Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes 748, 05508-000, Brazil.
Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes 748, 05508-000, Brazil.
J Nanosci Nanotechnol. 2021 Mar 1;21(3):1451-1461. doi: 10.1166/jnn.2021.19027.
A systematic study was carried out to evaluate the uptake and cytotoxicity of methotrexate (MTX) conjugated to superparamagnetic iron oxide nanoparticles (SPIONs) modified with glycerol phosphate (Glyc) and phosphorylethanolamine (PEA), using MCF-7 cancer cell line as model. The ligand shell composition was controlled in such a way to get SPIONs with nine different surface functionalization and up to three co-conjugated ligands but the very iron oxide core, in order to test and compare uptake and cytotoxicity, and verify possible additive effects. Folic acid (FA), the non-toxic analogue of MTX, was also explored as ligand for SPIONs. Glyc was shown to enhance dramatically the cellular uptake despite the high negative zeta potentials, whereas PEA, FA and MTX was found to have a much lower effect on the cellular uptake. Also, a significant ten times lowering of IC was observed for the co-conjugated MTX in the SPION-Glyc/PEA/MTX as compared to the free drug, whereas the analogue SPION-Glyc/PEA/FA nanoparticles exhibited no significant cytotoxicity. In short, the conjugation of MTX to SPIONs enhanced dramatically its cytotoxicity and decreased the IC value against MCF-7 tumor cells as compared to the free drug, probably due to the enhanced uptake of SPIONs as a result of their surface modification with Glyc/PEA, demonstrating that SPION-Glyc/PEA is a good nanocarrier for co-conjugated methotrexate.
进行了一项系统研究，以评估经甘油磷酸（Glyc）和磷乙醇胺（PEA）修饰的超顺磁性氧化铁纳米粒子（SPIONs）与甲氨蝶呤（MTX）偶联物的摄取和细胞毒性，使用 MCF-7 癌细胞系作为模型。以这样的方式控制配体壳的组成，得到具有九种不同表面功能化和多达三种共偶联配体的 SPIONs，但氧化铁核非常稳定，以测试和比较摄取和细胞毒性，并验证可能的附加效应。叶酸（FA），MTX 的无毒类似物，也被探索为 SPIONs 的配体。尽管具有高负 zeta 电位，但 Glyc 极大地增强了细胞摄取，而 PEA、FA 和 MTX 对细胞摄取的影响要小得多。此外，与游离药物相比，SPION-Glyc/PEA/MTX 中的共偶联 MTX 的 IC 降低了十倍，而 SPION-Glyc/PEA/FA 纳米粒子则没有表现出明显的细胞毒性。简而言之，与游离药物相比，MTX 与 SPIONs 的偶联极大地增强了其细胞毒性并降低了 IC 值，这可能是由于 Glyc/PEA 对 SPIONs 表面的修饰增强了其摄取，表明 SPION-Glyc/PEA 是共偶联甲氨蝶呤的良好纳米载体。
