Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model
Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model
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DOI：
10.1021/mp060132k
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Wu, Chao-Liang
中科院分区：
文献类型：
--
作者：
Chen, Yu-Hung;Tsai, Chiau-Yuang;Wu, Chao-Liang
甲氨蝶呤 (MTX) 是一种二氢叶酸还原酶的化学计量抑制剂，是一种用于治疗多种肿瘤的化疗药物。细胞药物输入受损和细胞药物输出增加可能使细胞对 MTX 产生耐药性。 MTX 当以可溶形式局部给药时，会通过毛细血管迅速吸收进入循环系统，这也可能是患者治疗失败的原因。为了更长时间地保留 MTX 在肿瘤细胞内并改变其药代动力学行为，我们提出了一种将 MTX 与金纳米颗粒 (AuNP) 结合作为药物载体的新配方。在本研究中，我们开发了 MTX-AuNP 缀合物，并检测了其体外细胞毒性作用和体内抗肿瘤作用。光谱检查表明，MTX 可以通过羧基 (-COOH) 直接结合到 AuNP 上，形成 MTX-AuNP 复合物，并从纳米颗粒中动力学释放。在用MTX-AuNP处理的肿瘤细胞中，MTX的积累比用游离MTX处理的肿瘤细胞更快、更高。值得注意的是，与等剂量的游离 MTX 相比，MTX-AuNP 对多种肿瘤细胞系表现出更高的细胞毒性作用。这可以归因于MTX-AuNP的“集中效应”。 MTX-AuNP 的给药可抑制 Lewis 肺癌 (LL2) 小鼠腹水模型中的肿瘤生长，而等剂量的游离 MTX 则没有抗肿瘤作用。总之，这些结果表明，通过将纳米材料与抗癌药物 MTX-AuNP 相结合，可能比游离 MTX 更有效地治疗癌症。
Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase, is a chemotherapeutic agent for treating a variety of neoplasms. Impairment of drug import into cells and increase in drug export from cells may render cells resistant to MTX. MTX, when locally administered in a soluble form, is rapidly absorbed through capillaries into the circulatory system, which may also account for therapeutic failure in patients. To retain MTX within tumor cells for longer duration and alter its pharmacokinetic behavior, we proposed a new formulation of MTX bound to the gold nanoparticle (AuNP) that serves as drug carriers. In this study, we developed the MTX-AuNP conjugate and examined its cytotoxic effect in vitro and antitumor effect in vivo. Spectroscopic examinations revealed that MTX can be directly bound onto AuNP via the carboxyl group (-COOH) to form the MTX-AuNP complex and kinetically released from the nanoparticles. The accumulation of MTX is faster and higher in tumor cells treated with MTX-AuNP than that treated with free MTX. Notably, MTX-AuNP shows higher cytotoxic effects on several tumor cell lines compared with an equal dose of free MTX. This can be attributed to the "concentrated effect" of MTX-AuNP. Administration of MTX-AuNP suppresses tumor growth in a mouse ascites model of Lewis lung carcinoma (LL2), whereas an equal dose of free MTX had no antitumor effect. In conclusion, these results suggest that by combining nanomaterials with anticancer drugs MTX-AuNP may be more effective than free MTX for cancer treatment.