齐多夫定脂质前药自组装体的研究
摘要
对于细胞内发挥疗效的药物来说,进入细胞内是很有必要的。水溶性药物经过亲脂衍生化能够提高对细胞膜的通透性;但脂溶性药物在体液中的传递又成为一个难题。为解决以上矛盾,本文以水溶性核苷类抗HIV药物齐多夫定(AZT)为模型药物,进行了自组装药物传递系统(Self-assembled drug delivery system, SADDS)的研究。即将AZT亲脂衍生化后制备其自组装体,并考察CPNZ自组装体体内外行为的一般规律。具体研究容包括:
1.脂质前药的合成设计并合成了抗HIV药物齐多夫定的4个脂质前药,即十四醇基膦酰齐多夫定(TPZ)、十六醇基膦酰齐多夫定(HPZ)、十八醇基膦酰齐多夫定(OPZ)和胆固醇基膦酰齐多夫定(CPNZ)以及活性中间体齐多夫定单膦酸酯。
2.脂质前药的理化性质溶解性主要由溶质分子与溶剂分子间的氢键作用和疏水相互作用决定。摇瓶法测得AZT在正辛醇/PBS(pH 7.4)体系中log P为0.0913, OPZ和CPNZ的实测logP值分别为0.552和0.928,前药的亲脂性明显增强;而OPZ和CPNZ的预测logP值分别为7.33和8.89,前药分子分布于油水界面,从而导致实测值小于预测值,即前药具有典型的两亲性。
3.自组装体的制备及结构特点采用乙醇注入法制备得到了高度分散、浓度高且均匀稳定的胆固醇基膦酰齐多夫定自组装体。通过微观手段观察,分析自组装体形成的自组装机理为:CPNZ分子在胆固醇基团的疏水相互作用和膦酰核苷基团的氢键作用下自发地排列成双分子层结构,近而弯曲形成球形囊泡;自组装体平均表观粒径100 nm,Zeta电位为-20.3mV。
4.自组装体的物理稳定性常压加热和高温高压下自组装体均稍有沉淀,且前药的含量都急剧下降。高速离心(<10000rpm)基本不会改变自组装体的粒度。冷藏放置1个月浓度几乎没有变化。高浓度样品重新分散易。
5.自组装体的化学稳定性以HPLC为含量测定方法,考察了不同pH缓冲液、不同动物血浆、以及家兔组织匀浆液对自组装体中CPNZ分子的水解情况。自组装体在强酸、强碱性缓冲液中很快水解成AZT,中性和弱酸性缓冲液中长时间保持稳定,t1/2在315 h以上;而在各动物血浆和家兔组织匀浆液中水解稍快,t1/2小于20 h。不同动物血浆中,CPNZ的水解速率没有显著差异。在家兔主要器官组织匀浆液中的稳定性有差异,肝脾中的t1/2小于2 h,肺中的t1/2约为10 h。
6.自组装体在动物体内的药代动力学和组织分布胆固醇基膦酰齐多夫定自组装体于家兔和大鼠静脉注射给药后迅速从血液向各主要组织(肝、脾、肺)分布,分布t1/2分别为4.37 min和4.22min;消除t1/2分别为48min和114min;有一定的长循环性。对巨噬系统,尤其是肝脾肺都有明显的靶向性。家兔给药0.5h后肝中的CPNZ量占给药剂量的50%以上,肝脾中CPNZ浓度远高于血浆和其它器官,其半衰期分别为21h和11h;大鼠给药0.5h后肝中的CPNZ量占给药剂量的42%以上,肝脾肺中CPNZ浓度也远高于血浆和其它器官,其半衰期分别为25h、15h和8h。且均具有靶组织内的缓释效应。HPLC测得家兔和大鼠体内CPNZ的降解产物AZT的浓度均很低。
本文制备得到了高度分散、均匀、稳定的胆固醇基膦酰齐多夫定(CPNZ)自组装体,证明了它是由CPNZ分子在水中依靠疏水相互作用和氢键作用自组装成的纳米级有序结构;在家兔和大鼠体内有明显的巨噬细胞系统靶向性和靶组织内的缓释效应。
It is necessary that drugs permeate cell membrane and enter cell for action in the cell. Water-solubility drugs through lipophilic derivation could improve cell membrane permeability, but it is difficult of lipophilic drugs to delivery in the body fluid. In order to solve the problems of cell membrane permeability and body fluid delivery of drugs in vivo, self-assemblies, take drugs to the targets directly and make them safe and efficient, belongs to a novel drug delivery system. Self-assembled drug delivery system (SADDS) was investigated in this paper using hydrophilic zidovudine (3’azido-3’-deoxythymidine, AZT) as a model drug. AZT was lipophilic derivated and then self-assemblies of AZT lipid prodrugs (CPNZ) were prepared. The main contents were described in detail as follows:
1. Synthesis of lipidic prodrug. Four lipidic prodrugs of anti-HIV nucleoside zidovudine were designed and synthesized, that is, 5′-tetradecanylphosphonyl-zidovudine(TPZ)、5′-hexadecanylphosphonyl-zidovudine(HPZ)、5′- o c t a d e c a n y l p h o s p h o n y l - z i d o v u d i n e ( O P Z ) a n d5′-cholesterylphosphonyl-zidovudine (CPNZ) and one key intermediate was AZT 5′-o-hydrogenphosphonate (PZT).
2. Characterization of lipidic prodrug. Solubility of OPZ and CPNZ was measured and hydrogen bonding and hydrophobic interaction are the key factors to determine solubility. The found LogP of OPZ and CPNZ in n-octanol/phosphate buffer solution (pH 7.4) system were 0.552 and 0.928, which were higher than Log P of AZT (0.0913), which suggested the lipophilicity of prodrug was greatly increased. The predicted Log P of OPZ and CPNZ were 7.33 and 8.89, which were different from the found ones. It suggested the prodrug could distribute in the interface of oil and water, that is, the prodrug possessed typical amphiphilic properties.
3. Preparation and characterization of CPNZ self-assemblies. Several methods were used to prepare CPNZ self-assemblies. Through prescription screening and optimization, CPNZ self-assemblies, a kind of suspension system of highly dispersed, high level and homogeneous, were prepared with EtOH injection method. The mechanism of self-assembly was presumed through a serious of microcosmic morphology and size determination: CPNZ molecules self-assembled to spherical vesicles by the hydrophobic interaction of cholesteryl moieties and under the action of the hydrogen bonding of phosphonyl nucleoside. The apparent particle size of CPNZ self-assemblies was about 100 nm. The surface Zeta potential was -20.3mV.
