脑靶向脂质体配体维生素C-胆甾偶联物的设计合成及初步脑靶向评价
|
摘要
目的合成一种新型的脑靶向脂质体配体——维生素C-胆甾偶联物,并初步评价其脑靶向性。方法以胆固醇和维生素C为原料,经9步反应得到目标配体。利用薄膜分散法制备脑靶向多西紫杉醇脂质体,通过HPLC法测定给药后小鼠脑中的药物浓度。结果与结论制备得到的配体经1H-NMR和MS谱确证。体内分布实验显示,该配体修饰的脂质体,其脑内多西紫杉醇的摄取率和峰浓度比分别是游离药物的2.51和4.38倍。本研究所设计并制备的维生素C-胆甾修饰脂质体是一种高效的脑靶向给药系统。
In this study,a novel brain targeting vitamin C(VC) derivative was designed and synthesized as liposome ligand for preparing novel liposome to achieve the effective delivery of drug formulations to brain by glucose transporter 1(GLUT1) and the Na+-dependent vitamin C transporter(SVCT2). The liposome was prepared and characterized for particle size,Zeta potential and encapsulation efficiency. The preliminary evaluation in vivo demonstrated that ligand Vc-cholcoated liposome had an improved targeting ability and significantly increased the area under the concentration-time of docetaxel(DTX) in brain compared to naked docetaxel and non-coated liposome. The relative uptaking efficiency and concentration efficiency were enhanced by 2. 51-and 4. 38-fold compared to that of naked docetaxel,respectively. Both distribution data and pharmacokinetic parameters suggested that the Vc-Chol-modified liposomal delivery system was a promising carrier to enhance CNS drug 's delivery ability into brain.
In this study,a novel brain targeting vitamin C(VC) derivative was designed and synthesized as liposome ligand for preparing novel liposome to achieve the effective delivery of drug formulations to brain by glucose transporter 1(GLUT1) and the Na+-dependent vitamin C transporter(SVCT2). The liposome was prepared and characterized for particle size,Zeta potential and encapsulation efficiency. The preliminary evaluation in vivo demonstrated that ligand Vc-cholcoated liposome had an improved targeting ability and significantly increased the area under the concentration-time of docetaxel(DTX) in brain compared to naked docetaxel and non-coated liposome. The relative uptaking efficiency and concentration efficiency were enhanced by 2. 51-and 4. 38-fold compared to that of naked docetaxel,respectively. Both distribution data and pharmacokinetic parameters suggested that the Vc-Chol-modified liposomal delivery system was a promising carrier to enhance CNS drug 's delivery ability into brain.
引文
[1]FAN W,WU Y,LI X K,et al.Design,synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen[J].Eur J Med Chem,2011,46(9):3651-3661.
[2]ZHAO Y,QU B Y,WU X Y,et al.Design,synthesis and biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen with“lock-in”function[J].Eur J Med Chem,2014,82:314-323.
[3]QIU S B,ZHAO Y,LIU S,et al.Design,synthesis and evaluation of dual-targeting prodrug co-modified by organic amine and L-ascorbic acid for CNS deli-very[J].Lett Drug Des Discov,2017,14(9):1065-1072.
[4]ZHAO Y,ZHANG L,PENG Y,et al.GLUT1-mediated venlafaxine-thiamine disulfide system-glucose conjugates with“lock-in”function for central nervous system delivery[J].Chem Biol Drug Des,2018,91(3):707-716.DOI:10.1111/cbdd.13128.
[5]吴勇,李晓岑,海俐.药物化学进展:体转运系统介导的脑靶向药物研究进展[M].北京:化学工业出版社,2015:299-320.
[6]CORPE C P,LEE J H,KWON O,et al.6-Bromo-6-deoxy-L-ascorbic acid[J].J Biol Chem,2005,280(7):5211-5220.
[7]QU B Y,LI X C,GUAN M,et al.Design,synthesis and biological evaluation of multivalent glucosides with high affinity as ligands for brain targeting liposomes[J].Eur J Med Chem,2014,72:110-118.
[2]ZHAO Y,QU B Y,WU X Y,et al.Design,synthesis and biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen with“lock-in”function[J].Eur J Med Chem,2014,82:314-323.
[3]QIU S B,ZHAO Y,LIU S,et al.Design,synthesis and evaluation of dual-targeting prodrug co-modified by organic amine and L-ascorbic acid for CNS deli-very[J].Lett Drug Des Discov,2017,14(9):1065-1072.
[4]ZHAO Y,ZHANG L,PENG Y,et al.GLUT1-mediated venlafaxine-thiamine disulfide system-glucose conjugates with“lock-in”function for central nervous system delivery[J].Chem Biol Drug Des,2018,91(3):707-716.DOI:10.1111/cbdd.13128.
[5]吴勇,李晓岑,海俐.药物化学进展:体转运系统介导的脑靶向药物研究进展[M].北京:化学工业出版社,2015:299-320.
[6]CORPE C P,LEE J H,KWON O,et al.6-Bromo-6-deoxy-L-ascorbic acid[J].J Biol Chem,2005,280(7):5211-5220.
[7]QU B Y,LI X C,GUAN M,et al.Design,synthesis and biological evaluation of multivalent glucosides with high affinity as ligands for brain targeting liposomes[J].Eur J Med Chem,2014,72:110-118.