Enzyme-Responsive Nanoemulsions as Tumor-Specific Ultrasound Contrast Agents for

酶响应纳米乳剂作为肿瘤特异性超声造影剂

• 批准号: 8009635
• 负责人: Andrew P Goodwin
• 金额: $ 8.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009635
• 关键词: Acoustics; Animals; Architecture; Award; Binding; Biocompatible; Biological; Biological Markers; Biological Models; Biology; Blood Circulation; Breast Adenocarcinoma; Breast Cancer Model; CCNE1 gene; California; Cancer Center; Cancer Patient; Carbon Nanotubes; Chemicals; Chemistry; Computers; Contrast Media; Crosslinker; DNA; Detection; Development; Dose; Early Diagnosis; Electrical Engineering; Emulsions; Engineering; Enzymes; Evaluation; Excision; Fluorocarbons; Funding; Gelatinase A; Goals; Gold; Head; Health; Human; Hybrids; Image; In Vitro; Inflammation; Institutional National Research Service Award; Laboratories; Legal patent; Ligands; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Mediating; Mentors; Mentorship; Methods; Microbubbles; Modeling; Mus; Nanostructures; Nanotechnology; Optics; Organic Synthesis; Pathway interactions; Peptide Hydrolases; Peptides; Phase; Polymers; Postdoctoral Fellow; Preparation; Process; Property; Radiology Specialty; Research; Research Personnel; Research Project Grants; Research Proposals; Resources; Science; Scientist; Screening procedure; Site; Stimulus; Structure; Surface; Suspension substance; Suspensions; System; Techniques; Technology; Testing; Therapeutic; Thrombin; Thrombosis; Training; Training Programs; Tumor Tissue; Ultrasonography; Universities; Work; base; cancer imaging; cancer therapy; clinical efficacy; crosslink; design; drug mechanism; imaging modality; improved; in vivo; innovation; instrumentation; malignant breast neoplasm; molecular imaging; nanoemulsion; nanoengineering; nanomaterials; nanoscale; novel; outcome forecast; overexpression; perfluoropentane; professor; public health relevance; research clinical testing; response; sensor; success; symposium; tumor; validation studies; vaporization

DESCRIPTION (provided by applicant): This proposal supports the application of Dr. Andrew Goodwin for a Pathway to Independence Award in Cancer Nanotechnology (RFA-CA-09-015). Already a promising junior scientist in organic synthesis, macromolecular engineering, and nanotechnology development for cancer imaging and therapy, Dr. Goodwin seeks to obtain training in benchtop and biological validation studies to become a successful independent innovator in cancer nanotechnology. Dr. Goodwin obtained his Ph. D from UC Berkeley in 2007 under the direction of Prof. Jean Frichet, where he designed new polymer architectures and novel release drug mechanisms for cancer therapy. He then continued to the Stanford University CCNE in the labs of Prof. Hongjie Dai, where he functionalized carbon nanotubes and gold nanostructures with new synthetic biocompatible assemblies to create novel hybrid nanostructures with enhanced photophysical properties for in vivo imaging and ex vivo sensors. Currently, he is a Postdoctoral Fellow in the Cancer Therapeutics Training Program at the University of California, San Diego, an NCI-funded T32 program. For the past year, he has been working with Prof. Sadik Esener on developing stimulus-responsive polymer-coated perfluorocarbon microbubbles as ultrasound contrast agents that activate only in regions of inflammation. Already this work has resulted in the filing of a patent and presentation at several conferences. To become a productive independent investigator in cancer nanotechnology, Dr. Goodwin will continue to be mentored by Prof. Sadik Esener, who is a Professor of Electrical and Computer Engineering and Nanoengineering and also the Director of the UCSD Center for Cancer Nanotechnology Excellence (Nanotumor Center). An expert in optical and acoustic detection technologies, Prof. Esener will train Dr. Goodwin in designing instrumentation for evaluation of ultrasound contrast agents and other detection systems. In addition, Prof. Esener will aid Dr. Goodwin in his transition to independence by mentoring him in the preparation and composition of research grants, mentorship of junior scientists, and management of laboratory space and resources. Dr. Goodwin will be co-mentored by Prof. Robert Mattrey, Prof. of Radiology at the Moores Cancer Center and the head of the UCSD In vivo Cancer and Molecular Imaging Center. Prof. Mattrey is an expert in the design, preparation, and clinical evaluation of perfluorocarbon ultrasound contrast agents, and he will train Dr. Goodwin in the design and implementation of biological models to evaluate the clinical efficacy of the proposed contrast agents. This research will be performed at the renowned University of California, San Diego in the Department of Nanoengineering and the Moores Cancer Center, a potent combination for the development of cancer nanotechnology. In his independent work, Dr. Goodwin will adapt the technology he developed at UCSD to create synthetic nanoemulsions that extravasate from circulation and accumulate at the tumor site but only become ultrasound contrast agents after activation by biomarker proteases. Nanoemulsions will be synthesized with a polymer coating that protects the nanoemulsion from vaporization but degrades when exposed to matrix metalloproteinase-2, which is secreted by many cancers. This process will expose ligands that will cause the aggregation and fusion of many nanoemulsions into larger structures, which then spontaneously transform into highly active ultrasound contrast agents during imaging. As the materials are non-toxic and ultrasound is an inexpensive imaging modality, development of this proposal could result in a powerful, safe, and affordable method of cancer imaging and screening. The development of new, promising nanotechnologies for cancer imaging and therapy will require the combination of many different fields of research, from synthesis to electrical engineering to materials science to biology. After receiving training in electrical engineering and animal studies, Dr. Goodwin will be able to design, synthesize, evaluate, and validate new nanomaterial imaging agents solely from his own expertise. With his substantial ability and ambition combined with outstanding mentors and institutional support, Dr. Goodwin is a prime candidate to excel in the independent development of innovative cancer nanotechnologies. PUBLIC HEALTH RELEVANCE: This proposal describes methods to synthesize, evaluate, and employ small, non-toxic droplets that become highly visible to ultrasound only in tumor tissue, which will aid immeasurably in the early detection and imaging of breast cancer and result in improved health and prognosis of cancer patients.

