Imaging of nanotherapeutic drug action

目前已有1000多名患者接受了不同化学成分的纳米胶囊化疗药物， 一般表现出较低的毒性，增加了有效载荷的肿瘤蓄积，偶尔有所改善 无进展生存。在实验上，已经有了更多数量的新结构和方法 由纳米技术联盟成员和其他团体首创。在小鼠身上进行测试通常包括测量 肿瘤大小、存活率或使用组织病理学和其他分子诊断。然而，尽管如此， 这些纳米材料在体内是如何工作或失败的，以及这些纳米材料的空间和 时间上的异质性是以及如何提高疗效的。拥有新的生物学洞察力，最近 导致这一应用的可行性研究(Sci Transl Med，2015；7,314ra183；NAT Comm 2015；6,8692)和 活体成像新技术的最新发展(NAT Commun 2013；4,1504；PLoS One 2013；8：e60988；NAT方式。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在以前是不可能的。这样做的目的是 项目是对治疗性纳米颗粒进行成像分析，解决纳米颗粒上的关键问题 分布(药代动力学，PK)和细胞反应(药效学，PD)：i)为什么目前不是临床 TNP更有效(目标1)；ii)使用亲和配体靶向肿瘤在多大程度上有助于提高疗效(目标1 2)和iii)我们能否通过纳米颗粒增强磁共振成像从无应答者中选择应答者(目标3)？我们 假设相当大比例的肿瘤细胞聚集是由肿瘤髓系细胞介导的 (巨噬细胞)而不是癌细胞，为进一步提高疗效提供了一种新的策略。尽最大努力 据我们所知，该项目是对现有联盟项目的补充，将对其他联盟有用 通过未来的互动在整个财团中提供成员。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。

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.