Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan.
Department of Pathology, Asahikawa Medical University, 1 Chome-1-1, Midorigaoka Higashi 2 Jo, Asahikawa, Hokkaido, 078-8510, Japan.
Biomaterials. 2021 Feb;269:120645. doi: 10.1016/j.biomaterials.2020.120645. Epub 2021 Jan 6.
In cancer, angiogenesis is a critical phenomenon of nascent blood vessel development to facilitate the oxygen and nutrient supply prerequisite for tumor progression. Therefore, targeting tumors at the angiogenesis step may be significant to prevent their advanced progression and metastasis. Although angiogenesis inhibitors can limit the further growth of tumors, complete eradication of tumors may not be possible by monotherapy alone. Therefore, a therapeutic regimen targeting both tumor growth and its vasculature is essential. Because reactive oxygen species (ROS) are fundamental to both angiogenesis and tumor growth, the use of antioxidants may be an effective dual approach to inhibit tumors. We previously confirmed that our original antioxidant nitroxide radical-containing nanoparticles (RNPs) such as pH-sensitive RNP and pH-insensitive RNP, effectively attenuates the tumorigenic and metastasis potentials of triple-negative breast cancer. In this study, we further investigated the efficacy of RNPs to limit the tumor progression by inhibiting the ROS-regulated cancer angiogenesis in a triple-negative breast cancer model. Here, we confirmed that RNPs significantly inhibited in vitro angiogenesis, attributed to the downregulation of the ROS-regulated angiogenesis inducer, vascular endothelial growth factor (VEGF) in the breast cancer cell line (MDA-MB231) and human umbilical vein endothelial cells (HUVEC), which was consistent with decreased cellular ROS. TEMPOL, a low-molecular-weight (LMW) control antioxidant, exhibited anti-angiogenic effects accompanied by cytotoxicity to the endothelial cells. In an in vivo xenograft model for breast cancer, RNPs exerted significant anti-tumor effect due to the decreased expression of tumor VEGF, which prevented accumulation of the endothelial cells. It should be noted that such efficacy of RNPs was obtained with negligible off-target effects. On the other hand, TEMPOL, because of its size, exerted anti-angiogenesis effect accompanied with injuries to the kidneys, which corroborated with previous reports. Our findings imply that RNPs are more potential antioxidants than their LMW counterparts, such as TEMPOL, for the management of breast cancers.
在癌症中，血管生成是新生血管发育的关键现象，有助于肿瘤进展所需的氧气和营养供应。因此，在血管生成阶段靶向肿瘤可能对于阻止其进一步进展和转移具有重要意义。尽管血管生成抑制剂可以限制肿瘤的进一步生长，但单独使用单一疗法可能无法完全消除肿瘤。因此，靶向肿瘤生长及其血管的治疗方案至关重要。由于活性氧 (ROS) 对血管生成和肿瘤生长都至关重要，因此使用抗氧化剂可能是抑制肿瘤的有效双重方法。我们之前证实，我们的原始抗氧化含氮氧化物自由基纳米颗粒 (RNP)，如 pH 敏感 RNP 和 pH 不敏感 RNP，可有效减弱三阴性乳腺癌的致瘤和转移潜力。在这项研究中，我们进一步研究了 RNP 通过抑制 ROS 调节的癌症血管生成来限制三阴性乳腺癌模型中肿瘤进展的功效。在这里，我们证实 RNP 显著抑制了体外血管生成，这归因于乳腺癌细胞系 (MDA-MB231) 和人脐静脉内皮细胞 (HUVEC) 中 ROS 调节的血管生成诱导剂血管内皮生长因子 (VEGF) 的下调，这与细胞内 ROS 的减少一致。低分子量 (LMW) 对照抗氧化剂 TEMPOL 表现出抗血管生成作用，同时对内皮细胞具有细胞毒性。在乳腺癌的体内异种移植模型中，由于肿瘤 VEGF 的表达减少，RNP 发挥了显著的抗肿瘤作用，阻止了内皮细胞的积累。应该注意的是，RNP 获得了这种功效，而没有明显的脱靶效应。另一方面，由于其尺寸，TEMPOL 发挥了抗血管生成作用，同时对肾脏造成了损伤，这与之前的报道一致。我们的研究结果表明，与 LMW 类似物（如 TEMPOL）相比，RNP 是更有潜力的抗氧化剂，可用于管理乳腺癌。
