甲氨蝶呤插层MgAl-LDH复合物的制备与释药性能
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摘要
以Mg(NO_3)2·6H_2O和Al(NO_3)_3·9H_2O为主要原料,采用共沉淀联合水热合成法制备了甲氨蝶呤插层镁铝层状双氢氧化物复合物(MTX-LDH),通过正交实验分析了主要工艺条件对MTX-LDH复合物载药率、粒径及其分散性的影响。结果表明:当反应温度为60℃、Mg(NO_3)2·6H_2O和Al(NO_3)_3·9H_2O的投入量分别为2.67和1.33 mmol、MTX和聚乙二醇400加入量分别为0.20 mmol和15 mL时,复合产物单分散性良好,粒径均值为175.6 nm,载药率达18.90%。利用FTIR、XRD、TG以及TEM对样品结构、热力学性质和微观形貌进行了测定。重点考察了MTX-LDH复合物在不同pH缓冲溶液中的释药性能,表明其具备pH响应型释放特性,在pH=5.8的弱酸环境中缓释效果良好,12h累积释药率为93.7%,并通过热力学释药模型确定其缓释机理为层板溶蚀与置换扩散并存的缓释机制。
Methotrexate intercalated Mg-Al layered double hydroxide composites(MTX-LDH) were prepared via combination of coprecipitation and hydrothermal synthesis by using Mg(NO_3)2·6 H_2 O and Al(NO_3)_3·9 H_2 O as main materials. The effects of main technological conditions on the drug loading rate,particle size and particle size dispersion of MTX-LDH were analyzed by orthogonal experiments. The results showed that the composites had good monodispersity with an average particle size of 175.6 nm, and exhibited high drug loading rate of 18.90% when the reaction temperature was 60 ℃, and the amount of Mg(NO_3)_2·6 H_2 O, Al(NO_3)_3·9 H_2 O, MTX and polyethylene glycol 400 were 2.67 mmol, 1.33 mmol, 0.20 mmol and 15 mL, respectively. The structure, thermodynamic properties and micro-morphology of the samples were studied by FTIR, XRD, TG and TEM. The release properties of MTX-LDH particles in different pH buffer solutions were investigated. The results indicated that the composites had pH-responsive release characteristics and good sustained release properties in weak acid environment(pH=5.8), and the cumulative release rate at 12 h was up to 93.7%. Moreover, the release mechanism of laminate dissolution coexisting with displacement diffusion was confirmed by the thermodynamic release model.
Methotrexate intercalated Mg-Al layered double hydroxide composites(MTX-LDH) were prepared via combination of coprecipitation and hydrothermal synthesis by using Mg(NO_3)2·6 H_2 O and Al(NO_3)_3·9 H_2 O as main materials. The effects of main technological conditions on the drug loading rate,particle size and particle size dispersion of MTX-LDH were analyzed by orthogonal experiments. The results showed that the composites had good monodispersity with an average particle size of 175.6 nm, and exhibited high drug loading rate of 18.90% when the reaction temperature was 60 ℃, and the amount of Mg(NO_3)_2·6 H_2 O, Al(NO_3)_3·9 H_2 O, MTX and polyethylene glycol 400 were 2.67 mmol, 1.33 mmol, 0.20 mmol and 15 mL, respectively. The structure, thermodynamic properties and micro-morphology of the samples were studied by FTIR, XRD, TG and TEM. The release properties of MTX-LDH particles in different pH buffer solutions were investigated. The results indicated that the composites had pH-responsive release characteristics and good sustained release properties in weak acid environment(pH=5.8), and the cumulative release rate at 12 h was up to 93.7%. Moreover, the release mechanism of laminate dissolution coexisting with displacement diffusion was confirmed by the thermodynamic release model.
引文
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[22]Huang Bowen(黄博文),Lv Xingbin(吕荥宾),Chen Jianjun(陈建钧),et al.Synthesis of Mg-Al hydrotalcite compounds and their application in phosphorus removal from waste water[J].Journal of Chemical Engineering of Chinese Universities(高校化学工程学报),2018,32(3):683-689.
[23]Ke Guojun(柯国军),Zhang Lin(张琳),Yang Pengfei(阳鹏飞),et al.Controlled synthesis of Mg-Al hydrotalcites with different morphologies and their adsorption performances for chloride ion[J].Fine Chemicals(精细化工),2017,34(10):1107-1113.