4. Physical stability of CPNZ self-assemblies. Physical stability was investigated through heating , high pressure, centrifugation (<10000rpm) and storing at -4℃. The results indicated they could aggregate, precipitate and content of CPNZ also decreased sharply, When CPNZ self-assemblies were heated and under high pressure. However, CPNZ self-assemblies were stable to a great extent through high speed centrifugation (<10000rpm). Content of CPNZ did not drop at -4℃for one month. High concentration (>20mg/ml) self-assemblies could redisperse easily with water.
5. Chemical stability of CPNZ self-assemblies. Chemical stability of CPNZ self-assemblies in buffer solutions of different pH, plasma of different animals and tissue homogenates of rabbit were all investigated, using an assay method of HPLC. CPNZ in CPNZ self-assemblies hydrolyzed quickly in strong acid and strong base buffer solution, but kept stable for a long period in neutral and weak acid surrounding in which t1/2 was more than 315 h, and in plasma of animals and tissue homogenates of rabbit, the hydrolysis of CPNZ was a bit faster with t1/2 of less than 20 h. However, the hydrolysis rate of CPNZ in a variety of animals was unmarkedly different. But the degradation rate of CPNZ in tissue homogenates of rabbit was very different. t1/2 in liver and spleen homogenates were less than 2 h, t1/2 in lung homogenates was ca. 10 h.
6. Pharmacokinetics and tissue distribution of CPNZ self-assemblies. After single bolus iv administration to rabbits and rats, CPNZ self-assemblies were eliminated quickly from blood circulation, distribution t1/2 in rabbits and rats were 4.37 min and 4.22min, respectively. elimination t1/2 in rabbits and rats were 48 min and 114min, respectively. It suggested that CPNZ self-assemblies had some longevity in the blood. Which was attributed to CHS-PEG1500, With regard to macrophage system, especially liver and spleen targeting and sustained releasing effects were shown in two animals. The CPNZ concent in liver occupied more than 50% and 42% of dose at 0.5h after bolus iv administration of CPNZ self-assemblies to rabbits and rats, respectively. Self-assemblies were targeted to liver, spleen and lung of rabbits and rats. The elimination t1/2 in liver and spleen of rabbits were 21h and 11h. The elimination t1/2 in liver, spleen and lung of rats were 25h, 15h and 11h.The concentration of AZT, the parent drug, was low, which mainly resulted from the rate of hydrolysis of CPNZ was much slower than the elimination of AZT and degradation products AZT in cells could phosphorylate by intracellular kinases.
A highly dispersed, homogeneous, stable self-assemblies of zidovudine lipidic prodrugs was prepared in this paper. A nano-size, ordered structure formed under the action of hydrophobic interaction and hydrogen bonding was proved. The self-assemblies were uptaked by monocyte macrophage quickly in rabbits and rats and sustainedly degraded into AZT.
1.脂质前药的合成设计并合成了抗HIV药物齐多夫定的4个脂质前药,即十四醇基膦酰齐多夫定(TPZ)、十六醇基膦酰齐多夫定(HPZ)、十八醇基膦酰齐多夫定(OPZ)和胆固醇基膦酰齐多夫定(CPNZ)以及活性中间体齐多夫定单膦酸酯。
2.脂质前药的理化性质溶解性主要由溶质分子与溶剂分子间的氢键作用和疏水相互作用决定。摇瓶法测得AZT在正辛醇/PBS(pH 7.4)体系中log P为0.0913, OPZ和CPNZ的实测logP值分别为0.552和0.928,前药的亲脂性明显增强;而OPZ和CPNZ的预测logP值分别为7.33和8.89,前药分子分布于油水界面,从而导致实测值小于预测值,即前药具有典型的两亲性。
3.自组装体的制备及结构特点采用乙醇注入法制备得到了高度分散、浓度高且均匀稳定的胆固醇基膦酰齐多夫定自组装体。通过微观手段观察,分析自组装体形成的自组装机理为:CPNZ分子在胆固醇基团的疏水相互作用和膦酰核苷基团的氢键作用下自发地排列成双分子层结构,近而弯曲形成球形囊泡;自组装体平均表观粒径100 nm,Zeta电位为-20.3mV。
4.自组装体的物理稳定性常压加热和高温高压下自组装体均稍有沉淀,且前药的含量都急剧下降。高速离心(<10000rpm)基本不会改变自组装体的粒度。冷藏放置1个月浓度几乎没有变化。高浓度样品重新分散易。
5.自组装体的化学稳定性以HPLC为含量测定方法,考察了不同pH缓冲液、不同动物血浆、以及家兔组织匀浆液对自组装体中CPNZ分子的水解情况。自组装体在强酸、强碱性缓冲液中很快水解成AZT,中性和弱酸性缓冲液中长时间保持稳定,t1/2在315 h以上;而在各动物血浆和家兔组织匀浆液中水解稍快,t1/2小于20 h。不同动物血浆中,CPNZ的水解速率没有显著差异。在家兔主要器官组织匀浆液中的稳定性有差异,肝脾中的t1/2小于2 h,肺中的t1/2约为10 h。
6.自组装体在动物体内的药代动力学和组织分布胆固醇基膦酰齐多夫定自组装体于家兔和大鼠静脉注射给药后迅速从血液向各主要组织(肝、脾、肺)分布,分布t1/2分别为4.37 min和4.22min;消除t1/2分别为48min和114min;有一定的长循环性。对巨噬系统,尤其是肝脾肺都有明显的靶向性。家兔给药0.5h后肝中的CPNZ量占给药剂量的50%以上,肝脾中CPNZ浓度远高于血浆和其它器官,其半衰期分别为21h和11h;大鼠给药0.5h后肝中的CPNZ量占给药剂量的42%以上,肝脾肺中CPNZ浓度也远高于血浆和其它器官,其半衰期分别为25h、15h和8h。且均具有靶组织内的缓释效应。HPLC测得家兔和大鼠体内CPNZ的降解产物AZT的浓度均很低。
本文制备得到了高度分散、均匀、稳定的胆固醇基膦酰齐多夫定(CPNZ)自组装体,证明了它是由CPNZ分子在水中依靠疏水相互作用和氢键作用自组装成的纳米级有序结构;在家兔和大鼠体内有明显的巨噬细胞系统靶向性和靶组织内的缓释效应。
It is necessary that drugs permeate cell membrane and enter cell for action in the cell. Water-solubility drugs through lipophilic derivation could improve cell membrane permeability, but it is difficult of lipophilic drugs to delivery in the body fluid. In order to solve the problems of cell membrane permeability and body fluid delivery of drugs in vivo, self-assemblies, take drugs to the targets directly and make them safe and efficient, belongs to a novel drug delivery system. Self-assembled drug delivery system (SADDS) was investigated in this paper using hydrophilic zidovudine (3’azido-3’-deoxythymidine, AZT) as a model drug. AZT was lipophilic derivated and then self-assemblies of AZT lipid prodrugs (CPNZ) were prepared. The main contents were described in detail as follows:
1. Synthesis of lipidic prodrug. Four lipidic prodrugs of anti-HIV nucleoside zidovudine were designed and synthesized, that is, 5′-tetradecanylphosphonyl-zidovudine(TPZ)、5′-hexadecanylphosphonyl-zidovudine(HPZ)、5′- o c t a d e c a n y l p h o s p h o n y l - z i d o v u d i n e ( O P Z ) a n d5′-cholesterylphosphonyl-zidovudine (CPNZ) and one key intermediate was AZT 5′-o-hydrogenphosphonate (PZT).
