佘振南,程晓波,邓意辉
SHE Zhen-nan,CHENG Xiao-bo,DENG Yi-hui(School of Pharmacy

• 1:沈阳药科大学药学院

摘要(Abstract)：

目的对胺(铵)离子梯度法载药的理论及条件选择进行综述。方法参阅近年来国内外文献共52篇,对胺(铵)离子梯度法的载药机制、理论模型、经验模型、药物性质、胺(铵)离子和反离子的选择等进行归纳、总结和分析。结果胺(铵)离子梯度法载药的动力主要来自于间接pH梯度、铵离子扩散电势以及内水相药物沉淀的生成;理论模型能够帮助研究者深刻理解载药机制,经验模型可直接指导载药参数的选择;药物性质、胺(铵)离子和反离子的种类均能影响药物的装载及释放。结论本文为胺(铵)离子梯度法载药的条件选择及相关制剂的开发提供了参考。
Objective To review the theories and protocols of the ammonium ion gradients for loading drugs into liposomes.Methods Drug loading mechanism,theoretical models,empirical models,drug properties,ammonium ion and the counterion of the ammonium ion gradients were summarized and analyzed on the basis of 52 published literatures.Results The driving forces of ammonium ion gradients for drug loading came from the indirect pH gradient,ammonium ion diffusion potential and generation of drug precipitation within the inner water phase of liposomes;the drug loading mechanism could be deeply understood with the help of theoretical model,and the parameters could be chosen guided by the empirical model;drug properties,ammonium ion and counterion could affect drug loading efficiency and release properties.Conclusions This article will provide references for the protocol construction of ammonium ion gradients and development of liposome formulations.

关键词(KeyWords)： 主动载药;胺(铵)离子梯度;反离子;脂质体
remote loading;ammonium ion gradient;counterion;liposome

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金资助项目(81072602)

作者(Author): 佘振南,程晓波,邓意辉
SHE Zhen-nan,CHENG Xiao-bo,DENG Yi-hui(School of Pharmacy

