二-（4-氯苯甲酰异羟肟酸）二正丁基合锡（DBDCT）脂质体的制备及其体内药代动力学研究
|
摘要
[二-(4-氯苯甲酰异羟肟酸)二正丁基合锡]( DBDCT )是一种新型的抗肿瘤化合物,课题组前期研究表明,该化合物有较高的抗癌活性,但其毒性较大,半衰期较短。脂质体作为一种新的剂型,不仅可以明显改善药物的药代动力学特征和体内分布,达到靶向和缓释的效果,还可降低药物的毒副作用。因此,本研究进行了DBDCT脂质体的研制,以期改善其药代动力学特性,并最终提高其治疗指数。
为控制DBDCT的质量,建立了测定脂质体中DBDCT的高效液相色谱法(HPLC)和测定DBDCT脂质体(DBDCT-L)包封率的葡聚糖凝胶微柱离心法。通过测定得出DBDCT脂质体的包封率为67.2%。
本实验采用薄膜分散法制备DBDCT脂质体,并在单因素实验的基础上,以包封率为指标综合评分,优化制备DBDCT脂质体的处方,其中胆固醇与卵磷脂质量比、卵磷脂用量和磷酸盐缓冲液的量这三个因素变化显著。对影响包封率的三个主要因素采用正交试验确定DBDCT脂质体的最佳制备处方为:胆固醇与卵磷脂质量比为1:6,卵磷脂用量为200mg,磷酸盐缓冲液的量为10ml。
脂质体的粒径大小及其分布运用激光粒度仪进行了考察,用透射电镜观察其形态,结果显示,粒度分布均匀,平均粒径为121.3nm,电子显微镜下观察脂质体为均匀的球状或近球状小囊泡。
通过对比脂质体溶液和DBDCT溶液之间的药动学参数和组织分布的数据,结果显示,脂质体组具有较大的血药浓度—时间曲线下面积,较低的清除率,药物在体内的消除半衰期明显延长;脂质体组在肝、脾、肺、肾中的分布也高于DBDCT溶液组,特别是在肝组织中的浓度最高。DBDCT脂质体制剂的药代动力学特征及组织分布的变化有利于提高其抗肿瘤活性。
通过小鼠体内的急性毒性实验,测定了DBDCT脂质体(DBDCT-L)在小鼠体内的半数致死量(LD50),以及其体外的抗肿瘤活性,结果显示,与原料组相比,脂质体组LD50增大,对于移植性肿瘤(H22)的抑瘤率也提高。
Di-n-butyl-di-(4-chlorobenzohydroxamato) tin (IV) (DBDCT) is a new antitumor compound with high activity and relatively low bioavailability. It could distribute and be eliminated rapidly in rat with a short half-time(T1/2) value. In this paper the liposome of DBDCT (DBDCT-L) was first prepared in order to improve the pharmacokinetics characteristics and finally to raise its therapeutic indexes.
In order to control the quality of DBDCTL, the method for determination of DBDCT quality by HPLC and for determination of encapsulation efficiency of DBDCT-L by Sephadex G-50 minicolumn using centrifugation technique were established. The encapsulation efficiency was calculated by comparing the amount of drug present in the final liposome suspension with that present prior to the removal of the non-incorporated drug. The entrapping efficiency is 67.2%.
Liposomes of DBDCT were prepared by thin film evaporation–extrusion technique. Orthogonal design was adopted to the formulation of DBDCT liposome on the basis of the score of the entrapment efficiency. According to the entrapment efficiency, various factors were studied. The orthogonal experimental design was chosen to optimize the condition of preparation DBDCT-L. The analysis showed (PC) 200mg, (PC/CH) 6:1, (PBS) 10ml, which were the optimal formulation.
The size, size distribution and shape of all batches of liposomes were determined using dynamic light scattering and negative staining electron microscopy. The mean diameter of the liposomes loaded with DBDCT was 128.3nm.
A comparison study of the pharmacokinetics and tissue distribution after intravenous administrations of the DBDCT-L with the corresponding free DBDCT to rats was investigated. Comparing with the free DBDCT, the DBDCT-L showed slower clearance, increased half-time and larger AUC value than those of the free DBDCT after intravenous administration to rats. Significant differences were observed in heart, liver, spleen, lung, kidney, brain and adrenal gland after administration of DBDCT-L and the free DBDCT. However, the distribution in the spleen, liver, lung and kidney of DBDCT-L was higher than those of the free DBDCT, especially the concentration distribution in liver is the highest which may be associated with the enhanced antitumor activity and indicated the possible target release of the drug.
The acute toxicity studies showed that the LD50 value of the DBDCT-L is higher than that of the free DBDCT. The further in vivo antitumor tests in mice showed that DBDCT-L displayed higher in vivo antitumor activity against the hepatocellular carcinoma H22 than those of the free DBDCT, and indicated that the liposomes could prolong the action-time of DBDCT in the system circulation, change its distribution in rats in vivo, reduce the acute toxicity and finally raise the antitumor activity.