2. Characterization of lipidic prodrug. Solubility of OPZ and CPNZ was measured and hydrogen bonding and hydrophobic interaction are the key factors to determine solubility. The found LogP of OPZ and CPNZ in n-octanol/phosphate buffer solution (pH 7.4) system were 0.552 and 0.928, which were higher than Log P of AZT (0.0913), which suggested the lipophilicity of prodrug was greatly increased. The predicted Log P of OPZ and CPNZ were 7.33 and 8.89, which were different from the found ones. It suggested the prodrug could distribute in the interface of oil and water, that is, the prodrug possessed typical amphiphilic properties.
3. Preparation and characterization of CPNZ self-assemblies. Several methods were used to prepare CPNZ self-assemblies. Through prescription screening and optimization, CPNZ self-assemblies, a kind of suspension system of highly dispersed, high level and homogeneous, were prepared with EtOH injection method. The mechanism of self-assembly was presumed through a serious of microcosmic morphology and size determination: CPNZ molecules self-assembled to spherical vesicles by the hydrophobic interaction of cholesteryl moieties and under the action of the hydrogen bonding of phosphonyl nucleoside. The apparent particle size of CPNZ self-assemblies was about 100 nm. The surface Zeta potential was -20.3mV.
4. Physical stability of CPNZ self-assemblies. Physical stability was investigated through heating , high pressure, centrifugation (<10000rpm) and storing at -4℃. The results indicated they could aggregate, precipitate and content of CPNZ also decreased sharply, When CPNZ self-assemblies were heated and under high pressure. However, CPNZ self-assemblies were stable to a great extent through high speed centrifugation (<10000rpm). Content of CPNZ did not drop at -4℃for one month. High concentration (>20mg/ml) self-assemblies could redisperse easily with water.
5. Chemical stability of CPNZ self-assemblies. Chemical stability of CPNZ self-assemblies in buffer solutions of different pH, plasma of different animals and tissue homogenates of rabbit were all investigated, using an assay method of HPLC. CPNZ in CPNZ self-assemblies hydrolyzed quickly in strong acid and strong base buffer solution, but kept stable for a long period in neutral and weak acid surrounding in which t1/2 was more than 315 h, and in plasma of animals and tissue homogenates of rabbit, the hydrolysis of CPNZ was a bit faster with t1/2 of less than 20 h. However, the hydrolysis rate of CPNZ in a variety of animals was unmarkedly different. But the degradation rate of CPNZ in tissue homogenates of rabbit was very different. t1/2 in liver and spleen homogenates were less than 2 h, t1/2 in lung homogenates was ca. 10 h.
6. Pharmacokinetics and tissue distribution of CPNZ self-assemblies. After single bolus iv administration to rabbits and rats, CPNZ self-assemblies were eliminated quickly from blood circulation, distribution t1/2 in rabbits and rats were 4.37 min and 4.22min, respectively. elimination t1/2 in rabbits and rats were 48 min and 114min, respectively. It suggested that CPNZ self-assemblies had some longevity in the blood. Which was attributed to CHS-PEG1500, With regard to macrophage system, especially liver and spleen targeting and sustained releasing effects were shown in two animals. The CPNZ concent in liver occupied more than 50% and 42% of dose at 0.5h after bolus iv administration of CPNZ self-assemblies to rabbits and rats, respectively. Self-assemblies were targeted to liver, spleen and lung of rabbits and rats. The elimination t1/2 in liver and spleen of rabbits were 21h and 11h. The elimination t1/2 in liver, spleen and lung of rats were 25h, 15h and 11h.The concentration of AZT, the parent drug, was low, which mainly resulted from the rate of hydrolysis of CPNZ was much slower than the elimination of AZT and degradation products AZT in cells could phosphorylate by intracellular kinases.
A highly dispersed, homogeneous, stable self-assemblies of zidovudine lipidic prodrugs was prepared in this paper. A nano-size, ordered structure formed under the action of hydrophobic interaction and hydrogen bonding was proved. The self-assemblies were uptaked by monocyte macrophage quickly in rabbits and rats and sustainedly degraded into AZT.
引文
[1] Barenholz Y. Liposome application: problems and prospects. Curr Opin Colloid Interface Sci, 2001, 6: 66-77.
[2] Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev, 2001, 53: 283-318.
[3] Vaizoglu MO, Speiser PP. Pharmacosomes - a novel drug delivery system. Acta Pharm Suec, 1986, 23: 163-172.
[4] Vaizoglu MO, Speiser PP. The pharmacosome drug delivery approach. Eur J Pharm Biopharm, 1992, 38: 1-6.
[5] 金义光,侯新朴. 基于脂质前药的自组装药物传递系统. 中国医药工业杂志, 2005, 36: 185-189.
[6] Jin Y. Nanotechnology in pharmaceutical manufacturing, in: (Shayne Cox Gad, ed.) Pharmaceutical Manufacturing Handbook: Production and Processes. John Wiley and Sons, Inc, 2008: 1249-1288.
[7] Jin Y, Qiao Y, Li M, et al. Langmuir monolayers of the long-chain alkyl derivatives of a nucleoside analogue and the formation of self-assembled nanoparticles. Colloid Surface B Biointerfaces, 2005, 42: 45-51.
[8] Jin Y, Tong L, Ai P, et al. Self-assembled drug delivery systems 1. Properties and in vitro/in vivo behavior of acyclovir self-assembled nanoparticles (SAN). Int J Pharm, 2006, 309: 199-207.
