Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
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DOI：
10.1038/ncomms9692
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发表时间：
2015-10-01
影响因子：
16.6
通讯作者：
Weissleder, Ralph
中科院分区：
文献类型：
--
作者：
Miller, Miles A.;Zheng, Yao-Rong;Weissleder, Ralph
治疗性纳米粒(TNPs)旨在将药物更安全、更有效地输送到癌症中，但由于体内了解有限，临床结果一直无法预测。在这里，我们使用肿瘤内TNP药代动力学和药效学的单细胞成像来更好地理解它们的异质性行为。模型TNPs由荧光铂(IV)前药和临床测试的聚合物平台(PLGA-b-PEG)组成，通过引导细胞摄取肿瘤相关巨噬细胞(TAM)来促进药物的长循环和改变聚集。对TNP载体、其药物有效载荷和单细胞DNA损伤反应的同时成像显示，TAMs是一个局部药物仓库，积累了大量的载体，从那里破坏DNA的铂有效载荷逐渐释放到邻近的肿瘤细胞。相应地，的衰竭减少了肿瘤内的TNP蓄积和疗效。因此，纳米疗法将TAMs用于药物输送，这对TNP的设计和选择患者进入试验具有重要意义。
Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumourassociated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.