Seymour L W
Department of Biological Sciences, University of Keele, Staffordshire, U.K.
Crit Rev Ther Drug Carrier Syst. 1992;9(2):135-87.
The biodistribution of soluble macromolecules is governed extensively by their ability to penetrate endothelial layers. Many solid tumors possess vasculature that is hyperpermeable to macromolecules, not always correlating with the presence of interendothelial cell fenestrations. The exact physiological mechanisms responsible for this nonspecific leakiness are not yet fully understood. Together with enhanced vascular permeability, however, tumors usually lack effective lymphatic drainage; consequently, they selectively accumulate circulating macromolecules (up to 10% of an i.v. dose per gram in mice). This "enhanced permeability and retention effect" (EPR effect) has been studied extensively, and it is thought to constitute the mechanism of action of SMANCS (styrene-maleic/anhydride-neocarzinostatin), now in regular clinical use in Japan for the treatment of hepatoma. It seems likely that EPR also contributes to the anticancer activity of the N-(2-hydroxypropyl)methacrylamide copolymer-anthracycline conjugates which are shortly to undergo clinical evaluation in the U.K.
可溶性大分子的生物分布在很大程度上取决于它们穿透内皮细胞层的能力。许多实体瘤拥有对大分子具有高通透性的脉管系统，这并不总是与内皮细胞窗孔的存在相关。导致这种非特异性渗漏的确切生理机制尚未完全了解。然而，与血管通透性增强同时出现的是，肿瘤通常缺乏有效的淋巴引流；因此，它们会选择性地积聚循环中的大分子（在小鼠中每克可达静脉注射剂量的10%）。这种“增强的通透性和滞留效应”（EPR效应）已得到广泛研究，并且被认为是SMANCS（苯乙烯-马来酸/酸酐-新制癌菌素）的作用机制，SMANCS目前在日本常规用于治疗肝癌。EPR似乎也有助于N-（2-羟丙基）甲基丙烯酰胺共聚物-蒽环类药物偶联物的抗癌活性，该偶联物即将在英国进行临床评估。