[24]Xia Zhiyong(夏志勇),Du Na(杜娜),Liu Jianqiang(刘建强),et al.Surface modification of layer double hydroxide particles by poly(ethylene glycol)and folic acid[J].Chemical Journal of Chinese Universities(高等学校化学学报),2013,34(3):596-600.
[25]Choi S J,Choy J H.Layered double hydroxide nanoparticles as target-specific delivery carriers:uptake mechanism and toxicity[J].Nanomedicine,2011,6(5):803-814.
[26]Lanone S,Rogerieux F,Geys J,et al.Comparative toxicity of 24manufactured nanoparticles in human alveolar epithelial and macrophage cell lines[J/OL].Part&Fibre Toxicol,2009,6(1):14.[2019-5-24].http://link.springer.com/article/10.1186/1743-8977-6-14.doi:10.1186/1743-8977-6-14.
[27]Senapati S,Thakur R,Verma S P,et al.Layered double hydroxides as effective carrier for anticancer drugs and tailoring of release rate through interlayer anions[J].Journal of Controlled Release,2016,224:186-198.
[28]Wang W Y,Liu H,Li S P,et al.Synthesis of methotrexatum intercalated zinc-aluminum-layered double hydroxides and the corresponding cell studies[J].Applied Clay Science,2016,121/122:103-110.
[29]Kong X,Jin L,Wei M,et al.Antioxidant drugs intercalated into layered double hydroxide:Structure and in vitro release[J].Applied Clay Science,2010,49(3):324-329.
[30]Li F,Jin L,Han J,et al.Synthesis and controlled release properties of prednisone intercalated Mg-Al layered double hydroxide composite[J].Industrial Engineering Chemistry Research,2009,48(12):5590-5597.
[2]Guan S,Liang R,Li C,et al.A supramolecular material fordualmodal imaging and targeted cancer therapy[J].Talanta,2017,165:297-303.
[3]Zhang M L,Yao Q F,Lu C,et al.Layered double hydroxide-carbon dot composite:high-performance adsorbent for removal of anionic organic dye[J].ACS Applied Materials Interfaces,2014,6:20225-20233.
[4]Li D,Zhang Y T,Yu M,et al.Cancer therapy and fluorescence imaging using the active release of doxorubicin from MSPs/Ni-LDHfolate targeting nanoparticles[J].Biomaterials,2013,34(32):7913-7922.
[5]Dong A J,Li X,Wang W W,et al.Layered double hydroxide modified by PEGylated hyaluronic acid as a hybrid nanocarrier for targeted drug delivery[J].Transactions of Tianjin University,2016,22(3):237-246.
[6]Zhu Y,Zhu R,Wang M,et al.Cancer therapy:anti-metastatic and anti-angiogenic activities of core-shell SiO2@LDH loaded with etoposide in non-small cell lung cancer[J].Advanced Science,2016,3(11):1600629.
[7]Zuo H,Chen W,Cooper H M,et al.A facile way of modifying layered double hydroxide nanoparticles with targeting ligandconjugated albumin for enhanced delivery to brain tumour cells[J].Acs Applied Materials Interfaces,2017,9(24):20444-20453.
[8]Howard S C,Mccormick J,Pui C H,et al.Preventing and managing toxicities of high-dose methotrexate[J].Oncologist,2016,21(12):1471-1482.
[9]Park J A,Young S H.Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma[J].Blood Research,2016,51(1):50-57.
[10]Oh J M,Man P,Kim S T,et al.Efficient delivery of anticancer drug MTX through MTX-LDH nanohybrid system[J].Journal of Physics Chemistry of Solids,2006,67(5):1024-1027.
[11]Kim J Y,Choi S J,Oh J M,et al.Anticancer drug-inorganic nanohybrid and its cellular interaction[J].Journal of Nanoscience and Nanotechnology,2007,7(11):3700-3705.
[12]Tian D Y,Liu Z L,Li S P,et al.Facile synthesis of methotrexate intercalated layered double hydroxides:Particle control,structure and bioassay explore[J].Mater Scienceand Engineering C,2014,45:297-305.
[13]Choi S J,Choi J H.Layered double hydroxide nanoparticles as target-specific delivery carriers:Uptake mechanism and toxicity[J].Nanomedicine,2011,6(5):803-814.