为控制DBDCT的质量,建立了测定脂质体中DBDCT的高效液相色谱法(HPLC)和测定DBDCT脂质体(DBDCT-L)包封率的葡聚糖凝胶微柱离心法。通过测定得出DBDCT脂质体的包封率为67.2%。
本实验采用薄膜分散法制备DBDCT脂质体,并在单因素实验的基础上,以包封率为指标综合评分,优化制备DBDCT脂质体的处方,其中胆固醇与卵磷脂质量比、卵磷脂用量和磷酸盐缓冲液的量这三个因素变化显著。对影响包封率的三个主要因素采用正交试验确定DBDCT脂质体的最佳制备处方为:胆固醇与卵磷脂质量比为1:6,卵磷脂用量为200mg,磷酸盐缓冲液的量为10ml。
脂质体的粒径大小及其分布运用激光粒度仪进行了考察,用透射电镜观察其形态,结果显示,粒度分布均匀,平均粒径为121.3nm,电子显微镜下观察脂质体为均匀的球状或近球状小囊泡。
通过对比脂质体溶液和DBDCT溶液之间的药动学参数和组织分布的数据,结果显示,脂质体组具有较大的血药浓度—时间曲线下面积,较低的清除率,药物在体内的消除半衰期明显延长;脂质体组在肝、脾、肺、肾中的分布也高于DBDCT溶液组,特别是在肝组织中的浓度最高。DBDCT脂质体制剂的药代动力学特征及组织分布的变化有利于提高其抗肿瘤活性。
通过小鼠体内的急性毒性实验,测定了DBDCT脂质体(DBDCT-L)在小鼠体内的半数致死量(LD50),以及其体外的抗肿瘤活性,结果显示,与原料组相比,脂质体组LD50增大,对于移植性肿瘤(H22)的抑瘤率也提高。
Di-n-butyl-di-(4-chlorobenzohydroxamato) tin (IV) (DBDCT) is a new antitumor compound with high activity and relatively low bioavailability. It could distribute and be eliminated rapidly in rat with a short half-time(T1/2) value. In this paper the liposome of DBDCT (DBDCT-L) was first prepared in order to improve the pharmacokinetics characteristics and finally to raise its therapeutic indexes.
In order to control the quality of DBDCTL, the method for determination of DBDCT quality by HPLC and for determination of encapsulation efficiency of DBDCT-L by Sephadex G-50 minicolumn using centrifugation technique were established. The encapsulation efficiency was calculated by comparing the amount of drug present in the final liposome suspension with that present prior to the removal of the non-incorporated drug. The entrapping efficiency is 67.2%.
Liposomes of DBDCT were prepared by thin film evaporation–extrusion technique. Orthogonal design was adopted to the formulation of DBDCT liposome on the basis of the score of the entrapment efficiency. According to the entrapment efficiency, various factors were studied. The orthogonal experimental design was chosen to optimize the condition of preparation DBDCT-L. The analysis showed (PC) 200mg, (PC/CH) 6:1, (PBS) 10ml, which were the optimal formulation.
The size, size distribution and shape of all batches of liposomes were determined using dynamic light scattering and negative staining electron microscopy. The mean diameter of the liposomes loaded with DBDCT was 128.3nm.
A comparison study of the pharmacokinetics and tissue distribution after intravenous administrations of the DBDCT-L with the corresponding free DBDCT to rats was investigated. Comparing with the free DBDCT, the DBDCT-L showed slower clearance, increased half-time and larger AUC value than those of the free DBDCT after intravenous administration to rats. Significant differences were observed in heart, liver, spleen, lung, kidney, brain and adrenal gland after administration of DBDCT-L and the free DBDCT. However, the distribution in the spleen, liver, lung and kidney of DBDCT-L was higher than those of the free DBDCT, especially the concentration distribution in liver is the highest which may be associated with the enhanced antitumor activity and indicated the possible target release of the drug.
The acute toxicity studies showed that the LD50 value of the DBDCT-L is higher than that of the free DBDCT. The further in vivo antitumor tests in mice showed that DBDCT-L displayed higher in vivo antitumor activity against the hepatocellular carcinoma H22 than those of the free DBDCT, and indicated that the liposomes could prolong the action-time of DBDCT in the system circulation, change its distribution in rats in vivo, reduce the acute toxicity and finally raise the antitumor activity.
引文
[1]李青山.有机锡抗癌配合物的合成及其抗癌机理的研究.南京大学博士学位论文.1996年9月,南京.
[2] Casini .A,Messori .L,Orioli .P. J. et al. Interactions of two cytotoxic organotin(Ⅳ) compoun -ds with calf thymus DNA[J] .Inorg. Biochem. 2001,85:297-300.
[3]杨志强等.具有实验抗癌活性的二烃基锡衍生物的研究进展.有机化学.1996,16:111.
[4]彭俊,苏怀德.有机锡化合物抗肿瘤生物活性研究.药学学报.1994,29:406-411.
[5]赵敬华.新型有机锡类抗癌先导化合物DBDPT的结构优化.山西医科大学硕士学位论文.2003,7,太原.
[6] A.J.Crowe, P.J.Smith, G.Atassi. Investigations into the Antitumor Acticity of Organotin Compounds1. Diorganotin Dihalide and Diepseudohalide Complexes. Chem. Biol .Interact, 1980, 43:171-178.
[7] Yunlan Li. Studies on Pharmacokinetics and Mechanism of Antitumor Di-n-butyl-(4-chlorobenzohydroxamato) Tin (Ⅳ) dichloride (DBDCT).(P HD.Disserati on)Taiyuan, Shanxi Medical University. 2008.
