Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University.
School of Pharmacy, Monash University Malaysia.
Chem Pharm Bull (Tokyo). 2020;68(7):583-588. doi: 10.1248/cpb.c20-00026.
A unique phenomenon in solid tumors, the enhanced permeability and retention (EPR) effect is now well known in the development of macromolecular anticancer therapy. However, cancers with low vascular permeability have posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator, such as nitric oxide (NO), could augment the endogenous EPR effect. However, the most important aim has been to construct an effective NO delivery system for cancer. Since it is well known that human serum albumin is one of the most important endogenous NO transport proteins in human circulation, for more than a decade we have demonstrated that S-nitrosated human serum albumin dimer (SNO-HSA-Dimer) becomes an enhancer of the EPR effect. Here, we summarize the enhanced effect of SNO-HSA-Dimer on the anticancer effect of macromolecular anticancer drugs such as PEGylated liposomal doxorubicin (Doxil). In C26-bearing mice with highly permeable vasculature, SNO-HSA-Dimer is able to increase more 3-fold the tumor accumulation of these anticancer drugs, thereby tripling their anticancer effects. Interestingly, the tumor accumulation of Doxil in B16-bearing mice, which are characterized by a low permeable vasculature, increased more than 6-fold in the presence of SNO-HSA-Dimer, and the improved accumulation of Doxil led to both increased survival and decreased tumor volume. These results strongly suggest that the more cancer is refractory, the more the SNO-HSA-Dimer could enhance the EPR effect via an endogenous albumin transport (EAT) system. Accordingly, we conclude that the EAT system is promising as a drug delivery system (DDS) strategy for refractory cancer therapy.
在实体肿瘤中存在一种独特的现象，即增强的通透性和保留（EPR）效应，现已广泛应用于大分子抗癌治疗的发展中。然而，血管通透性低的癌症给这些基于 EPR 的治疗系统带来了挑战。一种内在的血管调节剂，如一氧化氮（NO），可以增强内源性 EPR 效应。然而，最重要的目标一直是构建一种有效的用于癌症的 NO 传递系统。众所周知，人血清白蛋白是人类循环中最重要的内源性 NO 转运蛋白之一，十多年来，我们已经证明 S-亚硝基化人血清白蛋白二聚体（SNO-HSA-Dimer）成为 EPR 效应的增强剂。在这里，我们总结了 SNO-HSA-Dimer 对大分子抗癌药物如 PEG 化脂质体阿霉素（Doxil）的抗癌效果的增强作用。在 C26 荷瘤小鼠中，其血管通透性较高，SNO-HSA-Dimer 能够使这些抗癌药物的肿瘤蓄积增加 3 倍，从而使它们的抗癌效果增加 3 倍。有趣的是，在血管通透性较低的 B16 荷瘤小鼠中，Doxil 的肿瘤蓄积在 SNO-HSA-Dimer 的存在下增加了 6 倍以上，Doxil 的蓄积增加导致生存时间延长和肿瘤体积减小。这些结果强烈表明，癌症的耐药性越高，SNO-HSA-Dimer 通过内源性白蛋白转运（EAT）系统增强 EPR 效应的可能性就越大。因此，我们得出结论，EAT 系统有望成为治疗耐药性癌症的药物传递系统（DDS）策略。