[9] JinY, Qiao Y, Hou X. The effects of chain number and state of lipid derivatives of nucleosides on hydrogen bonding and self-assembly through the investigation of Langmuir-Blodgett films. Appl Surf Sci, 2006, 252: 7926-7929.
[10] 金义光, 艾萍, 李淼等. 阿昔洛韦药质体的制备和性质. 中国医药工业杂志, 2005, 36: 617-621.
[11] Jin Y, Xin R, Ai P, et al. Self-assembled drug delivery systems 2. Cholesterylderivatives of antiviral nucleoside analogues: Synthesis, properties and the vesicle formation. Int J Pharm, 2008, 350: 330-307.
[12] 金义光, 艾萍, 佟丽等. 新型靶向制剂阿昔洛韦药质体的家兔体内研究. 中华临床医药杂志, 2004, 5: 1-3.
[13] 金义光, 艾萍, 李淼等. 离子对高效液相色谱法测定阿昔洛韦脂质前药及前药的稳定性研究. 分析试验室, 2005, 24: 53-56.
[14] 金 义 光 , 艾 萍 . 核 苷 类 似 物 胆 固 醇 衍 生 物 . 发 明 专 利 , 申 请 号 200410090653.X
[15] 金义光, 李淼, 佟丽等. 核苷类似物脂质衍生物及其盐. 发明专利, 申请号 03148546.4
[16] 艾萍, 金义光, 陈大为. 去羟肌苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3: 227-234.
[17] Aquaro S, Calio R, Balzarini J, et al. Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. Antiviral Res, 2002, 55: 209-225.
[18] Mankertz J, von Baeyer H, Rokos K, et al. Cell specific uptake of antiretroviral drugs: AZT coupled to LDL inhibits HIV replication in human macrophages. Int J Clin Pharmacol Ther, 1995, 33: 85-88.
[19] Aquaro S, Bagnarelli P, Guenci T, et al.Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus. J Med Virol, 2002, 68: 479-488.
[20] Desormeaux A, Bergeron MG. Liposomes as drug delivery system: a strategic approach for the treatment of HIV infection. J Drug Target,1998, 6: 1-15.
[21] Dipali SR, Lin YJ, Ravis WR, et al. Pharmacokinetics and tissue distribution of a long circulating liposomal formulation of 29,39-dideoxyinosine. Int J Pharm, 1997, 152: 89-97.
[22] Bender AR, von Briesen H, Kreuter J, et al. Efficiency of Nanoparticles as a carrier system for antiviral agents in human immunodeficiency virus-Infectedhuman monocytes/macrophages in vitro. Antimicrob Agent Chemother, 1996, 40: 1467-1471.
[23] Faulds D, Brogden RN. Didanosine: a review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs, 1992, 44: 94-116.
[24] Konstantine KM, Xu ZS, Douglas FB, et al. Lymphatic targeting of anti-HIV nucleosides: distribution of 2′,3′-dideoxyinosine after intravenous and oral administration of dipalmitoylphosphatidyl prodrug in mice. Antiviral Re, 1997, 34: 91-99.
[25] David CB, William NC, Susan AC, et al. Synthesis and evaluation of 5′alkyl ester prodrugs of zidovudine for directed lymphatic delivery. Int J Pharm, 1996, 144: 61-70.
[26] Claption SD, Banmeet SA, Ashimk M. Effect of mono- and di-acylation on the ocular disposition of Ganciclovir: Physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs. J Pharm Sci, 2002, 91: 660-668.
[27] Pan-Zhou XR, Cretton-Scott E, Zhou XJ, et al.Comparative metabolism of the antiviral dimer 3′-azido-3′-deosythymidine-P-2′,3′-dideoxyinosine and the monomers Zidovudine and Didanosine by rat, monkey and human hepatocytes. Antimicrob Agents Chemother, 1997, 41: 2502-2510.
[28] Charles P. Susan M. Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment. Biochemistry, 1987, 26: 17-29.
[29] Andre D, Harvie P, Sylvie P, et al. Antiviral efficacy, intracellular uptake and pharmacokinetics of free and liposome-encapsulated 2′,3′-dideoxyinosine. AIDS, 1994, 8: 1544-1553.
[30] 金义光,艾萍,佟丽等. 新型靶向制剂阿昔洛韦药质体的家兔体内研究.中华临床医药杂志, 2004, 5: 1-3.
[31] Jin Y, Xin R, Ai P, et al. Self-assembled drug delivery systems 2. Cholesteryl derivatives of antiviral nucleoside analogues: Synthesis, properties and the vesicle formation. Int J Pharm, 2008, 350: 330-307.
[32] Krise JP, Stella VJ. Prodrugs of phosphates phosphonates and phosphinates. Adv Drug Deliv Rev, 1996, 19: 287-310.
[33] Giammona G, Cavallaro G, Fontana G, et al. Coupling of the antiviral agent zidovudine to polyaspartamide and in vitro drug release studies. J Controlled Release, 1998, 54: 321-331.
[34] Kennedy CA., Griffith HS, Mathison GE, Erythrocytosis after Zidovudine for AIDS. Ann Int Med, 1991, 114: 250-251.
[35] Martin JL, Brown CE, Matthews-Davis N, et al. Effect of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994, 38: 2743-2749.
[36] Zemlicka J.Lipophilic phosphoramidates as antiviral pronucleotides. Biochimica et Biophysica Acta, 2002, 1587 : 276-286.
[37] Rosowsky A, Fu H, Pai N, et al. Synthesis and in Vitro Activity of Long-Chain5′-O-[(Alkoxycarbonyl)phosphinyl]-3′-azido-3′-deoxythymidines against Wild-Type and AZT- and Foscarnet-Resistant Strains of HIV-1. J Med Chem,1997, 40: 2482-2490.
[38] Xiao Q, Ju Y, Yang XP, et al. Electrospray ionization mass spectrometry of AZT H-phosphonates conjugated with steroids. Rapid Commun Mass Spectrom, 2003, 17: 1405-1410.
[39] Kers I, Kers A , Stawifiski J. Aryl H-Phosphonates. 8. Simple and Efficient Method the for Preparation of Nucleoside H-Phosphonothioate Monoesters. Tetrahedron Lett, 1999, 40: 3945-3948.
[40] Kers A, Kers I, Stawifiski J, et al. Studies on Aryl H-phosphonates; Part 2: A General Method for the Preparation of Alkyl H-phosphonate Monoesters. Synthesis, 1995: 427-430.
