35 years of discussions with Prof. Maeda on the EPR effect and future directions
35 years of discussions with Prof. Maeda on the EPR effect and future directions
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DOI：
10.1016/j.jconrel.2022.06.035
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发表时间：
2022-07-01
影响因子：
10.8
通讯作者：
Matsumura, Yasuhiro
中科院分区：
文献类型：
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作者：
Matsumura, Yasuhiro
2021年5月，在首次宣布增强渗透性和保留（EPR）效果35年后，前田博士去世。EPR效应作为高分子量药物传递系统（DDS）的理论支柱，具有良好的生物相容性，已在世界范围内的实验小鼠模型中得到证实。然而，在临床实体肿瘤中，对EPR的作用认识不足，更重要的是DDS还没有成为肿瘤治疗的主流。前田博士和我都敏锐地意识到了这一点，35年来，我们一直在讨论如何应对这一问题，并努力通过采用不同的策略来弥补EPR效应的不足。前田博士提出了更有效地利用肿瘤血管渗透性并对肿瘤细胞施加氧化应激的方法。我提出了使用抗不溶性纤维蛋白抗体与抗癌剂缀合的癌症基质靶向（CAST）疗法，以克服临床实体癌中EPR效应的不足，所述实体癌具有丰富的基质组织。临床癌症被丰富的基质包围，并且由于这种基质屏障，即使在缺氧和营养不良的情况下也能存活。癌细胞对任何外部攻击都有抵抗力，包括抗癌药物和辐射。虽然不用说EPR效应在临床实体癌策略中很重要，但也需要在实体癌中提供累积和均匀分布的DDS。
In May 2021, 35 years after first announcing the enhanced permeability and retention (EPR) effect, Dr. Maeda passed away. As a theoretical pillar of high molecular weight drug delivery systems (DDS) with high biocompatibility, the EPR effect has been proven worldwide in experimental mouse models. However, in clinical solid tumors, awareness of the EPR effect is insufficient, and more importantly, DDS has not become the mainstream cancer treatment. Both Dr. Maeda and I were acutely aware of this, and for 35 years, we discussed what to do about it and strived to make up for the inadequacies of the EPR effect by employing different strategies. Dr. Maeda came up with ways to use tumor vascular permeability more effectively and to apply oxidative stress to tumor cells. I proposed cancer stromal targeting (CAST) therapy using the anti-insoluble fibrin antibody conjugated with an anticancer agent in order to overcome the insufficiency of the EPR effect in clinical solid cancers, which possess abundant stromal tissue. Clinical cancers are surrounded by an abundant stroma and survive even under hypoxia and malnutrition due to this stromal barrier. Cancer cells become resistant to any external attack, including with anticancer drugs and radiation. While it goes without saying that EPR effects are important in clinical solid cancer strategies, DDSs that offer both accumulation and even distribution in solid cancers are also required.