[8]侯雪梅,崔黎丽,李国栋,等.抗肿瘤药物靶向制剂研究进展.药学实践杂志, 2007, 25(5):273-275.
[9] Bangham, A.D, Standish, M.M, Watkins, J.C, et al. Diffusion of univalent ions across the lamellae of swollen phspholipids, J. Mol. Biol, 1965, 13:238-252.
[10]陈建明,张仰眉,高申.脂质体作为药物载体的研究进展[J].药学实践杂志. 2001, 19 (4):214-218.
[11]仵文英,薛红安,邹晶,等.脂质体制剂的靶向性特点及应用[J] .中国中医药杂志2004,2(5):
[12] Webb M S, Harasym T O, Masin D, et al. Sphingomyelin/cholesterol Liposomes Significantly Enhance the Pharamacokinetics and Therapeutic Properties of Vincristine in Murine and Human Tumor Models. Br J Cancer, 1995 10; 72 (4):896-904.
[13] Krishna R, Wabb M S, St Onge G, et al. Liposomal and Nonliposomal Drug Pharmacokinetics after Administration of Liposome-encapsulated Vincristine and Their Contribution to Drug Tissue Distribution Properties. J Pharmacol Exo Ther, 2001 9: 298(3): 1206-1212.
[14] Vaage J, Donovan D, Mayhew E, et al. Therapy of Mouse Mammary Carcinomas with Vincristine and Doxorubicin Encapsulated in Sterically Stabilized Liposomes. Int J,Cancer, 1993(54): 959-964.
[15]胡景莲.脂质体制备方法的研究进展[J] .中国临床医药研究杂志, 2004 , (113) :11872– 118741
[16] Oh YK, Nix DE, Straubinger RM. Formulation and efficacy of liposome encapsulated antibiotics for therapy of intracellular[J]. Antimi-cro Agents Chemother, 1995, 39(9):2104-2111.
[17]张冬青,程怡.脂质体的研究概况[J].中药新药与临床药理, 2002, 13(2):125-128.
[18]王英丽,张阳,王雪宝.抗癌药物脂质体的研究进展.中华临床医药, 2003, 4(14):38-39.
[19]平其能,现代药剂学.[M]北京,中国医药科技出版社,1998:621.
[20] A, se;em, S, Gabozpm, A, Barenhola, Y. Optimization and upscaling of Doxorubicin-containing liposomes for clinical use. J. Pharm. Sci, 1990, 79: 1045-1052.
[21] Barenholz Y. Liposome Application: problems and prospects. Current Opinion in Colloid&Interface Science, 2001, 6(1): 66-67.
[22] Drummond DC, Merey O, Hong K, et al. Optimizing Liposomes for Delivery of Chemotherapeutic Agents to solid Tumors. Pharmacological Reviews, 1999, 51(4): 692-723.
[23] Singh M, Ferdous AJ, Jackson TL. Stealth monensin liposomes as a potentiator of adriamycin in cancer treatment. J of Controlled Release, 1999, 59(1): 43-53.
[24] Gutman R L, Peacock G, Lu DR. Targeted drug delivery for brain cancer treatment. J of Controlled Release, 2000, 65(1): 31-41.
[25] Nagayasu A, Uchiyama K, Kiwada H. The size of liposomes: a factor which affects their targeting efficiency to tumor and therapeutic activity of liposomal antitumor drugs. Advanced Drug Delivery Reviews, 1999, 40 (1): 75-87.
[26] Shabbits JA, Chiu GN, Mayer LD. Development of an in vitro drug release assay that accurately predicts in vivo drug retention for liposome-based delivery system. J of Controlled Release, 2002, 65(1): 31-41.
[27] Torchilin VP. Drug Targeting. European Journal of Pharmaceutical Science 11, 2000, Suppl. 2: S81-S91.
[28] Qingshan Li, A. J. Pombeiro, F. A. Fatima. Diorganotin(IV) Derivatives of Substituted Benzohydroxamic Acids with High Antitumor Activity, Chem. Euro. J. 10 (2004) 1456-1462.
[29]郑俊民主编.经皮给药新剂型[M].人民卫生出版社,1997: 276-297.
[30] Qingshan Li, A. J. Pombeiro, F. A. Fatima. Diorganotin(IV) Derivatives of SubstitutedBenzohydroxamic Acids with High Antitumor Activity, Chem. Euro. J. 10 (2004) 1456-1462.
[31]王秀敏,邓英杰,赵春杰,等.β-榄香烯油水分配系数的测定[J].沈阳药科大学学报,2005,22(4): 289-320.
[32]丁平田等。中国医药工业杂志,1998:186-189.
[33]赵荣生,候新朴,严宝霞.两性霉素B脂质体的制备及稳定性研究[J].中国医药工业杂志, 2001,32(4): 160-163.
[34] Mequel Pons. Liposomes obtained by the ethanol injection method [J]. Int J Pharm 1993, 95: 51-56.
[35]陆斌.药物新剂型与新技术[M].北京:人民卫生出版社. 1998: 121-133.
[36]平其能等编著现代药剂学[M].中国医药科技出版社. 1998: 607-608.
[37] Madelmont CG, Lesieur S, Michel O. Characterization of loaded liposomes by size exclusion chromatography. J. Biochem. Biophys. Methods, 2003, 56 (1-3): 189-217.