[41] Xiao Q, Sun J, Ju Y, et al. Novel approach to the synthesis of AZT 5′-O-hydrogen phospholipids. Tetrahedron Lett, 2002, 43: 5281-5283.
[42] 邓意辉,蔡宏,李焕秋等. 胆固醇半琥珀酸酯囊泡的制备及 Ca2+聚集试验. 沈阳药科大学学报, 2001, 18: 84-87.
[43] 艾萍,金义光,陈大为. 去羟基苷药质体的制备及其在大鼠体内行为的研究.中国药剂学, 2005, 3: 227-235.
[44] Xiao Q, Ju Y, Yang XP, et al. Electrospray ionization mass spectrometry of AZT H-phosphonates conjugated with steroids. Rapid Commun Mass Spectrom, 2003, 17: 1405-1410.
[45] Yuin O, Kravtchenko A, Serebrovskaya L, et al. AIDS, 1998, 12:240.
[46] Cardona VMF, Ayi AI, Aubertin AM, et al. Antivir Res,1999, 42: 189.
[47] 苏德森,王思玲主编, 物理药剂学. 北京: 化学工业出版社, 2004: 64-74.
[48] David CB, William NC, Susan AC, et al. Synthesis and evaluation of 5′ alkyl ester prodrugs of zidovudine for directed lymphatic delivery. Int J Pharm, 1996, 144: 61-70.
[49] 刘文胜,罗维早,张志荣. N-山梨酰-5-氟脲嘧啶前体药物的体外降解动力学研究. 华西药学杂志, 2000, 15: 413-415.
[50] 陈国珍,黄贤智,刘文远等. 紫外可见分光光度法.上册. 北京:原子能出版社,1987: 31-34.
[51] Rabinow BE. Nanosuspensions in drug delivery. Nature, 2004, 3: 1-13.
[52] Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv, 1995, 70: 95-111.
[53] New RRC. Preparation of liposomes. In Liposome: a practical approach. Oxford: IRL Press, 1990: 33-104.
[54] 王大林,盛坤贤. 非离子表面活性剂囊泡作为药物载体的进展.中国医药工业杂志, 1998, 29: 235-240.
[55] Jin Y, Qiao Y, Hou X. The effects of chain number and state of lipid derivatives of nucleosides on hydrogen bonding and self-assembly through theinvestigation of Langmuir-Blodgett films. Appl Surf Sci, 2006, 252: 7926-7929.
[56] 金义光, 艾萍, 李淼等. 阿昔洛韦药质体的制备和性质. 中国医药工业杂志, 2005, 36: 617-621.
[57] 金义光, 侯新朴. 基于脂质前药的自组装药物传递系统. 中国医药工业杂志, 2005, 36: 185-189.
[58] ?eljka P, Nata?a ?B, Rolf S. Liposomal gels for vaginal drug delivery. Int J Pharm, 2001, 219: 139-149.
[59] Charles P. Susan M. Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment. Biochemistry, 1987, 26: 17-29.
[60] Szoka FJ, Papahadjopoulos D. Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci USA, 1978, 75: 4194-4198.
[61] 金义光, 艾萍, 李淼等. 阿昔洛韦药质体的制备和性质. 中国医药工业杂志, 2005, 36: 617-621.
[62] Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv, 1995, 70: 95-111.
[63] New RRC. Introduction. In Liposome: a practical approach. Oxford: IRL Press, 1990: 63-64.
[64] 艾萍,金义光,陈大为. 去羟基苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3: 227-235.
[65] Lourenco C, Teixeira M, Simoes S, et al. Steric stabilization of nanoparticles: size and surface properties. Int J Pharm, 1996, 138: 1-12.
[66] Allen TM, Romans AY, Kercret H, et al. Detergent removal during membrane reconstitution. Biochim Biophys Acta,1980, 601: 328-342.
[67] New RRC. Preparation of liposomes. In Liposome: a practical approach. Oxford: IRL Press, 1990: 1-32.
[68] Garbuzenko O, Barenholz Y, Priev A. Effect of grafted PEG on liposome size and on compressibility and packing of lipid bilayer. Chem Phys L,2005, 135: 117-129.
[69] 刘辉,汤韧,何晓霞等. 脂质体处方和制备方法对阿昔洛韦棕榈酸酯脂质体稳定性的影响.药学学报, 2002, 37: 563-566.
[70] Menger FM. Supramolecular chemistry and self-assembly. Proc Natl Acad Sci USA, 2002, 99: 4818-4822.
[71] Whitesides GM, Grzybowski B. Self-assembly at all scales. Science, 2002, 295: 2418-2421.
[72] British Pharmacopoiea, 1998: 1378.
[73] The United States Pharmacopoiea, 28: 2047-2050.
[74] 王伟,徐桂清,戴朝晖等. 齐多夫定含量的 HPLC 法测定. 南阳师范学院学报(自然科学版), 2003, 2: 48-49.
[75] Ahenafi Dunge, Nishi Sharda, Baljinder Singh, et al.Validated specific HPLC method for determination of zidovudine during stability studies. J Pharm Biomed Anal, 2005, 37: 1109-1114.
[76] Bengi Uslu, Sibel A.?zkan. Determination of lamivudine and zidovudine in binary mixtures using first derivative spectrophotometric, first derivative of the ratio-spectra and high-performance liquid chromatography-UV methods. Anal Chim Acta, 2002, 466: 175-185.
[77] Kritharides L, Jessup W, Gifford J, et al.A method for defining the stages of low-density lipoprotein oxidation by the separation of cholesterol- and cholesteryl ester-oxidation products using HPLC. Anal Biochem, 1993, 213: 79-89.
[78] Zhang R, Li L, Liu S, et al. An improved method of cholesterol determination in egg yolk by high performance liquid chromatography. Anal Chem, 1990, 62: 2728-2735.
[79] B?swart J, Kostiuk P, Vymlátil J, et al. High-performance liquidchromatographic determination of cholesteryl eaters in the blood of obese children. J Chromatogr, 1991, 571: 19-28.
[80] 艾萍, 金义光, 陈大为. 去羟肌苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3:227-234.
[81] 肖强,巨勇,赵玉芬. 一锅法合成 O-(3-薯蓣甙元)-O′-[5′-(3′-叠氮-3′-脱氧胸苷)]-氢亚磷酸酯. 高等学校化学学报, 2003, 24: 1427-1429.
[82] 艾萍. 去羟肌苷前药药质体的研究. 沈阳药科大学硕士学位论文. 2005, 6: 34-41.
