共载多西他赛和藤黄酸白蛋白纳米粒的处方优选和质量评价
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摘要
目的:利用星点设计-效应面法优化共载多西他赛(DTX)和藤黄酸(GA)白蛋白纳米粒(DTX-GA-BSA NPs)的处方,制备DTX-GA-BSA NPs并评价其质量。采用两药相互作用指数(CDI)筛选DTX和GA的最佳协同配比,为该纳米粒的应用与推广提供实验依据。方法:采用Nab~(TM)法制备DTX-GA-BSA NPs,以牛血清白蛋白(BSA)为载体材料。利用Design-Expert8. 0. 6软件设计实验和处理数据,以粒径和多分散性指数(PDI)的总评"归一值"(OD)以及包封率为评价指标,测定DTX-GABSA NPs的粒径,PDI,包封率和Zeta电位。利用噻唑蓝比色法分别测定DTX和GA对MGC-803和HGC-27细胞增殖的单独和协同抑制作用。结果:DTX-GA-BSA NPs的最优处方为BSA质量浓度5 g·L~(-1),水油体积比(水相与油相的体积比) 1∶17,药载比(药物与载体的质量比) 1∶10;模型预测值与实测值偏差较小,具有优良的预测性。DTX-GA-BSA NPs的平均粒径135. 8 nm,PDI=0. 09,Zeta电位-21. 4 mV。当DTX和GA浓度分别为0. 004,0. 12μmol·L~(-1)时,二者对MGC-803细胞的协同增殖抑制作用最显著;当DTX和GA浓度分别为0. 004,1μmol·L~(-1)时,二者对HGC-27细胞的协同增殖抑制作用最显著。结论:优选的DTX-GA-BSA NPs处方工艺稳定可靠,建立的数学模型具有良好预测能力和实用性。DTX和GA联用对MGC-803,HGC-27细胞均具有协同作用,但不呈浓度依赖性。
Objective: The formulation of co-loaded docetaxel( DTX) and gambogic acid( GA albumin nanoparticles( DTX-GA-BSA NPs) was optimized by central composite design-response surface methodology to prepare DTX-GA-BSA NPs,and its quality was evaluated. The optimal synergistic ratio of DTX and GA was screened by coefficient of drug interaction( CDI). Method: Nab~(TM)method was used to prepare DTX-GABSA NPs with bovine serum albumin( BSA) as the carrier material. Design-Expert 8. 0. 6 software was used to design the experiment and process the data,overall desirability( OD) of particle size and polydispersity index( PDI),encapsulation rate were taken as indexes. The particle size and Zeta potential of the nanoparticles were measured. Individual and synergistic inhibitory effects of DTX and GA on the proliferation of MGC-803 and HGC-27 cells were determined by methyl thiazolyl tetrazolium( MTT) assay,respectively. Result: The optimum prescription of DTX-GA-BSA NPs was as follows: BSA concentration of 5 g·L~(-1),water-oil phase volume ratio of 1 ∶ 17,drug-loading ratio( mass ration of drug to carrier) of 1 ∶ 10. The average particle size of DTX-GA-BSA NPs was 135. 8 nm and PDI was 0. 09,Zeta potential was -21. 4 mV. The deviation between the predicted value and the observed value of the model was small,the model had good predictability. For MGC-803 cell,when the concentrations of DTX and GA were 0. 004,0. 12 μmol·L~(-1),respectively( mass ratio of DTX to GA was 1 ∶ 23),the CDI value was the smallest and the synergistic proliferation inhibition was the most significant. For HGC-27 cell,when the concentrations of DTX and GA were 0. 004,1 μmol·L~(-1),respectively( mass ratio of DTX to GA was 1 ∶ 195), the synergistic proliferation inhibition was the most significant. Conclusion: The optimized formulation of DTX-GA-BSA NPs is stable and reliable. The established mathematical model has good predictive ability and practicability. DTX combined with GA has synergistic effect on MGC-803 and HGC-27 cells without concentration dependence.
Objective: The formulation of co-loaded docetaxel( DTX) and gambogic acid( GA albumin nanoparticles( DTX-GA-BSA NPs) was optimized by central composite design-response surface methodology to prepare DTX-GA-BSA NPs,and its quality was evaluated. The optimal synergistic ratio of DTX and GA was screened by coefficient of drug interaction( CDI). Method: Nab~(TM)method was used to prepare DTX-GABSA NPs with bovine serum albumin( BSA) as the carrier material. Design-Expert 8. 0. 6 software was used to design the experiment and process the data,overall desirability( OD) of particle size and polydispersity index( PDI),encapsulation rate were taken as indexes. The particle size and Zeta potential of the nanoparticles were measured. Individual and synergistic inhibitory effects of DTX and GA on the proliferation of MGC-803 and HGC-27 cells were determined by methyl thiazolyl tetrazolium( MTT) assay,respectively. Result: The optimum prescription of DTX-GA-BSA NPs was as follows: BSA concentration of 5 g·L~(-1),water-oil phase volume ratio of 1 ∶ 17,drug-loading ratio( mass ration of drug to carrier) of 1 ∶ 10. The average particle size of DTX-GA-BSA NPs was 135. 8 nm and PDI was 0. 09,Zeta potential was -21. 4 mV. The deviation between the predicted value and the observed value of the model was small,the model had good predictability. For MGC-803 cell,when the concentrations of DTX and GA were 0. 004,0. 12 μmol·L~(-1),respectively( mass ratio of DTX to GA was 1 ∶ 23),the CDI value was the smallest and the synergistic proliferation inhibition was the most significant. For HGC-27 cell,when the concentrations of DTX and GA were 0. 004,1 μmol·L~(-1),respectively( mass ratio of DTX to GA was 1 ∶ 195), the synergistic proliferation inhibition was the most significant. Conclusion: The optimized formulation of DTX-GA-BSA NPs is stable and reliable. The established mathematical model has good predictive ability and practicability. DTX combined with GA has synergistic effect on MGC-803 and HGC-27 cells without concentration dependence.
