Nanotechnology for Minimally Invasive Cancer Detection and Resection

描述（由申请人提供）：有效的手术切除肿瘤是癌症患者生存最重要的预测因素。虽然手术治愈了大约45%的癌症患者，但高达40%的患者由于无法检测到恶性和良性增生或正常组织之间的差异而复发肿瘤，导致癌组织切除不完全。此外，接受手术的患者往往因手术相关的损伤而生活质量下降。这项癌症纳米技术研究独立之路奖（K99/R00）提案的主要目标是将纳米技术的独特能力与创新的光学仪器相结合，通过微创手术改善恶性组织的检测和切除。这一挑战将通过结合纳米技术、仪器和外科肿瘤学方面的专业知识和研究方法来解决。该职业发展奖项有四个具体目标：(1)开发可生物降解和无毒的可激活荧光纳米颗粒探针；(2)研制一种小型化、柔性的术中荧光检测装置；(3)将微型、柔性光学装置与内窥镜相结合，实现肿瘤的微创检测；(4)评价光谱内窥镜应用于大型动物（犬）手术过程中自发性胸部肿瘤的效果，以提高疾病清除率和病理分期。实现这些特定目标将利用靶向和可激活的纳米颗粒来增加探针在癌组织中的特异性定位。通过光纤内窥镜成像系统检测和切除癌组织将通过更准确地检测手术边缘和残余肿瘤来降低肿瘤复发率，并减少手术相关的发病率，例如减少患者的疼痛、不适和残疾。我的近期职业目标是获得一个终身教职，专注于将纳米技术与外科肿瘤学相结合。从长远来看，我想领导一个科学、医学和工程相结合的研究项目，扩大将要研究的疾病的数量和类型。理想情况下，这项研究将在一个机构进行，在那里我可以参与到来自不同领域的学术和医学研究者。在该奖项的指导阶段，培训将集中在几个关键方面，以促进我作为一名独立研究者的发展，包括(1)为候选人提供光学纳米颗粒工程的坚实基础，(2)基于光纤的光谱和近红外成像仪器，以及(3)肿瘤外科微创腹腔镜手术的方法学挑战。培训将在埃默里-乔治亚理工学院生物医学工程系进行，导师是国际纳米技术专家、埃默里-乔治亚理工学院癌症纳米技术卓越中心主任聂舒明博士；在宾夕法尼亚大学，导师是胸外科研究实验室主任、胸外科主任Sunil Singhal博士。这两所机构的环境对于这个项目来说是理想的，因为我可以完全接触到最先进的纳米颗粒设计、合成和表征仪器；我将受益于仪器工程师的制造设备，以满足我的需求；以及一个高度协作的转化环境，这对于这个项目的成功发展至关重要，它将纳米技术与微创术中仪器相结合。此外，合作培训将由埃默里大学和佐治亚理工学院的光学和仪器方面的正式课程补充。

DESCRIPTION (provided by applicant): Effective surgical resection of tumors is the most important predictor for cancer patient survival. Although surgery is curative in approximately 45% of cancer patients, up to 40% of patients have recurrent tumors due to undetectable differences between malignant and benign hyperplasic or normal tissue, leading to incomplete resection of cancerous tissue. In addition, patients that undergo surgery often suffer a decreased quality of life due to injury associated with the surgery. The primary goal of this Pathway to Independence Award in Cancer Nanotechnology Research (K99/R00) proposal is to integrate the unique capabilities of nanotechnology with innovative optical instrumentation to improve detection and resection of malignant tissue through minimally invasive surgery. This challenge will be addressed by combining expertise and research methodology in nanotechnology, instrumentation, and surgical oncology. This career development award has four specific aims: (1) develop biodegradable and nontoxic activatable fluorescence nanoparticle probes; (2) develop a miniaturized and flexible device for intraoperative fluorescence detection; (3) integrate the miniaturized, flexible optical device with endoscopy for minimally invasive detection of tumors; and (4) evaluate the spectral endoscope using spontaneous thoracic tumors in large animals (canines) during surgery to improve disease clearance and pathological staging. Accomplishing these specific aims will utilize targeted and activatable nanoparticles to increase specific localization of the probes in cancerous tissue. Detecting and resecting cancerous tissue via the fiber optic endoscopic imaging system will decrease the rate of tumor recurrence by more accurately detecting surgical margins and residual cancer and reduce surgery associated morbidity, such as decreasing patient pain, discomfort, and disability. My immediate career goal is to obtain a tenure-track faculty position that focuses on integrating nanotechnology with surgical oncology. Long-term, I would like to lead a research program at the interface of science, medicine, and engineering and expand the number and types of diseases that will be investigated. Ideally this research would be performed at an institution where I can be involved with academic and medical investigators from diverse fields. Training during the mentored phase of this award will focus on several key aspects to facilitate my development to achieve these goals as an independent investigator, including (1) providing the candidate with a strong foundation in optical nanoparticle engineering, (2) instrumentation for fiber optic based spectral and near-infrared imaging, and (3) methodological challenges to minimally invasive laparoscopic procedures in surgical oncology. Training will take place in the Emory-Georgia Tech Biomedical Engineering Department under the mentorship of Dr. Shuming Nie, Ph.D., an international expert in nanotechnology and director of the Emory-Georgia Tech Center for Cancer Nanotechnology Excellence, and at the University of Pennsylvania under the co-mentorship of Dr. Sunil Singhal, M.D., Director of the Thoracic Surgery Research Laboratory and Chief of Thoracic Surgery. The environment at these two institutions is ideal for this project because I will have full access to the most advanced instrumentation for nanoparticle design, synthesis, and characterization; I will benefit from instrumentation engineers with fabrication facilities to meet my needs; and a highly collaborative translational environment, which is paramount for successful development of this project that integrates nanotechnology with minimally invasive intraoperative instrumentation. In addition, the collaborative training will be supplemented by formal coursework at Emory and Georgia Tech in optics and instrumentation. PUBLIC HEALTH RELEVANCE: This career development award seeks to integrate new and innovative nanotechnology methods in cancer surgery. The research performed here will develop methods using nanoparticles to assist surgeons in distinguishing tumor margins and residual tumors while using minimally invasive endoscopic surgery. The combined effect of increasing tumor delineation under minimally invasive laparoscopic surgery will have a profound impact on reducing the high mortality rates from cancer and the morbidity associated with surgery.