A detailed understanding of the factors governing nanomaterial biodistribution is needed to rationally design safe nanomedicines. This research details the pharmacokinetics of gold nanoparticle (AuNP) biodistribution after arterial infusion of 40 or 80 nm AuNP (1 μg/ml) into the isolated perfused porcine skin flap (IPPSF). AuNP had surface coatings consisting of neutral polyethylene glycol (PEG), anionic lipoic acid (LA), or cationic branched polyethylenimine (BPEI). Effect of a porcine plasma corona (PPC) on 40 nm BPEI and PEG-AuNP were assessed in the IPPSF. Au concentrations were determined by ICP/MS and arterial to venous concentration-time profiles were analyzed over 8 hr (4 hr infusion, 4 hr washout) using a two-compartment pharmacokinetic model. IPPSF viability and vascular function were assessed by change in glucose utilization, vascular resistance, or weight gain after perfusion. All AuNP demonstrated some degree of AuNP arterial extraction and skin flap retention, as well as enhanced kinetic parameters of tissue uptake; with BPEI-AuNP consistently having the greatest biodistribution even with a PPC. Toxicological effects were not detected. Transmission electron microscopy confirmed intracellular uptake of AuNP. These studies paralleled previous in vitro cell culture studies using the same AuNP in human endothelial and renal proximal tubule cells, hepatocytes, keratinocytes, showing BPEI-AuNP having the greatest uptake, although the presence of a PPC did not reduce IPPSF biodistribution as in the cell culture studies. These findings clearly indicate arterial to the venous extraction of AuNP after infusion with the magnitude of extraction being greatest with the BPEI surface coating and provide data and model structure necessary to construct the whole body physiologically based pharmacokinetic models capable of utilizing available in vitro data.

中文翻译：

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在动脉灌注到灌注的组织中后模拟金纳米颗粒的生物分布：表面涂层，尺寸和蛋白质电晕的影响

需要合理理解控制纳米材料生物分布的因素，才能合理设计安全的纳米药物。这项研究详细介绍了将40或80 nm AuNP（1μg/ ml）动脉输注到分离的灌注猪皮肤皮瓣（IPPSF）中后，金纳米颗粒（AuNP）生物分布的药代动力学。AuNP具有由中性聚乙二醇（PEG），阴离子硫辛酸（LA）或阳离子支链聚乙烯亚胺（BPEI）组成的表面涂层。在IPPSF中评估了猪血浆电晕（PPC）对40 nm BPEI和PEG-AuNP的影响。通过ICP / MS测定Au浓度，并使用两室药代动力学模型分析8小时（输注4小时，洗脱4小时）中动脉到静脉的浓度-时间曲线。IPPSF的生存能力和血管功能通过葡萄糖利用的变化进行评估，血管阻力或灌注后体重增加。所有AuNP均显示一定程度的AuNP动脉提取和皮瓣固位，以及增强的组织吸收动力学参数。即使使用PPC，BPEI-AuNP也始终具有最大的生物分布。未检测到毒理学作用。透射电子显微镜证实细胞内摄取AuNP。这些研究与以前的相似在人内皮细胞和肾近端小管细胞，肝细胞，角质形成细胞中使用相同的AuNP进行的体外细胞培养研究显示BPEI-AuNP具有最大的摄取，尽管PPC的存在并没有像细胞培养研究中那样降低IPPSF的生物分布。这些发现清楚地表明了输注后动脉对AuNP的静脉提取，其中BPEI表面涂层的提取幅度最大，并提供了构建能够利用可用体外数据的基于整体生理学的药代动力学模型所必需的数据和模型结构。