Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells
Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells
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DOI：
10.1021/acs.molpharmaceut.3c00720
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发表时间：
2023-10-18
影响因子：
4.9
通讯作者：
Maisel，Katharina
中科院分区：
文献类型：
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作者：
McCright，Jacob;Yarmovsky，Jenny;Maisel，Katharina
淋巴管作为药物传递的靶点受到了极大的关注，因为它们将材料从周围组织运送到形成获得性免疫的淋巴结处。已证明通过淋巴管将免疫调节物质输送到淋巴结可以增强其疗效，并在将药物输送到肠道淋巴管时提高药物的生物利用度。在这项研究中，我们用一组运动微分方程建立了淋巴管的三室模型，描述了纳米颗粒从周围组织到淋巴管的运输。我们使用了以前发表的数据并收集了额外的实验参数，包括纳米颗粒随时间的传输效率，还研究了纳米颗粒配方如何影响使用小分子抑制剂的细胞传输机制。这些实验数据被合并到运动学微分方程组中，并采用非线性、最小二乘曲线拟合算法来外推模型中的输运系数。随后的计算框架产生了一些第一批参数来描述淋巴管内皮细胞之间的运输动力学，并允许对进入淋巴管的运输驱动机制进行定量分析。我们的模型表明，跨细胞机制，如微吞噬和巨噬细胞吞噬，推动运输进入淋巴管。这些信息对于进一步设计调节药物输送的淋巴运输策略至关重要，特别是在淋巴水肿等正常淋巴功能受损的疾病中。
Lymphatic vessels have received significant attention as drug delivery targets, as they shuttle materials from peripheral tissues to the lymph nodes, where adaptive immunity is formed. Delivery of immune modulatory materials to the lymph nodes via lymphatic vessels has been shown to enhance their efficacy and also improve the bioavailability of drugs when delivered to intestinal lymphatic vessels. In this study, we generated a three-compartment model of a lymphatic vessel with a set of kinematic differential equations to describe the transport of nanoparticles from the surrounding tissues into lymphatic vessels. We used previously published data and collected additional experimental parameters, including the transport efficiency of nanoparticles over time, and also examined how nanoparticle formulation affected the cellular transport mechanisms using small molecule inhibitors. These experimental data were incorporated into a system of kinematic differential equations, and nonlinear, least-squares curve fitting algorithms were employed to extrapolate transport coefficients within our model. The subsequent computational framework produced some of the first parameters to describe transport kinetics across lymphatic endothelial cells and allowed for the quantitative analysis of the driving mechanisms of transport into lymphatic vessels. Our model indicates that transcellular mechanisms, such as micro- and macropinocytosis, drive transport into lymphatics. This information is crucial to further design strategies that will modulate lymphatic transport for drug delivery, particularly in diseases like lymphedema, where normal lymphatic functions are impaired.