Enhancement of Tumor-Targeted Delivery of Bacteria with Nitroglycerin Involving Augmentation of the EPR Effect
Enhancement of Tumor-Targeted Delivery of Bacteria with Nitroglycerin Involving Augmentation of the EPR Effect
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DOI：
10.1007/978-1-4939-3515-4_2
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Maeda, Hiroshi
中科院分区：
文献类型：
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作者：
Fang, Jun;Long, Liao;Maeda, Hiroshi
使用大小约为1 μ m的细菌，现在正成为一种有吸引力的癌症治疗策略。实体瘤对生物相容性大分子如聚合物偶联抗癌剂、脂质体和胶束表现出增强的渗透性和保留（EPR）效应。这种现象允许这种大分子的肿瘤选择性递送。我们在这里报告，静脉注射的细菌证明了类似于这些大分子的性质。因此，可以在肿瘤中选择性聚集的细菌可以用于癌症治疗。兼性或厌氧细菌即使在实体肿瘤中存在的缺氧条件下也会生长。我们早期发现，一氧化氮（NO）是促进EPR效应的最重要的因素之一，通过血管扩张，开放内皮细胞连接间隙，增加血流量的低血管肿瘤。在这里，我们描述了增强EPR效应的硝酸甘油（NG），一种常用的NO供体，在不同的肿瘤模型中使用各种大分子药物。更重要的是，我们报道了NG显著增强了静脉注射细菌后干酪乳杆菌向肿瘤的递送，NG治疗后肿瘤中细菌积累增加了10倍以上。这一发现表明NG具有增强细菌治疗癌症的潜在优势，并且需要进一步研究这种可能性。
The use of bacteria, about 1 mu m in size, is now becoming an attractive strategy for cancer treatment. Solid tumors exhibit the enhanced permeability and retention (EPR) effect for biocompatible macromolecules such as polymer-conjugated anticancer agents, liposomes, and micelles. This phenomenon permits tumor-selective delivery of such macromolecules. We report here that bacteria injected intravenously evidenced a property similar to that can of these macromolecules. Bacteria that can accumulate selectively in tumors may therefore be used in cancer treatment.Facultative or anaerobic bacteria will grow even under the hypoxic conditions present in solid tumors. We found earlier that nitric oxide (NO) was among the most important factors that facilitated the EPR effect via vasodilatation, opening of endothelial cell junction gaps, and increasing the blood fl ow of hypovascular tumors. Here, we describe the augmentation of the EPR effect by means of nitroglycerin (NG), a commonly used NO donor, using various macromolecular agents in different tumor models. More importantly, we report that NG signifi cantly enhanced the delivery of Lactobacillus casei to tumors after intravenous injection of the bacteria, more than a tenfold increase in bacterial accumulation in tumors after NG treatment. This fi nding suggests that NG has a potential advantage to enhance bacterial therapy of cancer, and further investigations of this possibility are warranted.