A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles
A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles
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DOI：
10.1152/japplphysiol.00389.2006
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发表时间：
2006-10-01
影响因子：
3.3
通讯作者：
Swartz, Melody A.
中科院分区：
文献类型：
--
作者：
Reddy, Sai T.;Berk, David A.;Swartz, Melody A.
定量注射大分子和纳米颗粒间质对流转运的灵敏体内模型。J Appl Physiol 101：1162-1169，2006.首次发表于2006年6月8日; doi：10.1152/japplphysiol.00389.2006。颗粒的有效间质转运对于注射的药物/诊断剂到达预期目标是必要的;然而，缺乏估计这种转运参数的定量方法。在这项研究中，我们开发了一种体内模型，用于评估注射的大分子和纳米颗粒的间质对流。将荧光标记的大分子和颗粒与参比溶质在恒定输注压力下皮内输注到小鼠尾尖中，并从空间和时间间隙浓度分布确定它们的相对对流系数。用共输注的参考溶质定量相对溶质速度消除了估计组织间液速度分布的需要，大大降低了实验的可变性。为了证明该模型的灵敏度和有用性，我们比较了大小（3，40，71和2,000 kDa和40 nm直径颗粒的葡聚糖），形状（线性葡聚糖71 kDa与69 kDa球状蛋白白蛋白）和电荷（阴离子与中性葡聚糖3 kDa）对间质对流的影响。我们发现这些分子之间的间隙运输率显着差异，并确认预期的运输现象，证明模型的灵敏度比较不同大小，形状和电荷的溶质。我们的数据表明，尺寸排阻（在特定尺寸范围内）主导分子对流，而机械阻碍减慢较大的分子和纳米颗粒;蛋白质对流慢于相同分子质量的线性分子，负表面电荷通过基质排斥增加对流。我们的体内模型大概是一个敏感和可靠的工具，用于评估和优化潜在的药物/诊断车辆，利用间质和淋巴传递途径。
A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles. J Appl Physiol 101: 1162-1169, 2006. First published June 8, 2006; doi:10.1152/japplphysiol.00389.2006.-Effective interstitial transport of particles is necessary for injected drug/diagnostic agents to reach the intended target; however, quantitative methods to estimate such transport parameters are lacking. In this study, we develop an in vivo model for evaluating interstitial convection of injected macromolecules and nanoparticles. Fluorescently labeled macromolecules and particles are coinfused with a reference solute at constant infusion pressure intradermally into the mouse tail tip, and their relative convection coefficients are determined from spatial and temporal interstitial concentration profiles. Quantifying relative solute velocity with a coinfused reference solute eliminates the need to estimate interstitial fluid velocity profiles, greatly reducing experimental variability. To demonstrate sensitivity and usefulness of this model, we compare the effects of size (dextrans of 3, 40, 71, and 2,000 kDa and 40-nm diameter particles), shape (linear dextran 71 kDa vs. 69 kDa globular protein albumin), and charge (anionic vs. neutral dextran 3 kDa) on interstitial convection. We find significant differences in interstitial transport rates between each of these molecules and confirm expected transport phenomena, testifying to sensitivity of the model in comparing solutes of different size, shape, and charge. Our data show that size exclusion (within a specific size range) dominates molecular convection, while mechanical hindrance slows larger molecules and nanoparticles; proteins convect slower than linear molecules of equal molecular mass, and negative surface charges increase convection through matrix repulsion. Our in vivo model is presumably a sensitive and reliable tool for evaluating and optimizing potential drug/diagnostic vehicles that utilize interstitial and lymphatic delivery routes.