[83] 齐宁宁. 齐多夫定双头基两亲前药自组装体系的研究. 沈阳药科大学硕士学位论文. 2007, 6: 38-41.
[84] Defrise-Quertain F, Chatelain P, Delmelle M, et al. Model studies for drug entrapment and liposome stability. In Liposome Technology, Vol 2. Gregoriadis G ed. Boca Raton, Folrida: CRC Press, 1984: 1-17.
[85] Wang BH, Siahaan T, Soltero RA.药物传递——原理与应用. 金义光,杜丽娜. 第 1 版第一次印刷,化学工业出版社,2008: 88-113.
[86] 毕殿洲主编. 药剂学. 第四版. 北京: 人民卫生出版社, 1999: 80-83.
[87] 刘昌孝主编. 实用药物动力学. 北京: 中国医药科技出版社, 2003: 243-244.
[88] 侯新朴,王继波,徐成等. 环胞苷前体药物脂质体的研究. 中国药学杂志, 1991, 26: 661-663.
[89] Jemal M, Hawthorne DJ. Quantitative determination of BMS-186716, a thiol compound in rat plasma by high-performance liquid chromatography-positive ion electrospray mass spectrometry after hydrolysis of the methyl acrylate adduct by the native esterases. J Chromatogr B, 1997, 698: 123-132.
[90] Grundker C. Cytotoxic luteinizing hormone-releasing hormone conjugates and their use in gynecological cancer therapy. Eur J Endocrinology, 2000, 143: 569-572.
[91] Vertut-Do? A, Ishiwata H, Miyajima K. Binding and uptake of liposomescontaining a poly(ethylene glycol) derivative of cholesterol (stealth liposomes) by the macrophage cell line J774: influence of PEG content and its molecular weight. Biochim Biophys Acta, 1996, 1278: 19-28.
[92] 金义光,艾萍,佟丽等. 新型靶向制剂阿昔洛韦药质体的家兔体内研究. 中华临床医药杂志, 2004, 5: 1-3.
[93] Giammona G, Cavallaro G, Fontana G, et al. Coupling of the antiviral agent zidovudine to polyaspartamide and in vitro drug release studies. J Controlled Release, 1998,54: 321-331.
[94] 艾萍, 金义光, 陈大为. 去羟肌苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3: 227-234.
[95] 吴红冰,邓意辉,周欣羽等. 齐多夫定棕榈酸酯脂质体的制备及在小鼠体内的药物分布. 沈阳药科大学学报,2007,24:65-69.
[96] 徐辉碧主编. 纳米医药. 第一版. 北京: 清华大学出版社, 2004:169-170.
[2] Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev, 2001, 53: 283-318.
[3] Vaizoglu MO, Speiser PP. Pharmacosomes - a novel drug delivery system. Acta Pharm Suec, 1986, 23: 163-172.
[4] Vaizoglu MO, Speiser PP. The pharmacosome drug delivery approach. Eur J Pharm Biopharm, 1992, 38: 1-6.
[5] 金义光,侯新朴. 基于脂质前药的自组装药物传递系统. 中国医药工业杂志, 2005, 36: 185-189.
[6] Jin Y. Nanotechnology in pharmaceutical manufacturing, in: (Shayne Cox Gad, ed.) Pharmaceutical Manufacturing Handbook: Production and Processes. John Wiley and Sons, Inc, 2008: 1249-1288.
[7] Jin Y, Qiao Y, Li M, et al. Langmuir monolayers of the long-chain alkyl derivatives of a nucleoside analogue and the formation of self-assembled nanoparticles. Colloid Surface B Biointerfaces, 2005, 42: 45-51.
[8] Jin Y, Tong L, Ai P, et al. Self-assembled drug delivery systems 1. Properties and in vitro/in vivo behavior of acyclovir self-assembled nanoparticles (SAN). Int J Pharm, 2006, 309: 199-207.
[9] JinY, Qiao Y, Hou X. The effects of chain number and state of lipid derivatives of nucleosides on hydrogen bonding and self-assembly through the investigation of Langmuir-Blodgett films. Appl Surf Sci, 2006, 252: 7926-7929.
[10] 金义光, 艾萍, 李淼等. 阿昔洛韦药质体的制备和性质. 中国医药工业杂志, 2005, 36: 617-621.
[11] Jin Y, Xin R, Ai P, et al. Self-assembled drug delivery systems 2. Cholesterylderivatives of antiviral nucleoside analogues: Synthesis, properties and the vesicle formation. Int J Pharm, 2008, 350: 330-307.
[12] 金义光, 艾萍, 佟丽等. 新型靶向制剂阿昔洛韦药质体的家兔体内研究. 中华临床医药杂志, 2004, 5: 1-3.
[13] 金义光, 艾萍, 李淼等. 离子对高效液相色谱法测定阿昔洛韦脂质前药及前药的稳定性研究. 分析试验室, 2005, 24: 53-56.
[14] 金 义 光 , 艾 萍 . 核 苷 类 似 物 胆 固 醇 衍 生 物 . 发 明 专 利 , 申 请 号 200410090653.X
[15] 金义光, 李淼, 佟丽等. 核苷类似物脂质衍生物及其盐. 发明专利, 申请号 03148546.4
[16] 艾萍, 金义光, 陈大为. 去羟肌苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3: 227-234.
[17] Aquaro S, Calio R, Balzarini J, et al. Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. Antiviral Res, 2002, 55: 209-225.
[18] Mankertz J, von Baeyer H, Rokos K, et al. Cell specific uptake of antiretroviral drugs: AZT coupled to LDL inhibits HIV replication in human macrophages. Int J Clin Pharmacol Ther, 1995, 33: 85-88.
[19] Aquaro S, Bagnarelli P, Guenci T, et al.Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus. J Med Virol, 2002, 68: 479-488.
[20] Desormeaux A, Bergeron MG. Liposomes as drug delivery system: a strategic approach for the treatment of HIV infection. J Drug Target,1998, 6: 1-15.
[21] Dipali SR, Lin YJ, Ravis WR, et al. Pharmacokinetics and tissue distribution of a long circulating liposomal formulation of 29,39-dideoxyinosine. Int J Pharm, 1997, 152: 89-97.
[22] Bender AR, von Briesen H, Kreuter J, et al. Efficiency of Nanoparticles as a carrier system for antiviral agents in human immunodeficiency virus-Infectedhuman monocytes/macrophages in vitro. Antimicrob Agent Chemother, 1996, 40: 1467-1471.