[38]程建峰,扈本荃,刘梅等.甘草酸脂质体的处方及制备工艺[J].第四军医大学学报,2006, 27 (7): 655-657.
[39] Fomuso LB, Corredig M, Akog CC. Metal-Catalyzed oxidation of a structure lipid model emulsion. J. Agric. Food Chem. 2002, 50(24): 7114-7119.
[40] Tang D, Borchman D. Temperature induced structural changes of beta-crystalline and sphingomyelin binding. Exp. Eye Res. 1998, 67 (1): 113-118.
[41]平其能.现代药剂学[M]北京,中国医药科技出版社,1998: 608-609.
[42]陆斌.药物新剂型与新技术[M].北京:人民卫生出版社. 2002: 53-54.
[43]周莉玲,王岩,刘清飞等.青藤碱脂质体包封率的测定[J].中国中药学杂志,2006, 31(9):731-734.
[44]国家药典委员会.中华人民共和国药典(二部) [M].北京:化学工业出版社, 2005.附录54
[45]官东秀,冯祚臻,邓联芬,等.气象色谱法测定冬虫夏草多糖脂质体口服液中氯仿残留量[J].中国医院药学杂志, 2005, 25(2):144-145.8
[46]薛继雄,周晖.毛细管气相色谱法测定替米沙坦中的有机溶剂残留量[J].中国医院药学杂志, 2007, 26(3)358-360.
[47]徐叔云,卞如濂,陈修,药理实验方法学,第三版,北京;人民卫生出版社.2001:1758-1765.
[48]殷中琼,喻印,贾仁勇,郑艳,陈瑞.青刺果种粨粉对鸡免疫器官胸腺和脾脏的影响.动物营养学报. 2007, 19 (3): 25-25.
[49] Shah VP, Midha KK, Dighe Shrikant, et al. Analytical methods validation: Bioavalability,Bioequivalence and pharmacokinetic studies [J]. J Pharm Sci, 1982, 8 (3):309.
[50] AWASTHI V D,GARCIA D,GOINS,B A et a1. Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits[J]. International Journal of Pharmaceutics, 2003, 253(1-2): 121-132.
[51] GUILLAUME P,AMAURY H,SOPHIE C,et a1. Pharmacokinetics of DTPA entrapped in conventional and long-circulating liposomes of different size for plutonium decorporation[J]. Journal of Controlled Release, 2005, 110(1): 177-188.
[1] Gregoriadis G, Ryman B E. Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases[J].Biochem J, 1971, 124(5):58.
[2] Symon Z, Peyser A. Tzemach D, et al. Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes [J]. Cancer, 1999, 86(1):72-78.
[3] Schwonzen M, Kurbacher C M, Mallmann P. Liposomal doxorubicin and weekly paclitaxel in the treatment of metastatic breast cancer [J]. Anticancer Drugs, 2000, 11(9), 681-685.
[4] Ghesquières H, Faivre S, Djafari L, et al. PhaseⅠdose escalation study of pegylated liposomal doxorubicin (Caelyx) in combination with topotecan in patients with advanced malignancies [J]. Invest New Drugs, 2006, 24(6): 418-421.
[5] Shama A, Mayhew E, Bolicsak L, et al.Activity of paclitaxel liposome formulations against human ovarian tumor xenografts.Int J Cancer, 1997, 71:103- 107.
[6] Cabanes A, Briggs KE, Gokhale PC, et al.Comparative in vivostudies with paclitaxel and liposome encapsulated paclitaxel.Int J Oncol, 1998, 12:1035- 1040.
[7]陈强,张其忠,刘健,等,紫杉醇脂质体与传统紫杉醇治疗乳腺癌和非小细胞肺癌的随机对照研究.中华肿瘤杂志, 2003, 25 ( 2) : 190- 192.
[8]周卫,吕琦,翁帼英.紫杉醇脂质体在大鼠体内的药动学.中国药科大学学报, 2000, 31( 6) : 443- 446.
[9] Sun Dong-sheng, Chen Jiang-hao, Ling Rui, et al. Treatment of hepatoma with liposome-encapsulated adriamycin administered into hepatic artery of rats [J]. World J Gastro-Enterol, 2006, 12(29): 4741-4744.
[10]王小晨,王向伟,秦燕,等.长春新碱脂质体的药代动力学及其抗肿瘤作用[J].实验动物与比较医学, 2007 27(1): 15-19.
[11] Klibanov A L, Maruyama K, Torchilin V P, et al. Am-phipathic polyethylene glycols effectively prolong the circula-tion time of liposomes [J]. FEBS Lett, 1990, 268(1): 235-237.
[12] Torchilin V P, Omelyanenko V G, Papisov M I, et al. Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity [J]. Biochim Biophys Acta, 1994, 1195(1):11-20.
[13] Gabizon A A, Pegylated liposomal doxorubicin: metamor-phosis of an old drug into a new form of chemotherapy [J]. Cancer Invest, 2001, 19(4):424-436.
[14] Rosenthal DI, Yom SS, Liu L, et al. A phase I study of SPI-077 (Stealth liposomalcisplatin) concurrent with radiation therapy for locally advanced head and neck cancer [J]. Invest New Drugs, 2002, 20(3): 343-349.
