Brenner Jacob S, Bhamidipati Kartik, Glassman Patrick M, Ramakrishnan N, Jiang Depeng, Paris Andrew J, Myerson Jacob W, Pan Daniel C, Shuvaev Vladimir V, Villa Carlos H, Hood Elizabeth D, Kiseleva Raisa, Greineder Colin F, Radhakrishnan Ravi, Muzykantov Vladimir R
Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA; Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nanomedicine. 2017 May;13(4):1495-1506. doi: 10.1016/j.nano.2016.12.019. Epub 2017 Jan 5.
Inflamed organs display marked spatial heterogeneity of inflammation, with patches of inflamed tissue adjacent to healthy tissue. To investigate how nanocarriers (NCs) distribute between such patches, we created a mouse model that recapitulates the spatial heterogeneity of the inflammatory lung disease ARDS. NCs targeting the epitope PECAM strongly accumulated in the lungs, but were shunted away from inflamed lung regions due to hypoxic vasoconstriction (HVC). In contrast, ICAM-targeted NCs, which had lower whole-lung uptake than PECAM/NCs in inflamed lungs, displayed markedly higher NC levels in inflamed regions than PECAM/NCs, due to increased regional ICAM. Regional HVC, epitope expression, and capillary leak were sufficient to predict intra-organ of distribution of NCs, antibodies, and drugs. Importantly, these effects were not observable with traditional spatially-uniform models of ARDS, nor when examining only whole-organ uptake. This study underscores how examining NCs' intra-organ distribution in spatially heterogeneous animal models can guide rational NC design.
发炎的器官表现出明显的炎症空间异质性，发炎组织斑块与健康组织相邻。为了研究纳米载体（NCs）如何在这些斑块之间分布，我们创建了一个小鼠模型，该模型概括了炎症性肺病急性呼吸窘迫综合征（ARDS）的空间异质性。靶向表位PECAM的NCs在肺部大量积聚，但由于缺氧性血管收缩（HVC）而被分流至远离发炎肺区域。相比之下，靶向ICAM的NCs在发炎肺中的全肺摄取量低于PECAM/NCs，但由于区域ICAM增加，其在发炎区域的NC水平明显高于PECAM/NCs。区域HVC、表位表达和毛细血管渗漏足以预测NCs、抗体和药物在器官内的分布。重要的是，在传统的ARDS空间均匀模型中，以及仅检查全器官摄取时，这些效应均无法观察到。这项研究强调了在空间异质性动物模型中检查NCs在器官内的分布如何能够指导合理的NC设计。
