| 引用本文: | 徐洪婷,费煊婷,陈若乔,胡巧红.还原响应型甲氨蝶呤/羟基喜树碱纳米粒的制备及体外评价[J].中国现代应用药学,2023,40(12):1694-1703. |
| XU Hongting,FEI Xuanting,CHEN Ruoqiao,HU Qiaohong.Preparation and in Vitro Evaluation of Reduction-responsive Methotrexate/Hydroxycamptothecin Nanoparticles[J].Chin J Mod Appl Pharm(中国现代应用药学),2023,40(12):1694-1703. |
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| 还原响应型甲氨蝶呤/羟基喜树碱纳米粒的制备及体外评价 |
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徐洪婷1, 费煊婷1, 陈若乔1, 胡巧红1,2
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1.广东药科大学, 药学院, 广州 510006;2.广东药科大学, 广东省药物新剂型重点实验室和广东省局部精准药物递药制剂工程技术研究中心, 广州 510006
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| 摘要: |
| 目的 合成药物-聚合物偶联物透明质酸-二硫键-甲氨蝶呤-亚油酸(hyaluronic acid-disulfide bond-methotrexate- linoleic acid，HA-SS-MTX-LA)，并以其为载体包载羟基喜树碱(hydroxycamptothecin，HCPT)制备纳米粒(nanoparticles，NPs)(HA-SS-MTX-LA@HCPT NPs)，考察该NPs的体外释药行为及体外抗肿瘤活性。方法 在1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、N-羟基琥珀酰亚胺的催化下，通过酰胺化反应合成药物-聚合物偶联物HA-SS-MTX-LA，并采用核磁共振氢谱、傅里叶变换红外光谱确证其化学结构。采用超声法制备HA-SS-MTX-LA NPs，以临界聚集浓度和粒径为指标，筛选获得LA和HA-SS-MTX的最佳投料比。以HCPT为模型药物，采用乳化溶剂挥发法包载药物，考察HA-SS- MTX-LA NPs的共载药性能。通过体外释放试验考察HA-SS-MTX-LA@HCPT NPs的还原响应性，采用MTT法考察其体外抗肿瘤活性。结果 成功制得HA-SS-MTX-LA NPs，LA和HA-SS-MTX的最佳摩尔投料比为1∶1，临界聚集浓度为60.50 mg×mL-1，NPs粒径为(226.6±2.5)nm，PDI为0.180±0.036。HA-SS-MTX-LA@HCPT NPs的粒径为(257.59±1.41)nm，PDI为0.132±0.009，包封率为(72.46±0.73)%，载药量为(11.51±0.32)%。体外释放结果表明药物在高浓度谷胱甘肽条件下可快速释放，MTT试验结果表明HA-SS-MTX-LA@HCPT NPs对HepG2细胞和Bel-7402细胞生长具有显著的抑制作用。结论 制得的HA-SS-MTX-LA@HCPT NPs粒径均匀，包封率和载药量较高，具有良好的共载药性能、还原响应性和抗肿瘤活性，同时可进一步提高HCPT和MTX的体外抗肿瘤效果。 |
| 关键词: 透明质酸 甲氨蝶呤 药物-聚合物偶联物 纳米粒 羟基喜树碱 |
| DOI：10.13748/j.cnki.issn1007-7693.20230012 |
| 分类号:R944 |
| 基金项目: |
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| Preparation and in Vitro Evaluation of Reduction-responsive Methotrexate/Hydroxycamptothecin Nanoparticles |
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XU Hongting1, FEI Xuanting1, CHEN Ruoqiao1, HU Qiaohong1,2
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1.Guangdong Pharmaceutical University, School of Pharmacy, Guangzhou 510006, China;2.Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems and Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangzhou 510006, China
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| Abstract: |
| OBJECTIVE To synthesize drug-polymer conjugate hyaluronic acid-disulfide bond-methotrexate-linoleic acid (HA-SS-MTX-LA), prepare nanoparticles(NPs)(HA-SS-MTX-LA@HCPT NPs) with it as a carrier by encapsulating hydroxycamptothecin(HCPT), and investigate its in vitro drug release behavior and in vitro antitumor activity.METHODS The drug-polymer conjugate HA-SS-MTX-LA was synthesized by amidation reaction under the catalysis of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N-hydroxy succinimde, and its structure was confirmed by hydrogen nuclear magnetic spectroscopy and Fourier transform infrared spectroscopy. HA-SS-MTX-LA NPs were prepared by ultrasound method. The critical aggregation concentration and particle size were used as indicators to optimize the feeding ratio of LA to HA-SS-MTX. Using HCPT as a model drug, HCPT-loaded HA-SS-MTX-LA NPs(HA-SS-MTX-LA@HCPT) were prepared by emulsifying solvent evaporation method to investigate the drug co-loading property. The reduction responsiveness of HA-SS-MTX-LA@HCPT NPs was evaluated by in vitro release test. The anti-tumor activity in vitro of drug-loaded nanoparticles was assessed by MTT assay. RESULTS HA-SS-MTX-LA NPs was prepared successfully. The optimal feeding ratio of LA to HA-SS-MTX was 1∶1, the critical aggregation concentration was 60.50 mg×mL-1, and the particle size was (226.6±2.5)nm with PDI of 0.180±0.036. The particle size of HA-SS-MTX-LA@ HCPT NPs was (257.59±1.41)nm with PDI of 0.132±0.009. The encapsulation efficiency and drug loading of HCPT were (72.46±0.73)% and (11.51±0.32)%, respectively. The in vitro release results showed that the drug could be rapidly released under high concentration of glutathione. The results of MTT experiment indicated that HA-SS-MTX-LA@HCPT NPs had a significant inhibitory effect on the growth of HepG2 liver cancer cells and Bel-7402 liver cancer cells. CONCLUSION The HA-SS- MTX-LA@HCPT NPs have uniform particle size, with high encapsulation efficiency and drug loading, good drug co-loading ability, good reduction responsiveness and anti-cancer activity. The anti-tumor effect of HCPT and MTX in vitro is further improved. |
| Key words: hyaluronic acid methotrexate drug-polymer conjugate nanoparticles hydroxycamptothecin |
