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

描述(由申请人提供)：本提案支持安德鲁·古德温博士在癌症纳米技术领域获得独立奖的申请(RFA-CA-09-015)。古德温博士在有机合成、大分子工程以及用于癌症成像和治疗的纳米技术开发方面已经是一名很有前途的初级科学家，他寻求获得桌面和生物验证研究方面的培训，以成为癌症纳米技术领域的成功独立创新者。 古德温博士于2007年在加州大学伯克利分校获得博士学位，在Jean Frichet教授的指导下，他为癌症治疗设计了新的聚合物体系结构和新颖的药物释放机制。然后，他继续前往斯坦福大学CCNE戴洪杰教授的实验室，在那里他用新的合成生物兼容组装件对碳纳米管和金纳米结构进行了功能化处理，创造出具有增强光物理性能的新型杂化纳米结构，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，该项目是NCI资助的T32项目。在过去的一年里，他一直在与萨迪克·埃森纳教授合作开发刺激响应性聚合物涂层全氟碳微泡，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陈述。 为了成为一名富有成效的癌症纳米技术独立研究员，古德温博士将继续接受Sadik Esener教授的指导，Esener教授是电气和计算机工程和纳米工程教授，也是加州大学圣地亚哥分校癌症纳米技术卓越中心(Nanotumor Center)的主任。作为光学和声学检测技术方面的专家，Esener教授将培训古德温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，埃森纳教授将通过指导古德温博士准备和组成研究补助金、指导初级科学家以及管理实验室空间和资源来帮助古德温博士过渡到独立。古德温博士将由罗伯特·马特里教授共同指导，他是摩尔癌症中心的放射学教授，也是加州大学圣迭戈分校体内癌症和分子成像中心的负责人。Mattrey教授是全氟碳超声造影剂设计、制备和临床评估方面的专家，他将培训古德温博士设计和实施生物模型，以评估建议的造影剂的临床疗效。这项研究将在著名的加州大学圣地亚哥分校纳米工程系和摩尔斯癌症中心进行，这是开发癌症纳米技术的有力组合。 在他的独立工作中，古德温博士将采用他在加州大学圣迭戈分校开发的技术来创造合成纳米乳剂，这种乳剂从循环中渗出，在肿瘤部位积聚，但只有在被生物标记物蛋白酶激活后才能成为超声造影剂。纳米乳液将用一种聚合物涂层合成，这种涂层可以保护纳米乳液不会蒸发，但在接触到基质金属蛋白酶-2时会降解，基质金属蛋白酶-2是许多癌症所分泌的。这一过程将暴露配体，这些配体将导致许多纳米乳剂聚集并融合成更大的结构，然后在成像过程中自发转化为高活性的超声造影剂。由于材料无毒，超声波是一种廉价的成像手段，这一提议的发展可能导致一种强大、安全和负担得起的癌症成像和筛查方法。 为癌症成像和治疗开发新的、有前途的纳米技术将需要许多不同领域的研究相结合，从合成到电气工程，到材料科学到生物学。在接受了电气工程和动物研究方面的培训后，古德温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显像剂。凭借他雄心勃勃的能力和雄心壮志，再加上杰出的导师和机构支持，古德温博士是在创新癌症纳米技术的独立开发方面出类拔萃的最佳人选。 与公共卫生相关：这项建议描述了合成、评估和使用仅在肿瘤组织中超声高度可见的无毒小液滴的方法，这将在乳腺癌的早期发现和成像方面提供不可估量的帮助，并改善癌症患者的健康和预后。

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.