Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China.
Drug Deliv Transl Res. 2021 Jun;11(3):1096-1106. doi: 10.1007/s13346-020-00832-2.
To reduce the side effects of methotrexate and increase its anti-inflammatory effect, we developed a drug delivery system, dextran sulfate-modified methotrexate-loaded layered double hydroxide nanocomposites (LDH-MTX-DS), with both targeting and pH-sensitivity for the treatment of rheumatoid arthritis. The nanocomposites had a mean particle size of 303.1 ± 8.07 nm, zeta potential of - 12.4 ± 0.7 mV, encapsulation efficiency of 49.64%, and loading efficiency of 16.81%. In vitro release experiments demonstrated that the drug was released faster in PBS at pH 5.5 than at pH 7.4, which reflected the pH-sensitivity of this system. Cellular uptake assays displayed higher cellular uptake rate of the dextran sulfate-modified targeting carrier compared with that of a non-targeting carrier (P < 0.01), which indicated that the LDH-MTX-DS could actively target scavenger receptors on the surface of activated RAW 264.7 cells. In vivo pharmacodynamic experiments showed that, after the second (P < 0.001) and third (P < 0.05) administrations, the preparation group exhibited significantly improved therapeutic efficacy in adjuvant-induced arthritis (AIA) rats when compared with free MTX alone. These results indicated that this drug delivery system was promising in the treatment of rheumatoid arthritis. Graphical abstract.
为了降低甲氨蝶呤的副作用并提高其抗炎效果，我们开发了一种载有甲氨蝶呤的葡聚糖硫酸酯修饰的层状双氢氧化物纳米复合材料（LDH-MTX-DS）的药物递送系统，该系统具有靶向性和 pH 敏感性，用于治疗类风湿性关节炎。该纳米复合材料的平均粒径为 303.1 ± 8.07nm，zeta 电位为-12.4 ± 0.7mV，包封效率为 49.64%，载药效率为 16.81%。体外释放实验表明，药物在 pH5.5 的 PBS 中比在 pH7.4 的 PBS 中释放更快，这反映了该系统的 pH 敏感性。细胞摄取实验显示，与非靶向载体相比，葡聚糖硫酸酯修饰的靶向载体具有更高的细胞摄取率（P<0.01），这表明 LDH-MTX-DS 可以主动靶向激活的 RAW264.7 细胞表面的清道夫受体。体内药效学实验表明，与单独使用游离 MTX 相比，在第二次（P<0.001）和第三次（P<0.05）给药后，制剂组在佐剂诱导的关节炎（AIA）大鼠中表现出显著改善的治疗效果。这些结果表明，该药物递送系统在治疗类风湿性关节炎方面具有广阔的应用前景。