[23] Faulds D, Brogden RN. Didanosine: a review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs, 1992, 44: 94-116.
[24] Konstantine KM, Xu ZS, Douglas FB, et al. Lymphatic targeting of anti-HIV nucleosides: distribution of 2′,3′-dideoxyinosine after intravenous and oral administration of dipalmitoylphosphatidyl prodrug in mice. Antiviral Re, 1997, 34: 91-99.
[25] David CB, William NC, Susan AC, et al. Synthesis and evaluation of 5′alkyl ester prodrugs of zidovudine for directed lymphatic delivery. Int J Pharm, 1996, 144: 61-70.
[26] Claption SD, Banmeet SA, Ashimk M. Effect of mono- and di-acylation on the ocular disposition of Ganciclovir: Physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs. J Pharm Sci, 2002, 91: 660-668.
[27] Pan-Zhou XR, Cretton-Scott E, Zhou XJ, et al.Comparative metabolism of the antiviral dimer 3′-azido-3′-deosythymidine-P-2′,3′-dideoxyinosine and the monomers Zidovudine and Didanosine by rat, monkey and human hepatocytes. Antimicrob Agents Chemother, 1997, 41: 2502-2510.
[28] Charles P. Susan M. Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment. Biochemistry, 1987, 26: 17-29.
[29] Andre D, Harvie P, Sylvie P, et al. Antiviral efficacy, intracellular uptake and pharmacokinetics of free and liposome-encapsulated 2′,3′-dideoxyinosine. AIDS, 1994, 8: 1544-1553.
[30] 金义光,艾萍,佟丽等. 新型靶向制剂阿昔洛韦药质体的家兔体内研究.中华临床医药杂志, 2004, 5: 1-3.
[31] Jin Y, Xin R, Ai P, et al. Self-assembled drug delivery systems 2. Cholesteryl derivatives of antiviral nucleoside analogues: Synthesis, properties and the vesicle formation. Int J Pharm, 2008, 350: 330-307.
[32] Krise JP, Stella VJ. Prodrugs of phosphates phosphonates and phosphinates. Adv Drug Deliv Rev, 1996, 19: 287-310.
[33] Giammona G, Cavallaro G, Fontana G, et al. Coupling of the antiviral agent zidovudine to polyaspartamide and in vitro drug release studies. J Controlled Release, 1998, 54: 321-331.
[34] Kennedy CA., Griffith HS, Mathison GE, Erythrocytosis after Zidovudine for AIDS. Ann Int Med, 1991, 114: 250-251.
[35] Martin JL, Brown CE, Matthews-Davis N, et al. Effect of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994, 38: 2743-2749.
[36] Zemlicka J.Lipophilic phosphoramidates as antiviral pronucleotides. Biochimica et Biophysica Acta, 2002, 1587 : 276-286.
[37] Rosowsky A, Fu H, Pai N, et al. Synthesis and in Vitro Activity of Long-Chain5′-O-[(Alkoxycarbonyl)phosphinyl]-3′-azido-3′-deoxythymidines against Wild-Type and AZT- and Foscarnet-Resistant Strains of HIV-1. J Med Chem,1997, 40: 2482-2490.
[38] Xiao Q, Ju Y, Yang XP, et al. Electrospray ionization mass spectrometry of AZT H-phosphonates conjugated with steroids. Rapid Commun Mass Spectrom, 2003, 17: 1405-1410.
[39] Kers I, Kers A , Stawifiski J. Aryl H-Phosphonates. 8. Simple and Efficient Method the for Preparation of Nucleoside H-Phosphonothioate Monoesters. Tetrahedron Lett, 1999, 40: 3945-3948.
[40] Kers A, Kers I, Stawifiski J, et al. Studies on Aryl H-phosphonates; Part 2: A General Method for the Preparation of Alkyl H-phosphonate Monoesters. Synthesis, 1995: 427-430.
[41] Xiao Q, Sun J, Ju Y, et al. Novel approach to the synthesis of AZT 5′-O-hydrogen phospholipids. Tetrahedron Lett, 2002, 43: 5281-5283.
[42] 邓意辉,蔡宏,李焕秋等. 胆固醇半琥珀酸酯囊泡的制备及 Ca2+聚集试验. 沈阳药科大学学报, 2001, 18: 84-87.
[43] 艾萍,金义光,陈大为. 去羟基苷药质体的制备及其在大鼠体内行为的研究.中国药剂学, 2005, 3: 227-235.
[44] Xiao Q, Ju Y, Yang XP, et al. Electrospray ionization mass spectrometry of AZT H-phosphonates conjugated with steroids. Rapid Commun Mass Spectrom, 2003, 17: 1405-1410.
[45] Yuin O, Kravtchenko A, Serebrovskaya L, et al. AIDS, 1998, 12:240.
[46] Cardona VMF, Ayi AI, Aubertin AM, et al. Antivir Res,1999, 42: 189.
[47] 苏德森,王思玲主编, 物理药剂学. 北京: 化学工业出版社, 2004: 64-74.
[48] David CB, William NC, Susan AC, et al. Synthesis and evaluation of 5′ alkyl ester prodrugs of zidovudine for directed lymphatic delivery. Int J Pharm, 1996, 144: 61-70.
[49] 刘文胜,罗维早,张志荣. N-山梨酰-5-氟脲嘧啶前体药物的体外降解动力学研究. 华西药学杂志, 2000, 15: 413-415.
[50] 陈国珍,黄贤智,刘文远等. 紫外可见分光光度法.上册. 北京:原子能出版社,1987: 31-34.
[51] Rabinow BE. Nanosuspensions in drug delivery. Nature, 2004, 3: 1-13.
[52] Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv, 1995, 70: 95-111.
[53] New RRC. Preparation of liposomes. In Liposome: a practical approach. Oxford: IRL Press, 1990: 33-104.
[54] 王大林,盛坤贤. 非离子表面活性剂囊泡作为药物载体的进展.中国医药工业杂志, 1998, 29: 235-240.
[55] Jin Y, Qiao Y, Hou X. The effects of chain number and state of lipid derivatives of nucleosides on hydrogen bonding and self-assembly through theinvestigation of Langmuir-Blodgett films. Appl Surf Sci, 2006, 252: 7926-7929.
[56] 金义光, 艾萍, 李淼等. 阿昔洛韦药质体的制备和性质. 中国医药工业杂志, 2005, 36: 617-621.
[57] 金义光, 侯新朴. 基于脂质前药的自组装药物传递系统. 中国医药工业杂志, 2005, 36: 185-189.
