透明质酸修饰新藤黄酸脂质体的制备及其在大鼠体内药动学及肝靶向研究
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摘要
目的考察透明质酸修饰的新藤黄酸脂质体在大鼠体内的药动学过程及其肝靶向性。方法大鼠尾静脉注射新藤黄酸溶液(GNA)、新藤黄酸脂质体(GNA-L)和透明质酸修饰的新藤黄酸脂质体(HAGNA-L),分别于给药后不同时间点取血及肝脏,样品经处理后进行HPLC分析,考察3种制剂的药动学参数及肝靶向性差异。结果研究结果显示,GNA、GNA-L和HA-GNA-L血浆半衰期(t_(1/2))分别为34.575、70.780和154.588 min,AUC(0～∞)分别为104.379、209.656和414.818μg·min·m L~(-1)。肝靶向实验结果表明,HA-GNA-L在肝脏中的分布显著高于GNA和GNA-L。结论与GNA和GNA-L相比,HA-GNA-L具有优异的药物代谢动力学过程,肝脏靶向指数高,对肝脏具有特异的靶向性。
Objective To determine the pharmacokinetics and liver targeting of hyaluronic acid coated gambogenic acid liposome in rats. Methods After the rats were injected GNA solution, GNA-L, and HAGNA-L via the tail vein, the blood and liver samples were collected at different time points. HPLC method was used to detect the concentration of GNA in the liver and plasma samples. The concentration-time profiles and pharmacokinetics parameters were obtained to get the variances. Results The elimination half-life of free GNA, GNA-L, and HA-GNA-L was 34.575, 70.780 and 154.588 min, respectively. The AUC(0 ～∞) of free GNA, GNA-L, and HA-GNA-L was 104.379, 209.656 and 414.818 μg·min·m L~(-1), respectively. HA-GNA-L had obviously increased distribution in the liver. Conclusion Compared with the GNA solution and GNA-L group, HA-GNA-L has excellent pharmacokinetic progress, and higher liver targeting index with specific liver targeting.
Objective To determine the pharmacokinetics and liver targeting of hyaluronic acid coated gambogenic acid liposome in rats. Methods After the rats were injected GNA solution, GNA-L, and HAGNA-L via the tail vein, the blood and liver samples were collected at different time points. HPLC method was used to detect the concentration of GNA in the liver and plasma samples. The concentration-time profiles and pharmacokinetics parameters were obtained to get the variances. Results The elimination half-life of free GNA, GNA-L, and HA-GNA-L was 34.575, 70.780 and 154.588 min, respectively. The AUC(0 ～∞) of free GNA, GNA-L, and HA-GNA-L was 104.379, 209.656 and 414.818 μg·min·m L~(-1), respectively. HA-GNA-L had obviously increased distribution in the liver. Conclusion Compared with the GNA solution and GNA-L group, HA-GNA-L has excellent pharmacokinetic progress, and higher liver targeting index with specific liver targeting.
引文
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[3]Yuan H,Li X,Zhang C,et al. Nanosuspensions as delivery system for gambogenic acid:characterization and in vitro/in vivo evaluation[J]. Drug Deliv,2016,23(8):2772-2779.
[4]He Y,Ding J,Lin Y,et al. Gambogenic acid alters chemosensitivity of breast cancer cells to Adriamycin[J]. BMC Complement Altern Med,2015,15(1):1-8.
[5]王训翠,朱国旗,程卉,等.新藤黄酸诱导人胃癌MGC-803细胞线粒体途径凋亡的实验研究[J].中药材,2014,37(1):95-99.
[6]Yuan H,Li X,Zhang C,et,al. Nanosuspensions as delivery system for gambogenic acid:characterization and in vitro/in vivo evaluation[J]. Drug Deliv,2016,23(8):2772-2779.
[7]Dufay Wojcicki A,Hillaireau H,Nascimento TL,et al.Hyaluronic acid-bearing lipoplexes:Physico-chemical characterization and in vitro targeting of the CD44 receptor[J]. J Control Release,2012,162(3):545-552.
[8]OhEJ,ParkK,KimKS,etal. Targetspecificand long-acting delivery of protein,peptide,and nucleotide therapeutics using hyaluronic acid derivatives[J]. J Control Release,2010,141(1):2-12.
[9]Stamenkovic I,Amiot M,Pesando JM,et al. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family[J]. Cell,1989,56(6):1057-1062.
[10]Stamenkovic I,Aruffo A,Amiot M,et al. The hematopoietic and epithelial forms of CD44 are distinct polypeptides with different adhesion potentials for hyaluronate-bearing cells[J]. EMBO J,1991,10(2):343-348.
[11]Sy MS,Guo YJ,Stamenkovic I. Distinct effects of two CD44 isoforms on tumor growth in vivo[J]. J Exp Med,1991,174(4):859-866.
[12]Birch M,Mitchell S,Hart IR. Isolation and characterization of human melanoma cell variants expressing high and low levels of CD44[J]. Cancer Res,1991,51(24):6660-6667.
[13]李卓麟.高性能聚丙烯酸酯乳液的合成及应用[D].广州:广东工业大学,2016.
[14]Choi KY,Saravanakumar G,Park JH,et al. Hyaluronic acid-based nanocarriers for intracellular targeting:Interfacial interactions with proteins in cancer[J]. Colloids Surf B Biointerfaces,2012,99:82-94.
[15]Song S,Chen F,Qi H,et al. Multifunctional tumor-targeting nanoparticles based on hyaluronic acid-mediated and p H-sensitive properties for efficient delivery of docetaxel[J].Pharm Res,2014,31(4):1032-1045.
[16]Li WH,Yi XL,Liu X,et al. Hyaluronic acid ion pairing nanoparticles for targeted tumor therapy[J]. J Control Release,2016,225:170-182.
[17]EloyJO,SouzaMC,PetrilliR,etal.Liposomesas carriers of hydrophilic small molecule drugs:strategies to enhance encapsulation and delivery[J]. Colloids Surf B Biointerfaces,2014,123:345-363.
[18]李祥,杜俊,向小四,等.脂质体在抗肿瘤药物中的应用研究进展[J].中南药学,2012,10(4):290-294.
[19]DonatoC,Nicolas T,ThaisLN,etal.Polysaccharide-coated liposomes by post-insertion of a hyaluronan-lipid conjugate[J]. Colloids Surf B Biointerfaces,2017,158:119-126.
[20]Lee AL,Venkataraman S,Sirat SB,et al. The use of cholesterol-containing biodegradable block copolymers to exploit hydrophobic interactions for the delivery of anticancer drugs[J]. Biomaterials,2012,33(6):1921-1928.
[21]LuoQ,Lin TY,ZhangCY,etal. Anovelglyceryl monoolein-bearingcubosomesforgambogenicacid:Preparation,cytotoxicity and intracellular uptake[J]. Int J Pharm,2015,493(1-2):30-39.