McCright Jacob, Yarmovsky Jenny, Maisel Katharina
Department of Bioengineering, University of Maryland College Park, College Park, Maryland 20742, United States.
Mol Pharm. 2024 Mar 4;21(3):1160-1169. doi: 10.1021/acs.molpharmaceut.3c00720. Epub 2023 Oct 18.
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.
淋巴管作为药物递送靶点受到了广泛关注，因为它们将物质从外周组织输送到淋巴结，而适应性免疫正是在淋巴结中形成的。经淋巴管将免疫调节物质递送至淋巴结已被证明可提高其疗效，并且当递送至肠道淋巴管时还能提高药物的生物利用度。在本研究中，我们用一组运动学微分方程建立了一个淋巴管的三室模型，以描述纳米颗粒从周围组织进入淋巴管的运输过程。我们使用了先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运输效率，还使用小分子抑制剂研究了纳米颗粒制剂如何影响细胞运输机制。这些实验数据被纳入运动学微分方程系统，并采用非线性最小二乘曲线拟合算法来推断我们模型中的运输系数。随后的计算框架得出了一些首批描述跨淋巴管内皮细胞运输动力学的参数，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，如微胞饮作用和巨胞饮作用，驱动物质进入淋巴管。这些信息对于进一步设计调节药物递送的淋巴运输策略至关重要，尤其是在淋巴水肿等正常淋巴功能受损的疾病中。
