Tumor necrosis factor α mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response
Tumor necrosis factor α mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response
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DOI：
10.1158/0008-5472.can-07-1599
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
ten Hagen, Timo L. M.
中科院分区：
文献类型：
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作者：
Seynhaeve, Ann L. B.;Hoving, Saske;ten Hagen, Timo L. M.
用化疗药物成功治疗实体瘤需要足够的水平到达肿瘤细胞。已提出肿瘤血管正常化以增强药物输送并改善肿瘤对化疗的反应。因此，增加肿瘤相关脉管系统的渗漏，并因此增强血管异常，也可以改善肿瘤反应。在目前的研究中，我们发现，除了低剂量的肿瘤坏死因子α（TNF）与聚乙二醇化长循环脂质体全身注射增加了这些脂质体的肿瘤蓄积5至6倍，这与增强的肿瘤反应密切相关。使用活体显微镜，我们可以更详细地研究脂质体在肿瘤内的分布。特别是100 μ m脂质体在TNF存在下有效地外渗到周围肿瘤组织中，并且这对肿瘤血管密度、分支和直径没有任何影响。接下来，我们在活体动物中观察到肿瘤细胞完整地吸收脂质体，然后进行细胞内降解。据我们所知，这是一个前所未有的观察。总之，TNF使更多的肿瘤血管具有渗透性，导致脂质体在整个肿瘤中更均匀的分布，这对于最佳的肿瘤反应至关重要。我们的结论是，递送纳米颗粒药物制剂到实体瘤受益于通过用血管活性药物如TNF进行血管操作来增强血管渗漏。
Successful treatment of solid tumors with chemotherapeutics requires that adequate levels reach the tumor cells. Tumor vascular normalization has been proposed to enhance drug delivery and improve tumor response to chemotherapy. Differently, augmenting leakage of the tumor-associated vasculature, and as such enhance vascular abnormality, may improve tumor response as well. In the present study, we show that addition of low-dose tumor necrosis factor alpha (TNF) to systemic injections with pegylated long circulating liposomes augmented the tumor accumulation of these liposomes 5- to 6-fold, which strongly correlated with enhanced tumor response. Using intravital microscopy, we could study the liposomal distribution inside the tumor in more detail. Especially 100 run liposomes effectively extravasate in the surrounding tumor tissue in the presence of TNF and this occurred without any effect on tumor vascular density, branching, and diameter. Next to that, we observed in living animals that tumor cells take up the liposomes intact, followed by intracellular degradation. To our knowledge, this is an unprecedented observation. Taken together, TNF renders more tumor vessels permeable, leading to a more homogeneous distribution of the liposomes throughout the tumor, which is crucial for an optimal tumor response. We conclude that delivery of nanoparticulate drug formulations to solid tumor benefits from augmenting the vascular leakage through vascular manipulation with vasoactive drugs like TNF.