Programa de Pós-Graduação em Biotecnologia (PPGB), Grupo de Pesquisa em Oncologia Celular e Molecular, Laboratório de Genômica Funcional, Biotecnologia/Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil.
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Int J Nanomedicine. 2014 Mar 25;9:1583-91. doi: 10.2147/IJN.S56506. eCollection 2014.
Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.
乳腺癌是最常见的女性癌症。甲氨蝶呤（MTX）是一种抗代谢药物，在乳腺癌治疗中仍然很重要。其疗效因癌细胞通过多种机制产生的耐药性而受到影响。本研究评估了 MTX 衍生物（MTX 二乙酯[MTX（OEt）2]）和 MTX（OEt）2 负载脂质核纳米囊泡在两种 MTX 耐药的乳腺癌腺癌细胞系 MCF-7 和 MDA-MB-231 中诱导的细胞凋亡和细胞周期停滞。制备的制剂具有适当的粒度分布。通过流式细胞术评估治疗反应。根据耐药机制，我们观察到细胞系之间存在不同的反应。对于 MCF-7 细胞，MTX（OEt）2 溶液和负载 MTX（OEt）2 的脂质核纳米囊泡的凋亡率明显高于未经处理的细胞和未负载脂质核纳米囊泡孵育的细胞。对于 MDA-MB-231 细胞，负载 MTX（OEt）2 的脂质核纳米囊泡在诱导细胞凋亡方面明显优于游离药物溶液。仅 MTX（OEt）2 溶液诱导 S 期细胞周期停滞。药物纳米封装提高了缺乏转运受体的 MTX 耐药细胞系的细胞凋亡诱导作用。
