Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments
Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments
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DOI：
10.1073/pnas.1006611107
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发表时间：
2010-09-21
影响因子：
11.1
通讯作者：
Radhakrishnan, Ravi
中科院分区：
文献类型：
--
作者：
Liu, Jin;Weller, Gregory E. R.;Radhakrishnan, Ravi
发展了一种基于Metropolis蒙特卡罗(MC)和加权直方图分析方法(WHAM)的计算方法来计算功能化纳米载体(NC)与内皮细胞(EC)表面之间的绝对结合自由能。计算的NC结合自由能景观产生了定量一致的结合亲和力，当直接与体外细胞培养实验中表达EC表面的特定抗体包裹的NCS(直径100 nm)和细胞内黏附分子-1(ICAM-1)的类似测量结果进行比较时。NC的抗体表面覆盖率(Ss)对结合模拟的影响揭示了一个阈值ss，低于该阈值，NC与ICAM-1的结合亲和力急剧降低，且低于单个抗ICAM-1分子与ICAM-1的结合亲和力。该模型表明，在阈值附近改变ss的主要影响是通过改变多价相互作用；然而，平移和转动熵的损失也是重要的。考虑剪切流和糖基化不会改变抗体表面覆盖率的计算阈值。描述SS对NC结合影响的计算趋势与抗ICAM-1包被的NCS体内靶向小鼠肺内皮细胞的实验结果非常一致。通过计算的NC破裂力分布与原子力显微镜(AFM)实验中的实测值之间的密切一致性，进一步验证了模型结果。与AFM、体外(细胞培养)和体内实验的三向定量一致建立了我们模型的力学、热力学和生理一致性。因此，我们的计算方案代表了一种定量和预测的方法，用于靶向血管药物输送中功能化纳米载体的模型驱动设计和优化。
A computational methodology based on Metropolis Monte Carlo (MC) and the weighted histogram analysis method (WHAM) has been developed to calculate the absolute binding free energy between functionalized nanocarriers (NC) and endothelial cell (EC) surfaces. The calculated NC binding free energy landscapes yield binding affinities that agree quantitatively when directly compared against analogous measurements of specific antibody-coated NCs (100 nm in diameter) to intracellular adhesion molecule-1 (ICAM-1) expressing EC surface in in vitro cell-culture experiments. The effect of antibody surface coverage (ss) of NC on binding simulations reveals a threshold ss value below which the NC binding affinities reduce drastically and drop lower than that of single anti-ICAM-1 molecule to ICAM-1. The model suggests that the dominant effect of changing ss around the threshold is through a change in multivalent interactions; however, the loss in translational and rotational entropies are also important. Consideration of shear flow and glycocalyx does not alter the computed threshold of antibody surface coverage. The computed trend describing the effect of ss on NC binding agrees remarkably well with experimental results of in vivo targeting of the anti-ICAM-1 coated NCs to pulmonary endothelium in mice. Model results are further validated through close agreement between computed NC rupture-force distribution and measured values in atomic force microscopy (AFM) experiments. The three-way quantitative agreement with AFM, in vitro (cell-culture), and in vivo experiments establishes the mechanical, thermodynamic, and physiological consistency of our model. Hence, our computational protocol represents a quantitative and predictive approach for model-driven design and optimization of functionalized nanocarriers in targeted vascular drug delivery.