An Ultra-Thin Molecular Imaging Skin for Intraoperative Imaging of Microscopic Residual Disease in Cancer

超薄分子成像皮肤，用于癌症微小残留病灶的术中成像

• 批准号: 9883791
• 负责人: Mekhail Anwar
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883791
• 关键词: Address; Advanced Malignant Neoplasm; Alloys; Antibodies; Area; Beds; Biodistribution; Biological Models; Cells; Cessation of life; Color; Complex; Consequentialism; Coupled; Custom; Data; Diagnosis; Disease; ERBB2 gene; Electronics; Ensure; Excision; Generations; Hand; Human; Image; Image-Guided Surgery; Injections; Kinetics; Knowledge; Label; Left; Lighting; Location; Malignant Neoplasms; Microscopic; Modernization; Molecular; Molecular Target; Neoplasm Metastasis; Operative Surgical Procedures; Optics; Patients; Performance; Photons; Postoperative Period; Problem Solving; Procedures; Property; Radiation therapy; Reagent; Recurrence; Residual Tumors; Resolution; Risk; Sampling; Sampling Errors; Sensitivity and Specificity; Sentinel Lymph Node; Signal Transduction; Silicon; Skin; Speed; Surface; Surgeon; Surgical Instruments; Surgically-Created Resection Cavity; Thinness; Time; Tissue imaging; Tissues; Toxic effect; Trastuzumab; Vision; Visualization; Woman; absorption; base; biomaterial compatibility; breast lumpectomy; cancer cell; cancer imaging; cancer recurrence; cancer risk; cancer subtypes; cancer surgery; density; design; draining lymph node; ex vivo imaging; fluorescence imaging; fluorophore; imager; imaging agent; imaging platform; improved; in vivo; in vivo imaging; insight; instrumentation; irradiation; lens; lymph nodes; malignant breast neoplasm; microscopic imaging; millimeter; minimally invasive; molecular imaging; mouse model; nanoparticle; neoplastic cell; novel; operation; optical imaging; tool; tumor; two-photon

Complete excision is essential for many early stage cancers however, microscopic disease, which cannot be seen or felt by the surgeon, surrounds the main tumor and lies in draining lymph nodes, and is often left behind. These residual tumor cells increase the risk of cancer returning or spreading in almost every cancer subtype, and may increase death from cancer. Additional treatments for patients at risk for MRD are limited to empiric delivery of radiotherapy to large areas, incurring toxicity and potentially missing MRD. Despite the advent of molecular imaging agents for surgical guidance, the imagers themselves remain the limiting reagent: relatively bulky optics required for high sensitivity fluorescence imaging restrict conventional imagers from thoroughly examining small, minimally invasive tumor cavities and lymph node basins. In this proposal we introduce an entirely new platform for optical imaging -- dispensing with conventional lenses and filters for color imaging in favor of time-resolved imaging. Leveraging the unique properties of highly-efficient alloyed upconverting nanoparticles, we introduce a CMOS-based time-resolved contact imaging array platform, monolithically integrated with infrared illumination, penetrating through the silicon imager itself and deep into tissue. The delayed and upconverted emission is detected and deblurred using a custom integrated circuit, thinned to just 25 microns, with on-chip angle-selective gratings replacing focusing lenses, realizing a molecular imaging skin. Here we solve the problem of real-time intraoperative identification of MRD by introduce a thin (<200​ ​μm) planar molecular imaging skin to “coat” the surface of surgical instrumentation, in essence transforming the tool itself into a microscopic imager. This ensures complete and thorough imaging of the entire complex-shaped tumor bed surface, optimizing complete resection of all disease in a single procedure addressing the issue of co-registration and sampling error​. ​Piloting this platform in a model system for breast cancer, in Aim 1 we explore the relationship between aUCNP size and biodistribution. In Aim 2, we fabricate a monolithically integrated molecular imaging skin using an IC-only with infrared through-illumination, and in Aim 3 we demonstrate our platform in a HER2+ breast cancer mouse model using an intratumoral injection of aUCNP alone, and conjugated to Trastuzumab, and anti-HER2 antibody. We choose breast cancer as microscopic residual disease is particularly prevalent and consequential: Over 25% of the 150,000 women diagnosed in the US annually with breast cancer treated with lumpectomy are found to have MRD post-operatively. MRD doubles the rate of cancer returning, from 15% to 30% over 15 years, often necessitating a second, or even third, re-excision; if left untreated, MRD could result in an additional 1,500 deaths from breast cancer annually.

完全切除对于许多早期癌症是必不可少的，然而，显微镜下的疾病， 它不能被外科医生看到或感觉到，围绕着主肿瘤，位于引流淋巴结中。 节点，并经常被抛在后面。这些残留的肿瘤细胞增加了癌症复发的风险， 几乎在所有癌症亚型中传播，并可能增加癌症死亡率。额外治疗 对于有MRD风险的患者，仅限于大面积经验性放疗， 毒性和可能缺失的MRD。尽管用于外科手术的分子成像剂的出现 在指导下，成像器本身仍然是限制试剂：高分辨率成像所需的相对笨重的光学器件。 灵敏度荧光成像限制了常规成像器彻底检查小的， 微创肿瘤腔和淋巴结盆。在本提案中，我们引入了一个全新的 光学成像平台--无需传统的彩色成像镜头和滤光片， 时间分辨成像。利用高效合金上转换的独特特性 纳米粒子，我们介绍了一个基于CMOS的时间分辨接触成像阵列平台， 单片集成红外照明，穿透硅成像器本身和深 组织中。延迟和上转换的发射被检测，并使用自定义 集成电路，厚度减薄至25微米，片上角度选择光栅取代聚焦 透镜，实现分子成像皮肤。 在这里，我们解决了实时术中识别MRD的问题，通过引入薄 （<200 μm）平面分子成像皮肤来“包覆”手术器械的表面，本质上 将工具本身转化为显微成像仪。这确保了完整和彻底的成像， 整个复杂形状的瘤床表面，优化所有疾病在一个单一的完整切除 处理共同登记和抽样误差问题的程序。 在模型中试用这个平台 系统用于乳腺癌，在目的1中，我们探索aUCNP大小和生物分布之间的关系。 在目标2中，我们使用仅具有红外的IC制造单片集成的分子成像皮肤。 在目标3中，我们在HER 2+乳腺癌小鼠中展示了我们的平台 使用肿瘤内注射单独的aUCNP以及与曲妥珠单抗和抗HER 2缀合的aUCNP的模型 抗体的我们选择乳腺癌是因为显微镜下残留疾病特别普遍， 结果：在美国每年诊断出乳腺癌的150，000名妇女中， 发现接受肿块切除术的患者术后存在MRD。MRD使癌症发病率增加一倍 15年内复发率从15%增加到30%，往往需要第二次甚至第三次再次切除; 如果不加以治疗，MRD每年可能导致另外1 500人死于乳腺癌。