DOI: 10.14066/j.cnki.cn21-1349/r.2012.10.013

参考文献(References)：

• [1]BANGHAM A D,STANDISH M M,WATKINS J C.Diffusion of univalent ions across the lamellae of swol-len phospholipids[J].J Mol Biol,1965,13(1):238-252.
• [2]MAURER N,FENSKE D B,CULLIS P R.Develop-ments in liposomal drug delivery systems[J].ExpertOpin Biol Ther,2001,1(5):923-947.
• [3]GUBERNATOR J.Active methods of drug loading intoliposomes:recent strategies for stable drug entrapmentand increased in vivo activity[J].Expert Opinion onDrug Delivery,2011,8(5):565-580.
• [4]NICHOLS J W,DEAMER D W.Catecholamine uptakeand concentration by liposomes maintaining pH gradi-ents[J].Biochimica et Biophysica Acta(BBA)-Bi-omembranes,1976,455(1):269-271.
• [5]HARAN G,COHEN R,BAR L K,et al.Transmem-brane ammonium sulfate gradients in liposomes produceefficient and stable entrapment of amphipathic weak ba-ses[J].Biochim Biophys Acta,1993,1151(2):201-215.
• [6]FENSKE D B,WONG K F,MAURER E,et al.Ionophore-mediated uptake of ciprofloxacin and vin-cristine into large unilamellar vesicles exhibitingtransmembrane ion gradients[J].Biochimica etBiophysica Acta(BBA)-Biomembranes,1998,1414(1/2):188-204.
• [7]GABIZON A,SHIOTA R,PAPAHADJOPOULOS D.Pharmacokinetics and tissue distribution of doxorubicinencapsulated in stable liposomes with long circulationtimes[J].J Natl Cancer Inst,1989,81(19):1484-1488.
• [8]GABIZON A,CATANE R,UZIELY B,et al.A pilotstudy of doxorubicin encapsulated in long-circulating(StealthR)liposomes in cancer patients[J].Proc AmSoc Clin Oncol,1992,11:124.
• [9]BOLOTIN E M,COHEN R,BAR L K,et al.Ammoniumsulfate gradients for efficient and stable remote loadingof amphipathic weak bases into liposomes and ligando-liposomes[J].Journal of Liposome Research,1994,4(1):455-479.
• [10]陈涛,王昭,韩欢牛,等.离子梯度载药法制备脂质体药物的研究进展[J].世界最新医学信息文摘,2004,3(4):1204-1209.
• [11]FRITZE A,HENS F,KIMPFLER A,et al.Remoteloading of doxorubicin into liposomes driven by a trans-membrane phosphate gradient[J].Biochimica et Bio-physica Acta(BBA)-Biomembranes,2006,1758(10):1633-1640.
• [12]LASIC D D.Transmembrane gradient driven phasetransitions within vesicles:lessons for drug delivery*1[J].Biochimica et Biophysica Acta(BBA)-Biomem-branes,1995,1239(2):145-156.
• [13]LASIC D D,FREDERIK P M,STUART M C A,et al.Gelation of liposome interior A novel method for drugencapsulation[J].FEBS letters,1992,312(2/3):255-258.
• [14]CEH B,LASIC D D.A Rigorous theory of remote load-ing of drugs into liposomes[J].Langmuir,1995,11(9):3356-3368.
• [15]RAMSAY E,ALNAJIM J,ANANTHA M,et al.A novelapproach to prepare a liposomal irinotecan formulationsthat exhibit significant therapeutic activity in vivo[J].Proceedings of the American Association for CancerResearch,2004,2004(1):148.
• [16]DICKO A,TARDI P,XIE Xiao-wei,et al.Role of cop-per gluconate/triethanolamine in irinotecan encapsula-tion inside the liposomes[J].International Journal ofPharmaceutics,2007,337(1/2):219-228.
• [17]MAURER-SPUREJ E,WONG K F,MAURER N,et al.Factors influencing uptake and retention of amino-con-taining drugs in large unilamellar vesicles exhibitingtransmembrane pH gradients[J].Biochimica et Bio-physica Acta(BBA)-Biomembranes,1999,1416(1/2):1-10.
• [18]TU Sheng.Ammonium sulfate gradient loading of weak-ly basic amphiphilic small molecules[D].Madison,WI,United States:The University of Wisconsin-madi-son,2011:39-46.
• [19]TU Sheng,MCGINNIS T,KRUGNER-HIGBY L,et al.A mathematical relationship for hydromorphone loadinginto liposomes with transmembrane ammonium sulfategradients[J].Journal of Pharmaceutical Sciences,2010,99(6):2672-2680.
• [20]HARRIGAN P R,WONG K F,REDELMEIER T E,etal.Accumulation of doxorubicin and other lipophilic a-mines into large unilamellar vesicles in response totransmembrane pH gradients[J].Biochimica et Bio-physica Acta(BBA)-Biomembranes,1993,1149(2):329-338.
• [21]HUANG C,MASON J T.Geometric packing constraintsin egg phosphatidylcholine vesicles[J].Proc Natl AcadSci,1978,75:308-310.
• [22]CEH B,LASIC D D.A rigorous theory of remote load-ing of drugs into liposomes:transmembrane potentialand induced pH-gradient loading and leakage of lipo-somes[J].Journal of Colloid and Interface Science,1997,185(1):9-18.
• [23]ZUCKER D,MARCUS D,BARENHOLZ Y,et al.Lipo-some drugs'loading efficiency:A working model basedon loading conditions and drug's physicochemical prop-erties[J].Journal of Controlled Release,2009,139:73-80.
• [24]BARENHOLZ Y,COHEN R.Rational design of amphi-philebased drug carriers and sterically stabilized carri-ers[J].Journal of Liposome Research,1995,5(4):905-932.
• [25]ALLEN T M,NEWMAN M S,WOODLE M C,et al.Pharmacokinetics and anti-tumor activity of vincris-tine encapsulated in sterically stabilized liposomes[J].International Journal of Cancer,1995,62(2):199-204.
• [26]GUBERNATOR J,CHWASTEK G,KORYCINS-KA M,et al.The encapsulation of idarubicin withinliposomes using the novel EDTA ion gradient meth-od ensures improved drug retention in vitro and invivo[J].Journal of Controlled Release,2010,146(1):68-75.
