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.

对于许多早期癌症来说，完全惊喜是微观疾病至关重要的 外科医生看不到或感受 节点，通常被留在后面。这些残留的肿瘤细胞增加了癌症返回或 在几乎每个癌症亚型中传播，并可能增加癌症死亡。其他治疗 对于有MRD的风险的患者，仅限于将放疗的经验分娩到大面积 毒性和可能缺少MRD。尽管有分子成像剂用于手术 指导，图像rs本身仍然是限制试剂：高的光学元件相对笨重 灵敏度荧光成像限制了常规图像，无法彻底检查 微创肿瘤腔和淋巴结低音。在此提案中，我们介绍了一个全新的 光学成像的平台 - 用传统的镜头和颜色成像的过滤器分发 时间分辨成像。利用高效合金上转换的独特性能 纳米颗粒，我们引入了基于CMO的时间分辨触点成像阵列平台， 单层与红外照明整合，穿过硅成像仪本身和深度 进入组织。使用自定义检测并禁用了延迟和向上的排放 集成电路，仅稀释至25微米，并带有片上选择性的光栅，以取代聚焦 镜片，意识到分子成像皮肤。 在这里，我们通过引入薄薄的 （<200μm）平面分子成像皮肤以“涂层”手术仪器表面，本质上 将工具本身转换为微观成像仪。这确保了完整而彻底的成像 整个复合形状的肿瘤床表面，优化了单个疾病的所有疾病的完整切除 解决共同注册和采样错误问题的过程。在模型中驾驶此平台 乳腺癌系统，在AIM 1中，我们探索了AUCNP大小与生物分布之间的关系。 在AIM 2中，我们使用红外线制造单层整合的分子成像皮肤 灌输，在AIM 3中，我们在HER2+乳腺癌鼠标中演示了我们的平台 单独使用肿瘤内注射AUCNP，并与曲妥珠单抗共轭和抗HER2 抗体。我们选择乳腺癌作为微观残留疾病特别普遍，并且 结果：每年在美国诊断为乳腺癌的15万名妇女中，超过25％ 发现接受肿块切除术治疗后术后有MRD。 MRD增加了癌症的速度 在15年内从15％到30％的返回，通常需要第二秒甚至第三个重新拆卸；如果 未经治疗，MRD每年可能导致乳腺癌死亡1,500人死亡。