Clauss M A, Jain R K
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890.
Cancer Res. 1990 Jun 15;50(12):3487-92.
Interstitial transport of fluorescein isothiocyanate-conjugated nonspecific polyclonal rabbit and sheep IgG was studied in normal (mature granulation) and neoplastic (VX2 carcinoma) tissues grown in a rabbit ear chamber. The interstitial concentration gradients after i.v. injection were analyzed to yield effective interstitial diffusion coefficients, Deff. The one-dimensional diffusion model underestimated Deff by a factor of up to 3 when compared with a two-dimensional model. Despite marked heterogeneities in Deff, the average values of Deff were higher in tumors than in normal tissue. Rabbit IgG moved faster in tumors than the sheep IgG by a factor of 2. When compared with the dextran of same molecular weight, the ratio of Deff between neoplastic and normal tissue decreased from 33 (dextran) to between 2 and 5 (sheep IgG and rabbit IgG, respectively). When compared with dextran of the same Stokes-Einstein radius, IgGs had a lower Deff in both tissue types. These results are consistent with the size, charge, and configuration of antibodies and the structure and charge of the interstitial matrix and suggest that the delivery of antibodies to tumors may be improved by modulating their charge, hydrophilicity, and antigenicity. The molecular weight dependence of Deff also provides a rational basis for the use of bifunctional antibodies and antibody-enzyme conjugates to increase the delivery of low molecular weight anticancer agents to solid tumors.
在兔耳室中生长的正常（成熟肉芽组织）和肿瘤（VX2癌）组织中，研究了异硫氰酸荧光素偶联的非特异性多克隆兔和羊IgG的间质转运。分析静脉注射后的间质浓度梯度以得出有效间质扩散系数Deff。与二维模型相比，一维扩散模型将Deff低估了高达3倍。尽管Deff存在明显的异质性，但肿瘤中的Deff平均值高于正常组织。兔IgG在肿瘤中的移动速度比羊IgG快2倍。与相同分子量的葡聚糖相比，肿瘤组织与正常组织之间的Deff比值从33（葡聚糖）降至2至5之间（分别为羊IgG和兔IgG）。与具有相同斯托克斯-爱因斯坦半径的葡聚糖相比，IgG在两种组织类型中的Deff均较低。这些结果与抗体的大小、电荷和构象以及间质基质的结构和电荷一致，并表明通过调节抗体的电荷、亲水性和抗原性，可以改善抗体向肿瘤的递送。Deff对分子量的依赖性也为使用双功能抗体和抗体-酶偶联物增加低分子量抗癌剂向实体瘤的递送提供了合理依据。
