How do Nanoparticles Target Cancer? An In Vivo Experimental/Mathematical Study

纳米粒子如何靶向癌症？

• 批准号: 8296498
• 负责人: Bryan Ronain Smith
• 金额: $ 17.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296498
• 关键词: Accounting; Address; Adherence; Animal Model; Animals; Area; Behavior; Binding; Blood Vessels; Blood flow; Cell surface; Characteristics; Clinic; Clinical; Communities; Computer Simulation; Data; Development; Diagnostic; Diagnostic Imaging; Discipline; Endothelium; Ensure; Evaluation; Expert Systems; Extravasation; Feedback; Future; Heterogeneity; Homing; Human; Image; Image Analysis; Injectable; Intravenous; Kinetics; Lead; Learning; Life; Ligands; Malignant Neoplasms; Medicine; Methods; Microscopic; Microscopy; Modeling; Mus; Nanostructures; Nanotechnology; Nanotubes; Neoplasms in Vascular Tissue; Particle Size; Performance; Physicians; Pre-Clinical Model; Property; Quantum Dots; Research Proposals; Reticuloendothelial System; Scientist; Screening for cancer; Shapes; Simulate; Site; Structure; Surface; Testing; Theoretical model; Therapeutic; Therapeutic Agents; Time; Toxic effect; Translating; Translations; Treatment Efficacy; Tumor Tissue; Vascular Endothelium; Work; World Health Organization; arm; base; cancer diagnosis; cancer imaging; cancer therapy; clinical application; design; improved; in vivo; innovation; insight; intravital microscopy; mathematical model; molecular transporter; nano; nanoparticle; neoplastic cell; neovasculature; particle; physical property; preclinical study; research study; simulation; single walled carbon nanotube; theories; therapy development; trend; tumor; uptake

DESCRIPTION (provided by applicant): This year (2010), cancer will become the world's biggest killer according to the World Health Organization. Nanotechnology is likely the game-changer needed to reverse this trend by revolutionizing cancer diagnosis and therapy. Injectable, targeted nanoparticles (NPs) in particular have enormous potential to seek, image, and destroy cancer. Yet despite the enormous diversity of NPs available, delivery remains perhaps the biggest obstacle to the realization of their clinical promise. The current paradigm in the selection of NPs as superior biomedical delivery vehicles critically does not account for the ability of different NP types to target tumor. This is because there currently exists very little understanding about the dynamic behavior of systemically injected NPs on the microscale. We have performed preliminary microscopy experiments on several NP types (with varied physical properties, such as quantum dots and nanotubes) in living mice that display broadly different targeting characteristics across the NP types we have tested. A chief objective of this proposal is therefore to guide selection of NPs for eventual use in intravenous delivery for clinical imaging and therapy by developing a fundamental understanding of NP behavior in living subjects via experimental observation and mathematical models. The proposal ultimately aims to understand the targeting behavior of NPs of diverse size and shape in the tumor of living subjects. Detailed mechanistic insight of NP targeting could yield a system for the intelligent empirical design of these agents for each application (i.e., personalization of medicine via customized nanostructures). Moreover, the optimal times for imaging or therapy with the selected NPs could be predicted. This could thus arm physicians with the ability to select the appropriate imaging/therapeutic agent and time-point, which would increase efficacy and lead to earlier cancer detection, increased therapeutic efficacy, and decreased NP-based toxicity. To understand nanoparticle behavior in tumors, this proposal delineates how intravital microscopy will be used to explore active, passive, and non-specific nanoparticle interactions within and around tumor tissue, including targeting to tumor blood vessel endothelium, extravasation, and targeting to tumor cell surfaces. However, intravital microscopy alone will not be sufficient to explain nanoparticle behavior in living animals. Because much time, effort, and money is forfeit on choosing nanoparticles inappropriate for a given application, an urgent need exists in the biomedical nanotechnology community to rigorously understand observed phenomena using advanced quantitative models. This proposal describes the development of mathematical models that realistically simulate nanoparticle binding to tumor blood vessels, pre-validating the nanoparticles chosen to enter pre-clinical models. Mathematical modeling in intimate association with intravital experiments will robustly inform and guide one another. This will result in a generalized framework by which to choose the appropriate size and shape of diagnostic/therapeutic nanoparticles to test in the lab and eventually in the clinic. This will thus much more rapidly lead to superior clinical applications for cancer-targeted nanoparticles.

描述（由申请人提供）：今年（2010年），根据世界卫生组织，癌症将成为世界上最大的杀手。纳米技术很可能是扭转这一趋势所需的游戏规则改变者，因为它革新了癌症的诊断和治疗。特别是可注射的靶向纳米颗粒（NPs）在寻找、成像和摧毁癌症方面具有巨大的潜力。然而，尽管可用的NPs种类繁多，但交付可能仍然是实现其临床前景的最大障碍。

项目成果

Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic Resistance.

• DOI: 10.1016/j.drup.2017.10.001
• 发表时间: 2017-11
• 期刊: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
• 作者: Owyong M;Hosseini-Nassab N;Efe G;Honkala A;van den Bijgaart RJE;Plaks V;Smith BR
• 通讯作者: Smith BR

Quantitative drug release monitoring in tumors of living subjects by magnetic particle imaging nanocomposite.

• DOI: 10.1021/acs.nanolett.9b01202
• 发表时间: 2019-09
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Xingjun Zhu;Jian-feng Li;Peng Peng-Peng;Niloufar Hosseini Nassab;B. Smith