[15] Working PK, Newman MS, Sullivan T, et al. Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in long-circulating, pegylated liposomes in cynomolgus monkeys [J]. Toxicol Sci, 1998, 46(1): 155-165.
[16] Iinuma H, Maruyama K, Okinaga K, et al. Intracellular targeting therapy of cisplatin-encapsulated transferrinpolyethylene glycol liposome on peritoneal dissemination ofgastric cancer[J]. Int J Cancer, 2002, 99(1): 130-137.
[17] Peleg - Shulman T,Gibson D,Cohen R,et al .Characterization of sterically stabilized cisplatin liposomes by nuclear magnetic resonance[J]. Biochim Biophys Acta, 2001, 1510(1-2):278-291.
[18]王杉,密捷波,李元宗,等.电感耦合等离子发射光谱法测定血清及组织中铂类药物[J].分析化学, 2003, 31(3): 287-291.
[19] Kale A, Torchilin V P. Enhanced transfection of tumor cells in v ivo using“Smart”pH -sensitive TAT-modified pegylated liposomes [J]. J Drug Target, 2007, 15 (7-8):538-545.
[20]苏东辉,沈鼎鸿,彭辉云等。上海免疫学杂志,1985:6(1):14。
[21]孟胜男,赵希贤,姜翠莲,等.大肠癌特异性卡莫氟免疫脂质体的体外抗癌活性研究[J ] .沈阳药科大学学报,2003 ,20 (5) :370-372.
[22] Pan X Q, ZHENG Xuan, SHI Guang-feng, et al. Strategy for t he t reatment of acute myelogenous leukemia based on folate receptorβ-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid [J] .Blood , 2002 , 100 (2) : 5942602.
[23]胡兰荣,齐晓峰,郑昌学等。生物化学杂志,1991, 7(3): 381.
[24] Hatakeyama H, Akita H , Maruyama K, et al . Factors governing the in vivo tissue uptake of transferring-coupled polyethylene glycol liposomes in vivo[J]. Int J Pharm, 2004, 281(1-2): 25-33.
[25] Iinuma H, Maruyama K, Okinaga K, et al. Int racellular targeting therapy of cisplatin-encapsulated transferring-polyethylene glycol liposome on peritoneal dissemination of gastric cancer [J] . Int J Cancer, 2002, 99 (1): 130-137.
[26]邹一愚,顾学裘,崛越勇。药学学报,1991,26(8): 622,
[27]邹一愚,顾学裘,崛越勇。药学学报,1991,27(9): 705.
[28]刘同刚,唐敏章,金发光.加温敏感阿霉素脂质体治疗小鼠荷Lewis肺癌[J] .第四军医大学学报,2003 ,24 (4) :335-337.
[29] Iga K, Hanmaguchi N, Igari Y et al. J Pharm Sci, 1991, 80(6): 522.
[30]刘启光,尹长城,沈子威等。生物化学与生物物理进展,1989,16(3):218.
[31] [31] Hong M S, Lim S J, Oh Y K, et al. pH-sensitive, serumstable and long-circulating liposomes as a new drug delivery system [J]. J Pharm Pharmacol, 2002, 54 (1): 51-58.
[32] Crowe.A.J, Smith.P.J, Atassi, G, Inorg. Chim.Acta. 1984(93):179.
[33] V. Narayanan, M.Nasr, K.P.Paull, et al. Tin-Based Antitumor Drugs. Berlin, Springer, Verlag. 1990, 201-206.
[34] A.J.Crowe. Antitumor activity of Tin Compounds.In: S. P. Fricker(Ed), Metal Compounds in Cancer Therapy. Chapman & Hall, London. 1994, 147-179.
[35] M. Gielen. Synthesis, Characterization and in-vitro Antitumor Activity of Dibutyltin Carboxylatrs Involving the Perfluorophenyl Moiety: Crystal Structure of the Dimetric Bis [(4-fluoro-and Pentafluoro-benzoato) di-n-butyltin]Oxides.Appl. Organoment. Chem.1995(9):639.
[36] Qingshan Li, A. J. Pombeiro, F. A. Fatima. Diorganotin(IV) Derivatives of Substituted Benzohydroxamic Acids with High Antitumor Activity, Chem. Euro. J. 10 (2004) 1456-1462.
[37] A.J.Crowe, P.J.Smith, and Ghanern Atassi, Investigations into the antitumour activity of organotin compounds. I. Diorganotin dihalide and di-pseudohalide complexes, Chem. Biol. Interact. 1980 (32): 171-178.
[38] Saxena A K, Huber F. Organotin Compounds and Cancer Chemotherapy.Coord. Chem.Rev. 1989, 95(1):109.
[39] Gielen M. Tin-Based Antitumor Drugs.Coord. Chem. Rev. 1996,151 (1):48.
[2] Casini .A,Messori .L,Orioli .P. J. et al. Interactions of two cytotoxic organotin(Ⅳ) compoun -ds with calf thymus DNA[J] .Inorg. Biochem. 2001,85:297-300.
[3]杨志强等.具有实验抗癌活性的二烃基锡衍生物的研究进展.有机化学.1996,16:111.
[4]彭俊,苏怀德.有机锡化合物抗肿瘤生物活性研究.药学学报.1994,29:406-411.
[5]赵敬华.新型有机锡类抗癌先导化合物DBDPT的结构优化.山西医科大学硕士学位论文.2003,7,太原.