引文
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[21] Nosrati H,Salehiabar M,Afroogh S,et al. Bovine serum albumin:an efficient biomacromolecule nanocarrier for improving the therapeutic efficacy of chrysin[J]. J Mol Liq,2018,271:639-646.
[22] Langer K,Balthasar S,Vogel V,et al. Optimization of the preparation process for human serum albumin(HAS)nanoparticles[J]. Int J Pharm,2003,257(1/2):169-180.
[23] ZHANG H,ZHANG L,YUAN P,et al. Preparation and in vitro release characteristics of curcumin in nanosuspensions[J]. China J Chin Mater Med,2011,36(2):132-135.
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[3] Cronin K A,Lake A J,Scott S,et al. Annual report to the nation on the status of cancer,partⅠ:national cancer statistics[J]. Cancer,2018,124(13):2785-2800.
[4]李丹,刘延庆. Survivin与胃癌的中西医研究进展[J].中国实验方剂学杂志,2018,24(19):124-130.
[5]耿龙龙,任鹏,李延海,等.胃癌治疗现状及新进展[J].医学理论与实践,2017,30(12):1744-1746,1749.
[6] Cerqueira B B,Lasham A,Shelling A N,et al.Nanoparticle therapeutics:technologies and methods for overcoming cancer[J]. Eur J Pharm Biopharm,2015,97(Pt A):140-151.
[7]安艳新,孙力勇,王菁.胃癌多药耐药细胞中FOXC1的表达及其意义[J].实用医药杂志,2017,34(8):687-689.
[8]郭鸣睿,王芳,陈立江,等.藤黄酸长循环纳米粒的制备及其抗肿瘤作用研究[J].中国新药杂志,2018,27(14):1639-1644.
[9] XU Y,WANG C,DING Y,et al. Nanoparticles with optimal ratiometric co-delivery of docetaxel with gambogic acid for treatment of multidrug-resistant breast cancer[J]. J Biomed Nanotechnol,2016,12(9):1774-1781.
[10] ZOU Z Y,WEI J,LI X L,et al. Enhancement of anticancer efficacy of chemotherapeutics by gambogic acid against gastric cancer cells[J]. Cancer Biother Radiopharm,2012,27(5):299-306.
[11]王杰,王亚杰,郝单丽,等.多西紫杉醇纳米胶束在小鼠体内的药代动力学及其肿瘤组织分布[J].中国实验方剂学杂志,2018,doi:10. 13422/j. cnki.syfjx. 20182310.
[12]朱钰叶,张玲.去甲斑蝥素白蛋白纳米粒的制备及质量评价[J].中国药师,2018,21(3):420-425.
[13]寇亮,麻燕罗,琨映,等.白蛋白纳米粒给药载体的研究进展[J].西北民族大学学报:自然科学版,2017,38(4):9-13.
[14]杨志杰,侯音璇,林霞,等.藤黄酸白蛋白纳米粒的制备及稳定性研究[J].中国药剂学杂志,2016,14(4):107-119.
[15] CHEN C H,CHEN M C,WANG J C,et al. Synergistic interaction between the HDAC inhibitor,MPT0E028,and sorafenib in liver cancer cells in vitro and in vivo[J].Clin Cancer Res,2014,20(5):1274-1287.
[16] QIU B,SUN X,ZHANG D,et al. TRAIL and paclitaxel synergize to kill U87 cells and U87-derived stem-like cells in vitro[J]. Int J Mol Sci,2012,13(7):9142-9156.
[17] WAN X A,SUN G P,WANG H,et al. Synergistic effect of paeonol and cisplatin on oesophageal cancer cell lines[J]. Dig Liver Dis,2008,40(7):531-539.
[18] LI W I,Anderson K W,Deluca P P. Kinetic and thermodynamic modeling of the formation of polymeric microspheres using solvent extraction/evaporation method[J]. J Control Release,1995,37(3):187-198.
[19] Chung T W,HUANG Y Y,LIU Y Z. Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres[J]. Int J Pharm,2001,212(2):161-169.
[20]季秀峰,石莉,邓意辉.白蛋白纳米粒药物传递系统的研究进展[J].沈阳药科大学学报,2010,27(12):968-978.
[21] Nosrati H,Salehiabar M,Afroogh S,et al. Bovine serum albumin:an efficient biomacromolecule nanocarrier for improving the therapeutic efficacy of chrysin[J]. J Mol Liq,2018,271:639-646.
[22] Langer K,Balthasar S,Vogel V,et al. Optimization of the preparation process for human serum albumin(HAS)nanoparticles[J]. Int J Pharm,2003,257(1/2):169-180.
[23] ZHANG H,ZHANG L,YUAN P,et al. Preparation and in vitro release characteristics of curcumin in nanosuspensions[J]. China J Chin Mater Med,2011,36(2):132-135.