Synthesis of controlled-size silver nanoparticles for the administration of methotrexate drug and its activity in colon and lung cancer cells.
Synthesis of controlled-size silver nanoparticles for the administration of methotrexate drug and its activity in colon and lung cancer cells.
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为了得到粒径分布较窄的氨甲喋呤(MTX)-AgNPs-MTX结合物，分别以硼氢化物和柠檬酸为还原/封端剂，控制合成了MTX-AgNPs-MTX纳米粒子。其表征为多分散的球形纳米粒子，平均尺寸约为13 nm，分布范围为7-21 nm。FTIR和EDX分析证实了MTX的存在。光谱测定表明，MTX通过羧基(-COOH)与柠檬酸盐分子交换而被化学吸附到AgNPs上。用不同量的MTX合成的AgNPs的载药量分别为28、31和40%。体外药物释放试验表明，所有结合量的甲氨蝶呤释放到AgNPs中的量在77%到85%之间，释放曲线相似。对于游离的甲氨蝶呤，纳米载体的加入延迟了其释放，也改变了其药代动力学。游离MTX在3h后释放符合一级动力学模型，而在AgNPs存在下，在前5小时内观察到快速的初始释放，随后在24小时后进入平台期。在这种情况下，AgNPs-MTX符合Higuchi模型，其增溶过程受扩散过程控制。经AgNPs-MTX处理的不同细胞株的流式细胞仪检测结果表明，两种试剂联合作用具有抗肿瘤作用，作用48小时后，结肠癌细胞株HTC-116的活细胞百分率降至40%。这种作用较弱，但对肺癌细胞系(A-549)仍显着。最后，斑马鱼与AgNPs-MTX的实验没有显示任何显著的细胞毒性效应，从而证实了通过将MTX偶联到AgNPs实现的全身药物毒性的降低。在斑马鱼模型中观察到的毒性降低也意味着AgNPs-MTX在治疗人类癌症的化疗中的使用可能有所改善。为了得到粒径分布较窄的氨甲喋呤(MTX)-AgNPs-MTX结合物，分别以硼氢化物和柠檬酸为还原/封端剂，控制合成了MTX-AgNPs-MTX纳米粒子。
A controlled synthesis of methotrexate (MTX) silver nanoparticles (AgNPs-MTX) using borohydride and citrate as reduction and reduction/capping agents, respectively, was performed in order to obtain AgNPs-MTX conjugates with a narrow size distribution. Their characterization showed polydispersed spherical shape nanoparticles with a mean size around 13 nm and distribution range between 7–21 nm. The presence of MTX was confirmed by FTIR and EDX analysis. Spectroscopic determinations suggest the chemisorption of MTX through a carboxylic group (–COOH) onto AgNPs via the exchange with a citrate molecule. Drug loading capacities calculated for AgNPs synthesized using different amounts of MTX were 28, 31 and 40%. In vitro drug release tests depicted similar release profiles for all conjugated amounts releasing between 77 to 85% of the initial MTX loaded into the AgNPs. With respect to free MTX, the addition of the nanocarrier delayed its release and also changed its pharmacokinetics. Free MTX is released after 3 hours following a first order kinetic model, whereas in the presence of AgNPs, a fast initial release is observed during the first 5 hours, followed by a plateau after 24 hours. In this case, AgNPs-MTX fitted a Higuchi model, where its solubilization is controlled by a diffusion process. Results obtained from flow cytometry of different cell lines treated with AgNPs-MTX demonstrated the combined anticancer effect of both reagents, decreasing the percentage of living cells in a colon cancer cell line (HTC-116) down to 40% after 48 hours of exposure. This effect was weaker but still significant for a lung cancer cell line (A-549). Finally, a zebrafish assay with AgNPs-MTX did not show any significant cytotoxic effect, confirming thereby the reduction of systemic drug toxicity achieved by coupling MTX to AgNPs. This observed toxicity reduction in the zebrafish model implies also a probable improvement of the usage of AgNPs-MTX in chemotherapy against human cancers. A controlled synthesis of methotrexate (MTX) silver nanoparticles (AgNPs-MTX) using borohydride and citrate as reduction and reduction/capping agents, respectively, was performed in order to obtain AgNPs-MTX conjugates with a narrow size distribution.
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