型中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，比较回声成像、荧光和壳的放射性标记以及药物载体颗粒的含量。 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、组织组织学以及长期研究，研究声波区域中微泡、脂质体/复合物和封装的细胞毒剂的体内积累生存动物研究。 3. 对凝血酶药物载体构建体进行超声激活；在活体显微镜检查期间在模型脉管系统区域选择性地释放凝血酶。监测流经目标组织的血液和微泡。 4. 证明在实体瘤本身或与细胞毒性载药颗粒组合的声波照射期间，超声触发的微泡结构中的凝血酶选择性地在肿瘤脉管系统区域中释放，从而抑制肿瘤生长。治疗后监测肿瘤内的血流。对药物载体配方和超声激活参数进行最终优化。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Focused ultrasound and microbubbles for enhanced extravasation.

DOI：
10.1016/j.jconrel.2010.06.012
发表时间：
2010-11-20
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Böhmer MR;Chlon CHT;Raju BI;Chin CT;Shevchenko T;Klibanov AL
通讯作者：
Klibanov AL

Ultrasound-triggered release of materials entrapped in microbubble-liposome constructs: a tool for targeted drug delivery.

DOI：
10.1016/j.jconrel.2010.07.115
发表时间：
2010-11-20
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Klibanov AL;Shevchenko TI;Raju BI;Seip R;Chin CT
通讯作者：
Chin CT

Nanobody-coupled microbubbles as novel molecular tracer.

DOI：
10.1016/j.jconrel.2011.12.007
发表时间：
2012-03-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Hernot S;Unnikrishnan S;Du Z;Shevchenko T;Cosyns B;Broisat A;Toczek J;Caveliers V;Muyldermans S;Lahoutte T;Klibanov AL;Devoogdt N
通讯作者：
Devoogdt N

An ultrasound contrast agent targeted to P-selectin detects activated platelets at supra-arterial shear flow conditions.