[6] A.J.Crowe, P.J.Smith, G.Atassi. Investigations into the Antitumor Acticity of Organotin Compounds1. Diorganotin Dihalide and Diepseudohalide Complexes. Chem. Biol .Interact, 1980, 43:171-178.
[7] Yunlan Li. Studies on Pharmacokinetics and Mechanism of Antitumor Di-n-butyl-(4-chlorobenzohydroxamato) Tin (Ⅳ) dichloride (DBDCT).(P HD.Disserati on)Taiyuan, Shanxi Medical University. 2008.
[8]侯雪梅,崔黎丽,李国栋,等.抗肿瘤药物靶向制剂研究进展.药学实践杂志, 2007, 25(5):273-275.
[9] Bangham, A.D, Standish, M.M, Watkins, J.C, et al. Diffusion of univalent ions across the lamellae of swollen phspholipids, J. Mol. Biol, 1965, 13:238-252.
[10]陈建明,张仰眉,高申.脂质体作为药物载体的研究进展[J].药学实践杂志. 2001, 19 (4):214-218.
[11]仵文英,薛红安,邹晶,等.脂质体制剂的靶向性特点及应用[J] .中国中医药杂志2004,2(5):
[12] Webb M S, Harasym T O, Masin D, et al. Sphingomyelin/cholesterol Liposomes Significantly Enhance the Pharamacokinetics and Therapeutic Properties of Vincristine in Murine and Human Tumor Models. Br J Cancer, 1995 10; 72 (4):896-904.
[13] Krishna R, Wabb M S, St Onge G, et al. Liposomal and Nonliposomal Drug Pharmacokinetics after Administration of Liposome-encapsulated Vincristine and Their Contribution to Drug Tissue Distribution Properties. J Pharmacol Exo Ther, 2001 9: 298(3): 1206-1212.
[14] Vaage J, Donovan D, Mayhew E, et al. Therapy of Mouse Mammary Carcinomas with Vincristine and Doxorubicin Encapsulated in Sterically Stabilized Liposomes. Int J,Cancer, 1993(54): 959-964.
[15]胡景莲.脂质体制备方法的研究进展[J] .中国临床医药研究杂志, 2004 , (113) :11872– 118741
[16] Oh YK, Nix DE, Straubinger RM. Formulation and efficacy of liposome encapsulated antibiotics for therapy of intracellular[J]. Antimi-cro Agents Chemother, 1995, 39(9):2104-2111.
[17]张冬青,程怡.脂质体的研究概况[J].中药新药与临床药理, 2002, 13(2):125-128.
[18]王英丽,张阳,王雪宝.抗癌药物脂质体的研究进展.中华临床医药, 2003, 4(14):38-39.
[19]平其能,现代药剂学.[M]北京,中国医药科技出版社,1998:621.
[20] A, se;em, S, Gabozpm, A, Barenhola, Y. Optimization and upscaling of Doxorubicin-containing liposomes for clinical use. J. Pharm. Sci, 1990, 79: 1045-1052.
[21] Barenholz Y. Liposome Application: problems and prospects. Current Opinion in Colloid&Interface Science, 2001, 6(1): 66-67.
[22] Drummond DC, Merey O, Hong K, et al. Optimizing Liposomes for Delivery of Chemotherapeutic Agents to solid Tumors. Pharmacological Reviews, 1999, 51(4): 692-723.
[23] Singh M, Ferdous AJ, Jackson TL. Stealth monensin liposomes as a potentiator of adriamycin in cancer treatment. J of Controlled Release, 1999, 59(1): 43-53.
[24] Gutman R L, Peacock G, Lu DR. Targeted drug delivery for brain cancer treatment. J of Controlled Release, 2000, 65(1): 31-41.
[25] Nagayasu A, Uchiyama K, Kiwada H. The size of liposomes: a factor which affects their targeting efficiency to tumor and therapeutic activity of liposomal antitumor drugs. Advanced Drug Delivery Reviews, 1999, 40 (1): 75-87.
[26] Shabbits JA, Chiu GN, Mayer LD. Development of an in vitro drug release assay that accurately predicts in vivo drug retention for liposome-based delivery system. J of Controlled Release, 2002, 65(1): 31-41.
[27] Torchilin VP. Drug Targeting. European Journal of Pharmaceutical Science 11, 2000, Suppl. 2: S81-S91.
[28] Qingshan Li, A. J. Pombeiro, F. A. Fatima. Diorganotin(IV) Derivatives of Substituted Benzohydroxamic Acids with High Antitumor Activity, Chem. Euro. J. 10 (2004) 1456-1462.
[29]郑俊民主编.经皮给药新剂型[M].人民卫生出版社,1997: 276-297.
[30] Qingshan Li, A. J. Pombeiro, F. A. Fatima. Diorganotin(IV) Derivatives of SubstitutedBenzohydroxamic Acids with High Antitumor Activity, Chem. Euro. J. 10 (2004) 1456-1462.
[31]王秀敏,邓英杰,赵春杰,等.β-榄香烯油水分配系数的测定[J].沈阳药科大学学报,2005,22(4): 289-320.
[32]丁平田等。中国医药工业杂志,1998:186-189.
[33]赵荣生,候新朴,严宝霞.两性霉素B脂质体的制备及稳定性研究[J].中国医药工业杂志, 2001,32(4): 160-163.
