槲皮素和白藜芦醇共载磁性固体脂质纳米粒的制备及其抑瘤作用评价
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摘要
目的:制备槲皮素和白藜芦醇共载磁性固体脂质纳米粒(QR-MSLN),探索合理表征方法并考察其对小鼠肝癌H22移植性肿瘤的抑瘤作用。方法:制备油酸表面修饰的磁性Fe_3O_4(OA-Fe_3O_4),采用红外光谱分析进行结构确证;采用乳化超声分散法制备QR-MSLN,分别采用透射电子显微镜、纳米粒径-Zeta电位测定仪观测其形态与粒径,邻二氮菲分光光度法测定制剂中铁含量,超滤离心法测定2种成分的包封率,振动样品磁强计测定其饱和磁化强度,透析法研究其体外释药行为;建立小鼠肝癌细胞(H22)移植瘤模型,评价在外加磁场下QR-MSLN对移植瘤的抑制作用。结果:QR-MSLN形态圆整,内部可见载有黑色磁性微粒,粒径(171. 9±2. 2) nm,铁质量浓度(1. 40±0. 46) g·L~(-1),饱和磁化强度7. 75 A·m2·kg~(-1),具有超顺磁性。槲皮素和白藜芦醇的包封率分别为99. 10%,80. 83%。与槲皮素和白藜芦醇原药、载药固体脂质纳米粒相比,QRMSLN的肿瘤抑制率显著增高(P <0. 01)。结论:制得的QR-MSLN粒径均匀、磁响应性好,对小鼠H22移植瘤具有明显的抑制作用。
Objective: To prepare magnetic solid lipid nanoparticles co-loaded quercetin and resveratrol( QR-MSLN),develop the reasonable characterization method,and investigate its inhibitory effect on transplanted hepatocarcinoma H22 tumor in mice. Method: Magnetic Fe_3O_4 particles coated with oleic acid( OA-Fe_3O_4) were synthesized and its structure was confirmed by Fourier transform infrared spectrometer( FT-IR). QR-MSLN was prepared by emulsion ultrasonic dispersion method, its morphology was examined by transmission electron microscopy,its particle size was determined by laser particle sizer. Concentration of Fe in the preparation was determined by phenanthroline spectrophotometry. The entrapment efficiency, saturation magnetization, in vitro release behavior were investigated by ultrafiltration centrifugation, vibrating sample magnetometer( VSM) and dialysis method,respectively. Mouse tumor model transplanted with hepatoma H22 ascites tumor was established and antitumor effect of QR-MSLN on H22 bearing mice were observed in the presence of an applied magnetic field.Result: Morphology of QR-MSLN was round, and black magnetic particles could be observed inside it, its particle size was( 171. 9 ± 2. 2) nm, the concentration of Fe was( 1. 40 ± 0. 46) g·L~(-1). The preparation exhibited apparent superparamagnetism and the saturation magnetization was 7. 75 A·m2·kg~(-1). The entrapment efficiencies of quercetin and resveratrol in QR-MSLN were 99. 10% and 80. 83%,respectively. QR-MSLN had a significantly higher effect of tumor inhibition than SLN( containing quercetin and resveratrol) and free drug( P <0. 01). Conclusion: QR-MSLN has uniform particle size and good magnetic response,and shows remarkable antitumor effect on H22 bearing mice.
Objective: To prepare magnetic solid lipid nanoparticles co-loaded quercetin and resveratrol( QR-MSLN),develop the reasonable characterization method,and investigate its inhibitory effect on transplanted hepatocarcinoma H22 tumor in mice. Method: Magnetic Fe_3O_4 particles coated with oleic acid( OA-Fe_3O_4) were synthesized and its structure was confirmed by Fourier transform infrared spectrometer( FT-IR). QR-MSLN was prepared by emulsion ultrasonic dispersion method, its morphology was examined by transmission electron microscopy,its particle size was determined by laser particle sizer. Concentration of Fe in the preparation was determined by phenanthroline spectrophotometry. The entrapment efficiency, saturation magnetization, in vitro release behavior were investigated by ultrafiltration centrifugation, vibrating sample magnetometer( VSM) and dialysis method,respectively. Mouse tumor model transplanted with hepatoma H22 ascites tumor was established and antitumor effect of QR-MSLN on H22 bearing mice were observed in the presence of an applied magnetic field.Result: Morphology of QR-MSLN was round, and black magnetic particles could be observed inside it, its particle size was( 171. 9 ± 2. 2) nm, the concentration of Fe was( 1. 40 ± 0. 46) g·L~(-1). The preparation exhibited apparent superparamagnetism and the saturation magnetization was 7. 75 A·m2·kg~(-1). The entrapment efficiencies of quercetin and resveratrol in QR-MSLN were 99. 10% and 80. 83%,respectively. QR-MSLN had a significantly higher effect of tumor inhibition than SLN( containing quercetin and resveratrol) and free drug( P <0. 01). Conclusion: QR-MSLN has uniform particle size and good magnetic response,and shows remarkable antitumor effect on H22 bearing mice.
