Imaging of nanotherapeutic drug action

纳米治疗药物作用的成像

• 批准号: 9261150
• 负责人: RALPH WEISSLEDER, MD, PHD
• 金额: $ 58.57万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-23 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261150
• 关键词: 2,4-Dinitrophenol; Abraxane; Address; Affinity; Albumin-Stabilized Nanoparticle Paclitaxel; Anatomy; Biological; Cell Death; Cells; Chemicals; Clinic; Clinical; Clinical Data; Clinical Trials; DNA Damage; Data; Development; Drug Kinetics; Drug effect disorder; FDA approved; Feasibility Studies; Folic Acid; Future; Goals; Heterogeneity; Histopathology; Human; Image; Image Analysis; Imaging technology; Immunocompetent; In Vitro; Label; Ligands; Magnetic Resonance Imaging; Magnetic nanoparticles; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Methods; Mitotic; Modeling; Mus; Myeloid Cells; Myeloproliferative disease; Nanotechnology; Paclitaxel; Patients; Peritoneum; Permeability; Phagocytes; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Play; Population; Preparation; Progression-Free Survivals; Resistance; Role; Testing; Therapeutic; Time; Toxic effect; Work; Xenograft procedure; base; cancer cell; cell killing; cell type; design; experimental study; improved; in vivo; in vivo imaging; innovation; insight; interest; intravital microscopy; macrophage; member; molecular diagnostics; mouse model; nanoencapsulated; nanoformulation; nanomaterials; nanoparticle; nanotherapeutic; neoplastic cell; novel therapeutics; predictive of treatment response; responders and non-responders; response; subcutaneous; treatment response; tumor

Well over a thousand patients have now received chemically distinct, nano-encapsulated chemotherapeutics, generally showing lower toxicity, increased tumoral accumulation of payloads and occasionally improved progression free survival. Experimentally, an even larger number of new constructs and approaches have been pioneered by Nanotechnology Alliance members and other groups. Testing in mice usually involves measuring tumor sizes, survival or the use of histopathology and other molecular diagnostics. Yet, despite these advances, much less is known on how these nanomaterials actually work or fail in vivo, what the spatial and temporal heterogeneity is and how efficacy can be improved. Armed with new biological insight from recent feasibility studies leading to this application (Sci Transl Med, 2015;7,314ra183; Nat Comm 2015;6,8692) and the recent developments of new in vivo imaging technologies (Nat Commun 2013;4,1504; PLoS One 2013;8:e60988; Nat Methods. 2015;12:577-585; ChemMedChem 2014;9:1131-5) we are now able to address these important cancer nanotechnology questions in ways that were not previously possible. The goal of this project is to perform imaging analyses of therapeutic nanoparticles, addressing key questions on nanoparticle distribution (pharmacokinetics, PK) and cellular response (pharmacodynamics, PD): i) why aren't current clinical TNP more efficient (aim 1); ii) how much does tumor targeting with affinity ligands help to improve efficacy (aim 2) and iii) can we select responders from non-responders by nanoparticle enhanced MR imaging (aim 3)? We hypothesize that a considerable proportion of tumor cell accumulation is mediated by tumoral myeloid cells (macrophages) rather than by cancer cells, offering a new strategy to further enhance efficacy. To the best of our knowledge, this project is complementary to existing Alliance projects and will be useful to other Alliance members across the consortium through future interactions. It will also provide a much needed biological understanding of nanoparticle enhanced MR imaging findings to interpret clinical data.

目前已有超过1000名患者接受了化学性质不同的纳米胶囊化化疗药物， 通常显示出较低的毒性，增加的肿瘤积聚的有效载荷，偶尔改善 无进展生存。在实验上，甚至有更多的新结构和方法已经被应用于实验。 由纳米技术联盟成员和其他团体开创。在小鼠中的测试通常包括测量 肿瘤大小、生存率或组织病理学和其他分子诊断的使用。然而，尽管这些 进展，更少的是知道这些纳米材料实际上是如何工作或在体内失败，什么空间和 时间异质性以及如何提高疗效。从最近的生物学观点出发， 导致该应用的可行性研究（Sci Transl Med，2015;7，314 ra 183; Nat Comm 2015; 6，8692）和 新的体内成像技术的最新发展（Nat Commun 2013; 4，1504; PLoS One 2013;8：e60988; Nat Methods. 2015;12：577-585; ChemMedChem 2014;9：1131-5），我们现在能够解决 这些重要的癌症纳米技术问题的方式是以前不可能的。这个目标 项目是对治疗性纳米颗粒进行成像分析，解决纳米颗粒的关键问题。 分布（药代动力学，PK）和细胞反应（药效学，PD）：i）为什么目前的临床研究 TNP更有效（目标1）; ii）用亲和配体靶向肿瘤有助于提高疗效（目标1） 2)和iii）我们可以通过纳米颗粒增强的MR成像从无应答者中选择应答者吗（目的3）？我们 假设相当大比例肿瘤细胞积聚是由肿瘤髓样细胞介导的 （巨噬细胞），而不是癌细胞，提供了一种新的策略，以进一步提高疗效。尽最大 据我们所知，该项目是对现有联盟项目的补充，并将对其他联盟项目有用。 通过未来的互动，联盟的成员。它还将提供一个急需的生物 理解纳米颗粒增强的MR成像结果以解释临床数据。