[34] Mequel Pons. Liposomes obtained by the ethanol injection method [J]. Int J Pharm 1993, 95: 51-56.
[35]陆斌.药物新剂型与新技术[M].北京:人民卫生出版社. 1998: 121-133.
[36]平其能等编著现代药剂学[M].中国医药科技出版社. 1998: 607-608.
[37] Madelmont CG, Lesieur S, Michel O. Characterization of loaded liposomes by size exclusion chromatography. J. Biochem. Biophys. Methods, 2003, 56 (1-3): 189-217.
[38]程建峰,扈本荃,刘梅等.甘草酸脂质体的处方及制备工艺[J].第四军医大学学报,2006, 27 (7): 655-657.
[39] Fomuso LB, Corredig M, Akog CC. Metal-Catalyzed oxidation of a structure lipid model emulsion. J. Agric. Food Chem. 2002, 50(24): 7114-7119.
[40] Tang D, Borchman D. Temperature induced structural changes of beta-crystalline and sphingomyelin binding. Exp. Eye Res. 1998, 67 (1): 113-118.
[41]平其能.现代药剂学[M]北京,中国医药科技出版社,1998: 608-609.
[42]陆斌.药物新剂型与新技术[M].北京:人民卫生出版社. 2002: 53-54.
[43]周莉玲,王岩,刘清飞等.青藤碱脂质体包封率的测定[J].中国中药学杂志,2006, 31(9):731-734.
[44]国家药典委员会.中华人民共和国药典(二部) [M].北京:化学工业出版社, 2005.附录54
[45]官东秀,冯祚臻,邓联芬,等.气象色谱法测定冬虫夏草多糖脂质体口服液中氯仿残留量[J].中国医院药学杂志, 2005, 25(2):144-145.8
[46]薛继雄,周晖.毛细管气相色谱法测定替米沙坦中的有机溶剂残留量[J].中国医院药学杂志, 2007, 26(3)358-360.
[47]徐叔云,卞如濂,陈修,药理实验方法学,第三版,北京;人民卫生出版社.2001:1758-1765.
[48]殷中琼,喻印,贾仁勇,郑艳,陈瑞.青刺果种粨粉对鸡免疫器官胸腺和脾脏的影响.动物营养学报. 2007, 19 (3): 25-25.
[49] Shah VP, Midha KK, Dighe Shrikant, et al. Analytical methods validation: Bioavalability,Bioequivalence and pharmacokinetic studies [J]. J Pharm Sci, 1982, 8 (3):309.
[50] AWASTHI V D,GARCIA D,GOINS,B A et a1. Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits[J]. International Journal of Pharmaceutics, 2003, 253(1-2): 121-132.
[51] GUILLAUME P,AMAURY H,SOPHIE C,et a1. Pharmacokinetics of DTPA entrapped in conventional and long-circulating liposomes of different size for plutonium decorporation[J]. Journal of Controlled Release, 2005, 110(1): 177-188.
[1] Gregoriadis G, Ryman B E. Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases[J].Biochem J, 1971, 124(5):58.
[2] Symon Z, Peyser A. Tzemach D, et al. Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes [J]. Cancer, 1999, 86(1):72-78.
[3] Schwonzen M, Kurbacher C M, Mallmann P. Liposomal doxorubicin and weekly paclitaxel in the treatment of metastatic breast cancer [J]. Anticancer Drugs, 2000, 11(9), 681-685.
[4] Ghesquières H, Faivre S, Djafari L, et al. PhaseⅠdose escalation study of pegylated liposomal doxorubicin (Caelyx) in combination with topotecan in patients with advanced malignancies [J]. Invest New Drugs, 2006, 24(6): 418-421.
[5] Shama A, Mayhew E, Bolicsak L, et al.Activity of paclitaxel liposome formulations against human ovarian tumor xenografts.Int J Cancer, 1997, 71:103- 107.
[6] Cabanes A, Briggs KE, Gokhale PC, et al.Comparative in vivostudies with paclitaxel and liposome encapsulated paclitaxel.Int J Oncol, 1998, 12:1035- 1040.
[7]陈强,张其忠,刘健,等,紫杉醇脂质体与传统紫杉醇治疗乳腺癌和非小细胞肺癌的随机对照研究.中华肿瘤杂志, 2003, 25 ( 2) : 190- 192.
[8]周卫,吕琦,翁帼英.紫杉醇脂质体在大鼠体内的药动学.中国药科大学学报, 2000, 31( 6) : 443- 446.
[9] Sun Dong-sheng, Chen Jiang-hao, Ling Rui, et al. Treatment of hepatoma with liposome-encapsulated adriamycin administered into hepatic artery of rats [J]. World J Gastro-Enterol, 2006, 12(29): 4741-4744.
[10]王小晨,王向伟,秦燕,等.长春新碱脂质体的药代动力学及其抗肿瘤作用[J].实验动物与比较医学, 2007 27(1): 15-19.
[11] Klibanov A L, Maruyama K, Torchilin V P, et al. Am-phipathic polyethylene glycols effectively prolong the circula-tion time of liposomes [J]. FEBS Lett, 1990, 268(1): 235-237.
[12] Torchilin V P, Omelyanenko V G, Papisov M I, et al. Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity [J]. Biochim Biophys Acta, 1994, 1195(1):11-20.
