Medina-Moreno Ana, El-Hammadi Mazen M, Martínez-Soler Gema I, Ramos Javier G, García-García Gracia, Arias José L
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada, 18011, Spain.
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Sevilla, 41012, Spain.
Drug Deliv Transl Res. 2025 May;15(5):1646-1659. doi: 10.1007/s13346-024-01701-y. Epub 2024 Sep 5.
Methotrexate successful therapy encounters various challenges in chemotherapy, such as poor oral bioavailability, low specificity, side effects and the development of drug resistances. In this study, it is proposed a dual-targeted nanocarrier comprising magnetite/chitosan nanoparticles for an efficient Methotrexate delivery. The formation of the particles was confirmed through morphological analysis using electron microscopy and elemental mappings via energy dispersive X-ray spectroscopy. These nanoparticles exhibited a size of ≈ 270 nm, a zeta potential of ≈ 24 mV, and magnetic responsiveness, as demonstrated by hysteresis cycle analysis and visual observations under a magnetic field. In addition, these particles displayed high stability, as evidenced by size and surface electric charge measurements, during storage at both 4 ºC and 25 ºC for at least 30 days. Electrophoretic properties were examined in relation to pH and ionic strength, confirming these core/shell nanostructure. The nanoparticles demonstrated a pH-responsive drug release as observed by a sustained Methotrexate release over the next 90 h under pH ≈ 7.4, while complete release occurred within 3 h under acidic conditions (pH ≈ 5.5). In the biocompatibility assessment, the magnetite/chitosan particles showed excellent hemocompatibility ex vivo and no cytotoxic effects on normal MCF-10 A and cancer MCF-7 cells. Furthermore, the Methotrexate-loaded nanoparticles significantly enhanced the antitumor activity reducing the half-maximal inhibitory concentration by ≈ 2.7-fold less compared to the free chemotherapeutic.
甲氨蝶呤在化疗中的成功治疗面临各种挑战，如口服生物利用度差、特异性低、副作用以及耐药性的产生。在本研究中，提出了一种由磁铁矿/壳聚糖纳米颗粒组成的双靶向纳米载体，用于高效递送甲氨蝶呤。通过电子显微镜进行形态分析以及通过能量色散X射线光谱进行元素映射，证实了颗粒的形成。这些纳米颗粒的尺寸约为270 nm，zeta电位约为24 mV，并且具有磁响应性，这通过磁滞回线分析和磁场下的视觉观察得到证明。此外，通过尺寸和表面电荷测量证明，这些颗粒在4 ºC和25 ºC下储存至少30天期间表现出高稳定性。研究了与pH和离子强度相关的电泳性质，证实了这些核/壳纳米结构。纳米颗粒表现出pH响应性药物释放，在pH≈7.4的条件下，甲氨蝶呤在接下来的90小时内持续释放，而在酸性条件（pH≈5.5）下3小时内完全释放。在生物相容性评估中，磁铁矿/壳聚糖颗粒在体外显示出优异的血液相容性，并且对正常MCF-10 A细胞和癌症MCF-7细胞没有细胞毒性作用。此外，与游离化疗药物相比，负载甲氨蝶呤的纳米颗粒显著增强了抗肿瘤活性，将半数最大抑制浓度降低了约2.7倍。