描述（由申请人提供）：本提案支持Andrew Goodwin博士申请癌症纳米技术独立奖（RFA-CA-09-015）。古德温博士已经是有机合成，大分子工程和癌症成像和治疗纳米技术开发方面有前途的初级科学家，他寻求获得台式和生物验证研究方面的培训，成为癌症纳米技术的成功独立创新者。 博士Goodwin于2007年在JeanBohet教授的指导下从加州大学伯克利分校获得博士学位，在那里他设计了用于癌症治疗的新型聚合物结构和新型释放药物机制。然后，他继续在斯坦福大学CCNE的Hongjie Dai教授的实验室工作，在那里，他用新的合成生物相容性组件功能化碳纳米管和金纳米结构，以创建具有增强的生物物理特性的新型混合纳米结构，用于体内成像和体外传感器。目前，他是加州大学圣地亚哥分校癌症治疗培训项目的博士后研究员，这是一个由NCI资助的T32项目。在过去的一年里，他一直与Sadik Esener教授合作开发刺激响应聚合物涂层的全氟化碳微泡，作为仅在炎症区域激活的超声造影剂。这项工作已经导致了专利的申请和在几个会议上的介绍。 为了成为癌症纳米技术的富有成效的独立研究者，古德温博士将继续接受萨迪克·埃森纳教授的指导，他是电气和计算机工程与纳米工程教授，也是加州大学圣地亚哥分校癌症纳米技术卓越中心（纳米肿瘤中心）的主任。Esener教授是光学和声学检测技术方面的专家，他将培训Goodwin博士设计用于评估超声造影剂和其他检测系统的仪器。此外，Esener教授将通过指导他准备和组成研究赠款，指导初级科学家以及管理实验室空间和资源来帮助Goodwin博士向独立过渡。Goodwin博士将由Moores癌症中心放射学教授、UCSD体内癌症和分子成像中心负责人Robert Mattrey教授共同指导。Mattrey教授是全氟化碳超声造影剂设计、制备和临床评价方面的专家，他将培训Goodwin博士设计和实施生物模型，以评价拟议造影剂的临床疗效。这项研究将在著名的加州大学圣地亚哥分校的纳米工程系和Moores癌症中心进行，这是癌症纳米技术发展的有力组合。 在他的独立工作中，Goodwin博士将采用他在UCSD开发的技术来创建合成纳米乳液，这些纳米乳液从循环中渗出并在肿瘤部位积聚，但只有在生物标志物蛋白酶激活后才能成为超声造影剂。纳米乳液将与聚合物涂层一起合成，该聚合物涂层保护纳米乳液免于蒸发，但当暴露于许多癌症分泌的基质金属蛋白酶-2时会降解。该过程将暴露配体，这将导致许多纳米乳液聚集和融合成更大的结构，然后在成像过程中自发地转化为高活性的超声造影剂。由于材料无毒，超声是一种廉价的成像方式，该提案的发展可能会导致一种强大，安全和负担得起的癌症成像和筛查方法。 新的，有前途的癌症成像和治疗纳米技术的发展将需要许多不同的研究领域的结合，从合成到电气工程，材料科学到生物学。在接受电气工程和动物研究的培训后，Goodwin博士将能够仅凭自己的专业知识设计，合成，评估和验证新的纳米材料成像剂。凭借他的能力和雄心，加上杰出的导师和机构支持，古德温博士是独立开发创新癌症纳米技术的主要候选人。 公共卫生相关性：该提案描述了合成、评估和使用仅在肿瘤组织中对超声高度可见的小的无毒液滴的方法，这将极大地有助于乳腺癌的早期检测和成像，并改善癌症患者的健康和预后。