New Ultrastructural 3D Optical Imaging of Tumor Endothelium for Cancer Nanomedicine Development

用于癌症纳米药物开发的肿瘤内皮细胞新超微结构 3D 光学成像

• 批准号: 10334986
• 负责人: Stefan Wilhelm
• 金额: $ 24.49万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334986
• 关键词: 3-Dimensional; Active Biological Transport; Address; Adopted; Affect; Biological; Biology; Blood Vessels; Breast; Breast Cancer Patient; Breast Oncology; Cancerous breast; Cells; Centers of Research Excellence; Clinical; Clinical Treatment; Data; Development; Diffusion; Drug Delivery Systems; Electrons; Endothelial Cells; Endothelium; Engineering; Exhibits; Fees; Future; Generations; Human; Image; Interdisciplinary Study; Intracellular Transport; Intravenous; Kinetics; Label; Laser Scanning Confocal Microscopy; Lasers; Lateral; Malignant Neoplasms; Mediating; Medical Imaging; Medical center; Mentors; Methods; Microscope; Microscopy; Oklahoma; Optical Methods; Optics; Pathway interactions; Property; Research; Research Project Grants; Research Support; Resolution; Resources; Route; Scanning; Side; Specimen; Technology; Testing; Three-Dimensional Imaging; Time; Tissue Model; Tissues; Transmission Electron Microscopy; Treatment Efficacy; Tumor Tissue; United States National Institutes of Health; Vesicle; advanced breast cancer; base; blood-brain tumor barrier; cancer imaging; cancer therapy; chemotherapy; design; diffraction of light; drug efficacy; experience; image registration; imaging approach; imaging capabilities; imaging modality; imaging platform; improved; inhibitor; innovation; intravenous administration; light scattering; malignant breast neoplasm; nanomedicine; nanoparticle; novel; optical imaging; preservation; spatiotemporal; success; transcytosis; translational cancer research; tumor

Project 2: New Ultrastructural 3D Optical Imaging of Tumor Endothelium for Cancer Nanomedicine Development ABSTRACT The long-term objective of this project is to engineer a new generation of safer and more effective breast cancer nanomedicines that improve drug delivery to tumors by efficiently overcoming the blood-tumor barrier via transcytosis. As a first step, we propose to establish a new ultrastructural 3D super-resolution optical imaging platform to track and quantify in a label-free manner the intracellular nanoparticle transport and transcytosis. Nanoparticle transcytosis is a novel delivery pathway in cancer nanomedicine and may occur through two major intracellular routes: (1) vesicle mediated intracellular transport, and (2) shuttling of nanoparticles via intracellular tubules. However, it is unknown which pathway results in more efficient nanoparticle transcytosis and whether these routes favor specific nanoparticle sizes to date. To differentiate between the vesicle and tubule-mediated nanoparticle transport routes, ultrastructural 3D imaging of whole endothelial cells is needed. Our objective is to establish a 3D super-resolution optical microscopy as a novel and unique method to understand the intracellular pathways that nanoparticles take during transcytosis. Using our unique label-fee 3D super-resolution imaging approach, we will test the hypothesis that nanoparticle size will determine the nanoparticle transcytosis pathway and transcytosis efficiency in breast-cancer associated endothelial cells. For this purpose, we propose the following two Specific Aims. Aim 1 is to establish 3D super-resolution optical microscopy of breast-cancer associated endothelial cells in combination with label-free nanoparticle imaging. Aim 2 is to quantify nanoparticle transcytosis in human breast cancer associated endothelial cells. In order to optimally conduct the proposed research tasks and pursue the success of this project, the research project leader (RPL) has two experienced mentors and also assembled a multidisciplinary research team with unique and synergistic expertise in the nanomedicine, tumor vascular biology, super-resolution microscopy, and breast oncology. This project will comprehensively investigate a unique imaging approach as a platform technology that can be applied to visualize and study the nanoparticle transport in different tissues and cells in 3D at ultrastructural resolution using conventional optical microscopes. As a result, using this novel imaging method can help design and implement the optimal nanoparticle properties for intracellular nanoparticle transport and transcytosis to significantly improve efficacy of the drug delivery to tumor tissues in cancer treatment. Success of this project will provide the essential preliminary study data and scientific evidence to support the RPL to apply for the NIH R01 project (i.e., PAR-20-284 – Innovative Research in Cancer Nanomedicine) in the future.

项目2：新的超微结构3D肿瘤内皮的光学成像用于癌症纳米医学 发展 抽象的 该项目的长期目标是设计新一代更安全，更有效的乳房 通过有效克服血液肿瘤屏障，可以通过 转胞病。作为第一步，我们建议建立一个新的超微结构3D超分辨率光学成像 以无标签方式跟踪和量化细胞内纳米颗粒的转运和跨胞菌病的平台。 纳米颗粒转胞菌病是癌症纳米医学中的一种新型递送途径，可能通过两个主要发生 细胞内路线：（1）囊泡介导的细胞内转运，（2）通过细胞内穿梭纳米颗粒 小管。但是，尚不清楚哪种途径会导致更有效的纳米粒子转胞菌病以及是否是否 迄今为止，这些路线有利于特定的纳米颗粒大小。区分囊泡和管介导的 需要纳米颗粒的传输路线，整个内皮细胞的超微结构3D成像。我们的目标是 建立3D超分辨率光学显微镜作为一种新颖而独特的方法来了解细胞内 纳米颗粒在转胞膜过程中采取的途径。使用我们独特的标签 - 费用3D超分辨率成像 方法，我们将检验以下假设：纳米颗粒大小将决定纳米颗粒的跨经细胞增多症途径 和乳腺癌相关内皮细胞中的胞胞病效率。为此，我们建议 遵循两个具体目标。目标1是建立乳腺癌的3D超分辨率光学显微镜 相关的内皮细胞与无标记的纳米颗粒成像结合使用。目标2是量化纳米颗粒 人类乳腺癌相关的内皮细胞的转介症。为了最佳地进行提出的 研究任务并纯粹是该项目的成功，研究项目负责人（RPL）有两个经验丰富的 导师，还组建了一个具有独特和协同专业知识的多学科研究团队 纳米医学，肿瘤血管生物学，超分辨率显微镜和乳房肿瘤学。这个项目将 全面研究一种独特的成像方法，作为一种可以可视化的平台技术 并在超微结构分辨率下研究不同组织和细胞中不同组织和细胞中的纳米颗粒传输 常规光学显微镜。结果，使用这种新颖的成像方法可以帮助设计和实施 细胞内纳米颗粒转运和转胞膜的最佳纳米颗粒特性至显着 提高癌症治疗中药物递送到肿瘤组织的效率。该项目的成功将提供 基本的初步研究数据和科学证据，以支持RPL申请NIH R01项目（即 PAR-20-284 - 未来癌症纳米医学的创新研究。