[13] Gabizon A A, Pegylated liposomal doxorubicin: metamor-phosis of an old drug into a new form of chemotherapy [J]. Cancer Invest, 2001, 19(4):424-436.
[14] Rosenthal DI, Yom SS, Liu L, et al. A phase I study of SPI-077 (Stealth liposomalcisplatin) concurrent with radiation therapy for locally advanced head and neck cancer [J]. Invest New Drugs, 2002, 20(3): 343-349.
[15] Working PK, Newman MS, Sullivan T, et al. Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in long-circulating, pegylated liposomes in cynomolgus monkeys [J]. Toxicol Sci, 1998, 46(1): 155-165.
[16] Iinuma H, Maruyama K, Okinaga K, et al. Intracellular targeting therapy of cisplatin-encapsulated transferrinpolyethylene glycol liposome on peritoneal dissemination ofgastric cancer[J]. Int J Cancer, 2002, 99(1): 130-137.
[17] Peleg - Shulman T,Gibson D,Cohen R,et al .Characterization of sterically stabilized cisplatin liposomes by nuclear magnetic resonance[J]. Biochim Biophys Acta, 2001, 1510(1-2):278-291.
[18]王杉,密捷波,李元宗,等.电感耦合等离子发射光谱法测定血清及组织中铂类药物[J].分析化学, 2003, 31(3): 287-291.
[19] Kale A, Torchilin V P. Enhanced transfection of tumor cells in v ivo using“Smart”pH -sensitive TAT-modified pegylated liposomes [J]. J Drug Target, 2007, 15 (7-8):538-545.
[20]苏东辉,沈鼎鸿,彭辉云等。上海免疫学杂志,1985:6(1):14。
[21]孟胜男,赵希贤,姜翠莲,等.大肠癌特异性卡莫氟免疫脂质体的体外抗癌活性研究[J ] .沈阳药科大学学报,2003 ,20 (5) :370-372.
[22] Pan X Q, ZHENG Xuan, SHI Guang-feng, et al. Strategy for t he t reatment of acute myelogenous leukemia based on folate receptorβ-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid [J] .Blood , 2002 , 100 (2) : 5942602.
[23]胡兰荣,齐晓峰,郑昌学等。生物化学杂志,1991, 7(3): 381.
[24] Hatakeyama H, Akita H , Maruyama K, et al . Factors governing the in vivo tissue uptake of transferring-coupled polyethylene glycol liposomes in vivo[J]. Int J Pharm, 2004, 281(1-2): 25-33.
[25] Iinuma H, Maruyama K, Okinaga K, et al. Int racellular targeting therapy of cisplatin-encapsulated transferring-polyethylene glycol liposome on peritoneal dissemination of gastric cancer [J] . Int J Cancer, 2002, 99 (1): 130-137.
[26]邹一愚,顾学裘,崛越勇。药学学报,1991,26(8): 622,
[27]邹一愚,顾学裘,崛越勇。药学学报,1991,27(9): 705.
[28]刘同刚,唐敏章,金发光.加温敏感阿霉素脂质体治疗小鼠荷Lewis肺癌[J] .第四军医大学学报,2003 ,24 (4) :335-337.
[29] Iga K, Hanmaguchi N, Igari Y et al. J Pharm Sci, 1991, 80(6): 522.
[30]刘启光,尹长城,沈子威等。生物化学与生物物理进展,1989,16(3):218.
[31] [31] Hong M S, Lim S J, Oh Y K, et al. pH-sensitive, serumstable and long-circulating liposomes as a new drug delivery system [J]. J Pharm Pharmacol, 2002, 54 (1): 51-58.
[32] Crowe.A.J, Smith.P.J, Atassi, G, Inorg. Chim.Acta. 1984(93):179.
[33] V. Narayanan, M.Nasr, K.P.Paull, et al. Tin-Based Antitumor Drugs. Berlin, Springer, Verlag. 1990, 201-206.
[34] A.J.Crowe. Antitumor activity of Tin Compounds.In: S. P. Fricker(Ed), Metal Compounds in Cancer Therapy. Chapman & Hall, London. 1994, 147-179.
[35] M. Gielen. Synthesis, Characterization and in-vitro Antitumor Activity of Dibutyltin Carboxylatrs Involving the Perfluorophenyl Moiety: Crystal Structure of the Dimetric Bis [(4-fluoro-and Pentafluoro-benzoato) di-n-butyltin]Oxides.Appl. Organoment. Chem.1995(9):639.
[36] Qingshan Li, A. J. Pombeiro, F. A. Fatima. Diorganotin(IV) Derivatives of Substituted Benzohydroxamic Acids with High Antitumor Activity, Chem. Euro. J. 10 (2004) 1456-1462.
[37] A.J.Crowe, P.J.Smith, and Ghanern Atassi, Investigations into the antitumour activity of organotin compounds. I. Diorganotin dihalide and di-pseudohalide complexes, Chem. Biol. Interact. 1980 (32): 171-178.
[38] Saxena A K, Huber F. Organotin Compounds and Cancer Chemotherapy.Coord. Chem.Rev. 1989, 95(1):109.
[39] Gielen M. Tin-Based Antitumor Drugs.Coord. Chem. Rev. 1996,151 (1):48.