• [27]HATTORI Y,SHI Li,DING Wu-xiao,et al.Novelirinotecan-loaded liposome using phytic acid withhigh therapeutic efficacy for colon tumors[J].Jour-nal of Controlled Release,2009,136(1):30-37.
• [28]DRUMMOND D C,NOBLE C O,GUO Z,et al.Development of a highly active nanoliposomal irinote-can using a novel intraliposomal stabilization strategy[J].Cancer Research,2006,66(6):3271.
• [29]LASIC D D,BARENHOLZA Y.Ammonium sulfate gra-dients for efficient and stable remote loading of am-phipathic weak bases into liposomes and ligandolipo-somes[J].Journal of Liposome Research,1994,4(1):455-479.
• [30]BOMAN N L,MASIN D,MAYER L D,et al.Liposomalvincristine which exhibits increased drug retention andincreased circulation longevity cures mice bearing P388tumors[J].Cancer Research,1994,54(11):2830.
• [31]NOBLE C O,GUO Z,HAYES M E,et al.Characteriza-tion of highly stable liposomal and immunoliposomalformulations of vincristine and vinblastine[J].CancerChemotherapy and Pharmacology,2009,64(4):741-751.
• [32]ZHIGALTSEV I V,MAURER N,EDWARDS K,et al.Formation of drug-arylsulfonate complexes inside lipo-somes:a novel approach to improve drug retention[J].Journal of Controlled Release,2006,110(2):378-386.
• [33]ABRAHAM S A,WATERHOUSE D N,MAYER L D,et al.The liposomal formulation of doxorubicin[J].Methods Enzymol,2005,391:71-97.
• [34]WASSERMAN V,KIZELSZTEIN P,GARBUZENKOO,et al.The antioxidant tempamine:In vitro antitumorand neuroprotective effects and optimization of liposom-al encapsulation and release[J].Langmuir,2007,23(4):1937-1947.
• [35]LI Xin-gong,HIRSH D J,CABRAL-LILLY D,et al.Doxorubicin physical state in solution and inside lipo-somes loaded via a pH gradient[J].Biochimica et Bio-physica Acta(BBA)-Biomembranes,1998,1415(1):23-40.
• [36]GALLOIS L,FIALLO M,GARNIER-SUILLEROT A.Comparison of the interaction of doxorubicin,daunoru-bicin,idarubicin and idarubicinol with large unilamel-lar vesicles:Circular dichroism study[J].Biochimicaet Biophysica Acta(BBA)-Biomembranes,1998,1370(1):31-40.
• [37]GALLOIS L,FIALLO M,LAIGLE A,et al.The Overallpartitioning of anthracyclines into phosphatidyl contai-ning model membranes depends neither on the drugcharge nor the presence of anionic phospholipids[J].European Journal of Biochemistry,1996,241(3):879-887.
• [38]DOS SANTOS N,WATERHOUSE D,MASIN D,et al.Substantial increases in idarubicin plasma concentra-tion by liposome encapsulation mediates improved anti-tumor activity[J].Journal of Controlled Release,2005,105(1/2):89-105.
• [39]LAVELLE F,BISSERY M C,ANDRE S,et al.Preclin-ical evaluation of CPT-11 and its active metabolite SN-38[J].Seminars in oncology,1996,23(1 Suppl 3):11-20.
• [40]KELLER J H,ENSMINGER W D.Stability of cancerchemotherapeutic agents in a totally implanted drug de-livery system[J].American Journal of Health-SystemPharmacy,1982,39(8):1321.
• [41]COHEN M H,JOHNSTON-EARLY A,HOOD M A,etal.Drug precipitation within iv tubing:a potential haz-ard of chemotherapy administration[J].Cancer Treat-ment Reports,1985,69(11):1325.
• [42]OTO E,VAAGE J,QUINN Y,et al.The effect of vin-cristine¨?polyanion complexes in STEALTH liposomeson pharmacokinetics,toxicity and anti tumor activity[J].Cancer Chemotherapy and Pharmacology,1996,39(1):138-142.
• [43]JOHNSTON M J W,SEMPLE S C,KLIMUK S K,etal.Therapeutically optimized rates of drug release canbe achieved by varying the drug-to-lipid ratio in liposo-mal vincristine formulations[J].Biochimica et Bio-physica Acta(BBA)-Biomembranes,2006,1758(1):55-64.
• [44]GABIZON A,BARENHOLZ Y.Method for drug load-ing in liposomes:US,20100247629A1[P].2010-09-30.
• [45]佘振南,翟文君,邓意辉.“加速血液清除”现象中的免疫机制分析[J].沈阳药科大学学报,2011,28(9):760-768.
• [46]MA Yan-ling,YANG Qiang,WANG Long,et al.Re-peated injections of PEGylated liposomal topotecan in-duces accelerated blood clearance phenomenon in rats[J].European Journal of Pharmaceutical Sciences,2012,45(5):539-545.
• [47]FINNEY J L,BOWRON D T.Anion bridges and saltingout[J].Current Opinion in Colloid&Interface Sci-ence,2004,9(1/2):59-63.
• [48]ZHANG Yan-jie,CREMER P S.Interactions betweenmacromolecules and ions:the Hofmeister series[J].Current Opinion in Chemical Biology,2006,10(6):658-663.
• [49]HOLZ M,GRUNDER R,SACCO A,et al.Nuclearmagnetic resonance study of self-association of smallhydrophobic solutes in water:salt effects and the lyo-tropic series[J].Journal of the Chemical Society,Fara-day Transactions,1993,89(8):1215-1222.
• [50]BOWRON D T,FINNEY J L.Structure of a salt-amphi-phile-water solution and the mechanism of salting out[J].The Journal of Chemical Physics,2003,118:8357.
• [51]LI Xin-gong,HIRSH D J,CABRAL-LILLY D,et al.Doxorubicin physical state in solution and inside lipo-somes loaded via a pH gradient[J].Biochim BiophysActa,1998,1415(1):23-40.
• [52]MUI B L,CULLIS P R,PRITCHARD P H,et al.Influ-ence of plasma on the osmotic sensitivity of large unila-mellar vesicles prepared by extrusion[J].Journal ofBiological Chemistry,1994,269(10):7364.