引文
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[15]高文慧,刘世霆,范彩霞,等.叶酸-羧甲基壳聚糖-超小超顺磁氧化铁纳米粒在大、小鼠体内的药代动力学、组织分布及磁共振响应特征[J].药学学报,2011,46(7):845-851.
[2] Nam J S,Sharma A R,Nguyen L T,et al. Application of bioactive quercetin in oncotherapy:from nutrition to nanomedicine[J]. Molecules,2016,21(1):E108.
[3] Boydens C,Pauwels B,Vanden Daele L,et al.Resveratrol and quercetin protect isolated mouse corpora cavernosa from in vitro-induced diabetic erectile dysfunction[J]. Cardiovasc Diabetol,2016, doi:10. 1186/s12933-016-0366-9.
[4] Cote B,Carlson L J,RAO D A,et al. Combinatorial resveratrol and quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro and in vivo[J]. J Control Release,2015,213:128-133.
[5] Arias N,Macarulla M T,Aguirre L,et al. The combination of resveratrol and quercetin enhances the individual effects of these molecules on triacylglycerol metabolism in white adipose tissue[J]. Eur J Nutr,2016,55(1):341-348.
[6] WANG M,CHEN L,LIU D,et al. Metabolomics highlights pharmacological bioactivity and biochemical mechanism of traditional Chinese medicine[J]. Chem Biol Interact,2017,273:133-141.
[7] Naseri N,Valizadeh H,Zakeri-Milani P,et al. Solid lipid nanoparticles and nanostructured lipid carriers:structure,preparation and application[J]. Adv Pharm Bull,2015,5(3):305-313.
[8] Muoz de Escalona M,Sáez-Fernández E,Prados J C,et al. Magnetic solid lipid nanoparticles in hyperthermia against colon cancer[J]. Int J Pharm,2016,504(1/2):11-19.
[9] Gulshan F. Preparation of alumina-iron oxide compounds by coprecipitation and gel evaporation methods and their characterization[J]. J Eng Res(Kuwait),2015,3(2):1-8.
[10]黄苏苏,谢波,凌家俊,等.二氢卟吩e6磁性声敏纳米脂质体的制备及质量评价[J].中国实验方剂学杂志,2017,23(8):21-26.
[11] Ribeiro V G P,Barreto A C H,Denardin J C,et al.Magnetic nanoparticles coated with anacardic acid derived from cashew nut shell liquid[J]. J Mater Sci,2013,48(22):7875-7882.
[12] Benbettaeb N,Chambin O,Karbowiak T,et al. Release behavior of quercetin from chitosan-fish gelatin edible films influenced by electron beam irradiation[J]. Food Control,2016,66:315-319.
[13] Bose S,DU Y,Takhistov P,et al. Formulation optimization and topical delivery of quercetin from solid lipid based nanosystems[J]. Int J Pharm,2013,441(1/2):56-66.
[14]吴玉梅,陈晓兰,唐红艳,等.雪上一枝蒿总生物碱微乳凝胶的制备及质量评价[J].中国实验方剂学杂志,2016,22(20):10-13.
[15]高文慧,刘世霆,范彩霞,等.叶酸-羧甲基壳聚糖-超小超顺磁氧化铁纳米粒在大、小鼠体内的药代动力学、组织分布及磁共振响应特征[J].药学学报,2011,46(7):845-851.