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至关重要，然而，微观疾病， 外科医生看不见或摸不到，它围绕着主要肿瘤并位于引流淋巴中 这些残留的肿瘤细胞会增加癌症复发或复发的风险。 在几乎所有癌症亚型中传播，并可能增加癌症死亡人数。 对于有 MRD 风险的患者，仅限于对大面积进行经验性放疗，这会导致 尽管用于外科手术的分子成像剂出现了，但毒性和潜在的 MRD 缺失仍然存在。 指导，成像仪本身仍然是限制试剂：高要求所需的相对笨重的光学器件 灵敏度荧光成像限制了传统成像仪彻底检查小、 在这项提案中，我们引入了一种全新的微创肿瘤腔和淋巴结盆地。 光学成像平台——放弃传统的镜头和滤光片以支持彩色成像 利用高效合金上转换的独特性能。 纳米颗粒，我们推出了基于 CMOS 的时间分辨接触成像阵列平台， 与红外照明单片集成，穿透硅成像仪本身并深入 使用定制的方法检测延迟和上转换的发射并进行去模糊。 集成电路，薄至仅 25 微米，片上角度选择光栅取代聚焦 镜片，实现皮肤分子成像。 这里我们通过引入一种薄型的解决方案来解决术中MRD的实时识别问题。 （<200μm）平面分子成像皮肤本质上是“覆盖”手术器械的表面 将工具本身转变为显微成像仪，这确保了完整、彻底的成像。 整个复杂形状的肿瘤床表面，优化一次性完全切除所有疾病 解决共同配准和抽样误差问题的程序在模型中试用该平台。 乳腺癌系统，在目标 1 中，我们探讨了 aUCNP 大小与生物分布之间的关系。 在目标 2 中，我们使用仅具有红外功能的 IC 制造单片集成分子成像皮肤 穿透照明，在目标 3 中，我们在 HER2+ 乳腺癌小鼠中展示了我们的平台 使用单独瘤内注射 aUCNP 并与曲妥珠单抗和抗 HER2 缀合的模型 我们选择乳腺癌是因为显微镜下残留疾病特别普遍并且 后果：美国每年诊断出 150,000 名女性，其中超过 25% 患有乳腺癌 接受肿瘤切除术治疗后发现 MRD 使癌症发生率增加一倍。 15 年内复发率从 15% 上升到 30%，如果出现这种情况，通常需要第二次甚至第三次重新切除； 如果不及时治疗，MRD 每年可能导致 1,500 人死于乳腺癌。