[14]Choi S J,Oh J M,Choi J H.Biocompatible ceramic nanocarrier for drug delivery with high efficiency[J].Journal-Ceramic Society Japan,2009,1175(1365):543-549.
[15]Zeng Meigui(曾美桂),Li Xiaodong(李晓东)Li Shuping(李淑萍).Preparation and bioassay explore of methotrexatum/zinc-aluminum layered double hydroxides[J].Scientia Sinica Chimica(中国科学:化学),2014,44(10):1553-1661.
[16]Zhang Xiaoqing(张晓晴),Zeng Meigui(曾美桂),Li Shuping(李淑萍).Influence of different solvents on the property of methotrexate/layered double hydroxides[J].Acta Chimica Sinica(化学学报),2013,71:246-254.
[17]Tian D Y,Wang Y,Li S P,et al.Synthesis of methotrexatum intercalated layered double hydroxides by different methods:Biodegradation process and bioassay explore[J].Applied Clay Science,2015,118:87-98.
[18]Deshmukh A S,Chauhan P N,Noolvi M N,et al.Polymeric micelles:Basic research to clinical practice[J].International Journal of Pharmaceutics,2017,532(1):249-268.
[19]Wu J,Deng A,Wei J,et al.Synthesis and in vitro evaluation of pH-sensitive magnetic nano composites as methotrexate delivery system for targeted cancer therapy[J].Materials Science Engineering C,2017,71:132-140.
[20]Ren Jin(任锦),Liang Liang(梁良),Zhou Yu(周瑜),et al.Progress in cancer diagnosis and treatment based on layered double hydroxide nanomaterials[J].Chinese Journal of Modern Applied Pharmacy(中国现代应用药学),2018,35(5):774-780.
[21]Huo Xiaolei(霍晓磊),Liu Suqing(柳素青),Li Shuping(李淑萍).Controllable synthesis of methotrexatum/layered double hydroxide nanohybrids to improve their anticancer efficacy[J].Chinese Journal of Inorganic Chemistry(无机化学学报),2014,30(6):1331-1338.
[22]Huang Bowen(黄博文),Lv Xingbin(吕荥宾),Chen Jianjun(陈建钧),et al.Synthesis of Mg-Al hydrotalcite compounds and their application in phosphorus removal from waste water[J].Journal of Chemical Engineering of Chinese Universities(高校化学工程学报),2018,32(3):683-689.
[23]Ke Guojun(柯国军),Zhang Lin(张琳),Yang Pengfei(阳鹏飞),et al.Controlled synthesis of Mg-Al hydrotalcites with different morphologies and their adsorption performances for chloride ion[J].Fine Chemicals(精细化工),2017,34(10):1107-1113.
[24]Xia Zhiyong(夏志勇),Du Na(杜娜),Liu Jianqiang(刘建强),et al.Surface modification of layer double hydroxide particles by poly(ethylene glycol)and folic acid[J].Chemical Journal of Chinese Universities(高等学校化学学报),2013,34(3):596-600.
[25]Choi S J,Choy J H.Layered double hydroxide nanoparticles as target-specific delivery carriers:uptake mechanism and toxicity[J].Nanomedicine,2011,6(5):803-814.
[26]Lanone S,Rogerieux F,Geys J,et al.Comparative toxicity of 24manufactured nanoparticles in human alveolar epithelial and macrophage cell lines[J/OL].Part&Fibre Toxicol,2009,6(1):14.[2019-5-24].http://link.springer.com/article/10.1186/1743-8977-6-14.doi:10.1186/1743-8977-6-14.
[27]Senapati S,Thakur R,Verma S P,et al.Layered double hydroxides as effective carrier for anticancer drugs and tailoring of release rate through interlayer anions[J].Journal of Controlled Release,2016,224:186-198.
[28]Wang W Y,Liu H,Li S P,et al.Synthesis of methotrexatum intercalated zinc-aluminum-layered double hydroxides and the corresponding cell studies[J].Applied Clay Science,2016,121/122:103-110.
[29]Kong X,Jin L,Wei M,et al.Antioxidant drugs intercalated into layered double hydroxide:Structure and in vitro release[J].Applied Clay Science,2010,49(3):324-329.
[30]Li F,Jin L,Han J,et al.Synthesis and controlled release properties of prednisone intercalated Mg-Al layered double hydroxide composite[J].Industrial Engineering Chemistry Research,2009,48(12):5590-5597.