[58] ?eljka P, Nata?a ?B, Rolf S. Liposomal gels for vaginal drug delivery. Int J Pharm, 2001, 219: 139-149.
[59] Charles P. Susan M. Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment. Biochemistry, 1987, 26: 17-29.
[60] Szoka FJ, Papahadjopoulos D. Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci USA, 1978, 75: 4194-4198.
[61] 金义光, 艾萍, 李淼等. 阿昔洛韦药质体的制备和性质. 中国医药工业杂志, 2005, 36: 617-621.
[62] Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv, 1995, 70: 95-111.
[63] New RRC. Introduction. In Liposome: a practical approach. Oxford: IRL Press, 1990: 63-64.
[64] 艾萍,金义光,陈大为. 去羟基苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3: 227-235.
[65] Lourenco C, Teixeira M, Simoes S, et al. Steric stabilization of nanoparticles: size and surface properties. Int J Pharm, 1996, 138: 1-12.
[66] Allen TM, Romans AY, Kercret H, et al. Detergent removal during membrane reconstitution. Biochim Biophys Acta,1980, 601: 328-342.
[67] New RRC. Preparation of liposomes. In Liposome: a practical approach. Oxford: IRL Press, 1990: 1-32.
[68] Garbuzenko O, Barenholz Y, Priev A. Effect of grafted PEG on liposome size and on compressibility and packing of lipid bilayer. Chem Phys L,2005, 135: 117-129.
[69] 刘辉,汤韧,何晓霞等. 脂质体处方和制备方法对阿昔洛韦棕榈酸酯脂质体稳定性的影响.药学学报, 2002, 37: 563-566.
[70] Menger FM. Supramolecular chemistry and self-assembly. Proc Natl Acad Sci USA, 2002, 99: 4818-4822.
[71] Whitesides GM, Grzybowski B. Self-assembly at all scales. Science, 2002, 295: 2418-2421.
[72] British Pharmacopoiea, 1998: 1378.
[73] The United States Pharmacopoiea, 28: 2047-2050.
[74] 王伟,徐桂清,戴朝晖等. 齐多夫定含量的 HPLC 法测定. 南阳师范学院学报(自然科学版), 2003, 2: 48-49.
[75] Ahenafi Dunge, Nishi Sharda, Baljinder Singh, et al.Validated specific HPLC method for determination of zidovudine during stability studies. J Pharm Biomed Anal, 2005, 37: 1109-1114.
[76] Bengi Uslu, Sibel A.?zkan. Determination of lamivudine and zidovudine in binary mixtures using first derivative spectrophotometric, first derivative of the ratio-spectra and high-performance liquid chromatography-UV methods. Anal Chim Acta, 2002, 466: 175-185.
[77] Kritharides L, Jessup W, Gifford J, et al.A method for defining the stages of low-density lipoprotein oxidation by the separation of cholesterol- and cholesteryl ester-oxidation products using HPLC. Anal Biochem, 1993, 213: 79-89.
[78] Zhang R, Li L, Liu S, et al. An improved method of cholesterol determination in egg yolk by high performance liquid chromatography. Anal Chem, 1990, 62: 2728-2735.
[79] B?swart J, Kostiuk P, Vymlátil J, et al. High-performance liquidchromatographic determination of cholesteryl eaters in the blood of obese children. J Chromatogr, 1991, 571: 19-28.
[80] 艾萍, 金义光, 陈大为. 去羟肌苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3:227-234.
[81] 肖强,巨勇,赵玉芬. 一锅法合成 O-(3-薯蓣甙元)-O′-[5′-(3′-叠氮-3′-脱氧胸苷)]-氢亚磷酸酯. 高等学校化学学报, 2003, 24: 1427-1429.
[82] 艾萍. 去羟肌苷前药药质体的研究. 沈阳药科大学硕士学位论文. 2005, 6: 34-41.
[83] 齐宁宁. 齐多夫定双头基两亲前药自组装体系的研究. 沈阳药科大学硕士学位论文. 2007, 6: 38-41.
[84] Defrise-Quertain F, Chatelain P, Delmelle M, et al. Model studies for drug entrapment and liposome stability. In Liposome Technology, Vol 2. Gregoriadis G ed. Boca Raton, Folrida: CRC Press, 1984: 1-17.
[85] Wang BH, Siahaan T, Soltero RA.药物传递——原理与应用. 金义光,杜丽娜. 第 1 版第一次印刷,化学工业出版社,2008: 88-113.
[86] 毕殿洲主编. 药剂学. 第四版. 北京: 人民卫生出版社, 1999: 80-83.
[87] 刘昌孝主编. 实用药物动力学. 北京: 中国医药科技出版社, 2003: 243-244.
[88] 侯新朴,王继波,徐成等. 环胞苷前体药物脂质体的研究. 中国药学杂志, 1991, 26: 661-663.
[89] Jemal M, Hawthorne DJ. Quantitative determination of BMS-186716, a thiol compound in rat plasma by high-performance liquid chromatography-positive ion electrospray mass spectrometry after hydrolysis of the methyl acrylate adduct by the native esterases. J Chromatogr B, 1997, 698: 123-132.
[90] Grundker C. Cytotoxic luteinizing hormone-releasing hormone conjugates and their use in gynecological cancer therapy. Eur J Endocrinology, 2000, 143: 569-572.
[91] Vertut-Do? A, Ishiwata H, Miyajima K. Binding and uptake of liposomescontaining a poly(ethylene glycol) derivative of cholesterol (stealth liposomes) by the macrophage cell line J774: influence of PEG content and its molecular weight. Biochim Biophys Acta, 1996, 1278: 19-28.
[92] 金义光,艾萍,佟丽等. 新型靶向制剂阿昔洛韦药质体的家兔体内研究. 中华临床医药杂志, 2004, 5: 1-3.
[93] Giammona G, Cavallaro G, Fontana G, et al. Coupling of the antiviral agent zidovudine to polyaspartamide and in vitro drug release studies. J Controlled Release, 1998,54: 321-331.
[94] 艾萍, 金义光, 陈大为. 去羟肌苷药质体的制备及其在大鼠体内行为的研究. 中国药剂学, 2005, 3: 227-234.
[95] 吴红冰,邓意辉,周欣羽等. 齐多夫定棕榈酸酯脂质体的制备及在小鼠体内的药物分布. 沈阳药科大学学报,2007,24:65-69.
[96] 徐辉碧主编. 纳米医药. 第一版. 北京: 清华大学出版社, 2004:169-170.