Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer
Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer
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DOI：
10.1186/1477-3155-11-4
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发表时间：
2013-02-16
影响因子：
10.2
通讯作者：
Bao, Sonia N.
中科院分区：
文献类型：
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作者：
Brettas Carneiro, Marcella Lemos;Peixoto, Raphael C. A.;Bao, Sonia N.
背景：含有超顺磁性氧化铁纳米颗粒的磁性液体作为化疗纳米载体是一个有吸引力的平台。最近，我们开发了一种用柠檬酸铑（II）包覆的磁赤铁矿纳米颗粒制剂，与游离柠檬酸铑（II）制剂相比，其对乳腺癌细胞的体外细胞毒性增强高达4.6倍。在这项工作中，我们评估的抗肿瘤活性和毒性诱导这些制剂在Balb/c小鼠荷原位4 T1 breast carcinoma.Methods：小鼠进行了评估，通过分析血象，血清丙氨酸氨基转移酶，铁，肌酐水平的治疗毒性; DNA片段和骨髓细胞的细胞周期;和肝，肾和肺组织学。此外，肿瘤体积缩小，组织学和免疫组化证实了柠檬酸铑（II）和磁赤铁矿纳米粒子包覆柠檬酸铑（II）的抗肿瘤活性。结果：关于治疗的毒性，没有实验组有血清ALT或肌酐水平的改变，这一建议是由小鼠肝脏和肾脏的组织病理学检查证实。各实验组骨髓细胞DNA断裂率均低于15%。另一方面，柠檬酸铑（II）官能化磁赤铁矿和游离柠檬酸铑（II）的络合物导致肿瘤的显著生长抑制和CD 31和Ki-67染色的降低。总的来说，我们证明了柠檬酸铑（II）和涂有铑（II）的磁赤铁矿纳米颗粒，柠檬酸盐制剂在瘤内给药后对4 T1转移性乳腺癌细胞系表现出抗肿瘤作用。这种抗肿瘤作用之后是细胞增殖和微血管形成的抑制以及以坏死和纤维化为特征的肿瘤组织损伤。值得注意的是，这是第一份发表的报告，证明了用柠檬酸铑（II）涂覆的磁赤铁矿纳米颗粒的治疗效果。这种治疗延长了治疗小鼠的生存期，而不会引起明显的全身毒性，这加强了其在未来乳腺癌治疗应用中的用途。
Background: Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma.Methods: Mice were evaluated with regard to the treatments' toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry.Results: Regarding the treatments' toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining.Conclusions: In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite nanoparticles coated with rhodium (II) citrate. This treatment prolonged the survival period of treated mice without inducing apparent systemic toxicity, which strengthens its use for future breast cancer therapeutic applications.