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.

中文翻译：

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通过内源性白蛋白转运系统进行难治性癌症治疗的药物输送系统。

实体肿瘤中的一种独特现象，即增强的通透性和保留（EPR）效应在高分子抗癌疗法的开发中已众所周知。然而，低血管通透性的癌症对这些基于EPR的治疗系统提出了挑战。内在的血管调节剂，例如一氧化氮（NO），可能会增强内源性EPR效应。但是，最重要的目标是构建有效的癌症NO传递系统。众所周知，人血清白蛋白是人循环中最重要的内源性NO转运蛋白之一，十多年来，我们证明了S-亚硝化人血清白蛋白二聚体（SNO-HSA-Dimer）可以增强人血清白蛋白。 EPR效果。这里，我们总结了SNO-HSA-Dimer对大分子抗癌药物（例如PEG化脂质体阿霉素（Doxil®））的抗癌作用。在具有高渗透性脉管系统的带有C26的小鼠中，SNO-HSA-Dimer能够使这些抗癌药物的肿瘤蓄积增加3倍以上，从而使它们的抗癌作用提高三倍。有趣的是，具有S16-SHA-Dimer的Doxil®在具有B16的荷瘤小鼠中的肿瘤蓄积以低渗透性脉管系统为特征，增加了6倍以上，而Doxil®蓄积的改善导致两者均增加。生存和肿瘤体积减少。这些结果强烈表明，癌症越难治，SNO-HSA-Dimer可以通过内源性白蛋白转运（EAT）系统增强EPR效果。因此，