Imaging of nanotherapeutic drug action

纳米治疗药物作用的成像

基本信息

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
项目类别：
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

项目摘要

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.

超过一千名患者现已接受化学性质不同的纳米封装化疗药物，通常表现出较低的毒性、增加的有效负载的肿瘤积累以及偶尔的改善无进展生存期。实验上，已经出现了更多的新结构和方法由纳米技术联盟成员和其他团体首创。小鼠测试通常涉及测量肿瘤大小、存活率或组织病理学和其他分子诊断的使用。然而，尽管有这些进步，但人们对这些纳米材料在体内如何实际工作或失效、空间和性能如何等方面知之甚少。时间异质性以及如何提高功效。凭借最近的新生物学见解导致该应用的可行性研究（Sci Transl Med，2015；7,314ra183；Nat Comm 2015；6,8692）和新体内成像技术的最新发展（Nat Commun 2013;4,1504; PLoS One 2013;8:e60988;纳特方法。 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以以前不可能的方式解决。此举的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）为什么目前临床上没有 TNP 更高效（目标 1）； ii) 亲和配体靶向肿瘤对提高疗效有多大帮助（目标 2) 和 iii) 我们能否通过纳米粒子增强 MR 成像从无反应者中选择有反应者（目标 3）？我们假设相当大比例的肿瘤细胞积累是由肿瘤骨髓细胞介导的（巨噬细胞）而不是癌细胞，提供了进一步增强疗效的新策略。尽最大努力据我们所知，该项目是对现有联盟项目的补充，并将对其他联盟有用通过未来的互动来了解整个联盟的成员。它还将提供急需的生物了解纳米颗粒增强磁共振成像结果以解释临床数据。