Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice.
Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice.
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DOI：
10.2147/dddt.s143942
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Luo L
中科院分区：
文献类型：
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作者：
Gao L;Xia L;Zhang R;Duan D;Liu X;Xu J;Luo L
甲氨蝶呤广泛用于多种恶性肿瘤的化疗。然而，甲氨蝶呤毒性大、药代动力学差、安全边际窄限制了其临床应用。本研究的目的是开发含有甲氨蝶呤的缓释植入物，并评估植入物在肿瘤内植入后的抗肿瘤活性。我们采用熔融成型技术制备了甲氨蝶呤、聚（D， l -丙交酯-羟基乙酸酯）和聚乙二醇4000。这些植入物在药物含量、形态、体外和体内释放谱方面进行了表征。采用差示扫描量热法（DSC）和傅里叶变换红外光谱法（FTIR）研究了植入物的理化性质。此外，在肉瘤180小鼠模型中测试了植入物的抗肿瘤活性。植入物被制成固体棒。扫描电镜图像显示植入物表面光滑，表明甲氨蝶呤均匀分散在聚合物基质中。DSC和FTIR结果表明，植入体中甲氨蝶呤与聚合物没有明显的相互作用。植入物的体内和体外释放均表现为甲氨蝶呤的爆发性释放和缓释。肿瘤内植入甲氨蝶呤植入物可有效延缓肿瘤生长。此外，植入物剂量的增加导致更高的肿瘤抑制率，而没有额外的全身毒性。这些结果表明，甲氨蝶呤负载的植入物在肉瘤180小鼠模型中具有显著的抗肿瘤功效，并且没有剂量限制的副作用，并且表明植入物可能作为肿瘤内递送系统用于治疗癌症。
Methotrexate is widely used in chemotherapy for a variety of malignancies. However, severe toxicity, poor pharmacokinetics, and narrow safety margin of methotrexate limit its clinical application. The aim of this study was to develop sustained-release methotrexate-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation. We prepared the implants containing methotrexate, poly(D,L-lactide-co-glycolide), and polyethylene glycol 4000 with the melt-molding technique. The implants were characterized with regards to drug content, morphology, in vitro, and in vivo release profiles. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were carried out to investigate the physicochemical properties of the implants. Furthermore, the antitumor activity of the implants was tested in a sarcoma 180 mouse model. The implants were prepared as solid rods. Scanning electron microscopy images showed a smooth surface of the implant, suggesting that methotrexate was homogeneously dispersed in the polymeric matrix. The results of DSC and FTIR indicated that no significant interaction between methotrexate and the polymer was observed in the implants. Both in vitro and in vivo release profiles of the implants were characterized by burst release followed by sustained release of methotrexate. Intratumoral implantation of methotrexate-loaded implants could efficiently delay tumor growth. Moreover, an increase in the dose of implants led to a higher tumor suppression rate without additional systemic toxicity. These results demonstrate that methotrexate-loaded implants had significant antitumor efficacy in a sarcoma 180 mouse model without dose-limiting side effects, and suggest that the implants could be potentially applied as an intratumoral delivery system to treat cancer.