PAMAM树状大分子负载和释放阿霉素的耗散粒子动力学模拟
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摘要
采用耗散粒子动力学模拟方法研究了药物输送载体聚酰胺-胺(PAMAM)树状大分子对抗癌药物阿霉素(DOX)的负载和释放行为。构建了PAMAM树状大分子的粗粒化模型,该模型能准确地重现树状大分子的构象性质。考察了PAMAM树状大分子代数(G)对DOX负载以及pH环境对DOX释放的影响。模拟结果表明,PAMAM树状大分子主要通过疏水作用将DOX包封于内部空腔,G6和G7 PAMAM树状大分子的负载能力较强,因为其孔隙率较高,内部有更多的疏水空腔。在低pH环境下,PAMAM树状大分子结构发生变化,DOX分子能快速地从其中释放,主要原因是PAMAM的伯胺、叔胺和DOX伯胺发生质子化,质子化基团间的静电排斥作用使得PAMAM树状大分子发生溶胀,导致其内部空腔暴露,促进了DOX的释放。本工作可以为基于树状大分子的药物输送体系的设计和优化提供参考。
Dissipative particle dynamics(DPD) simulations were employed to study the loading and release behaviors of anticancer drug doxorubicin(DOX) by drug delivery carrier polyamidoamine(PAMAM) dendrimers. A coarse-grained(CG) model for PAMAM dendrimers was first constructed, which reproduced the conformational properties of PAMAM dendrimers accurately. The effects of PAMAM dendrimer generation(G) on DOX loading and the environment pH on DOX release were investigated. Simulation results showed that PAMAM dendrimers mainly encapsulated DOX into their interior cavities through hydrophobic interaction. The encapsulation capacity of G6 and G7 PAMAM dendrimers were much better than PAMAM of lower generations, because there were more hydrophobic cavities inside G6 or G7 dendrimers for their high porosity. At low pH, PAMAM dendrimers underwent conformational changes, thus DOX molecule escaped from dendrimers quickly. Such phenomena are mainly caused by the protonation of primary amines and tertiary amines in PAMAM dendrimers and primary amines in DOX. The electrostatic repulsion between these charged groups will lead PAMAM dendrimers swelling immensely and the inner cavities being exposed, which promotes the release of DOX molecules. This work could provide useful guidance for the design and optimization of dendrimer-based drug delivery systems.
Dissipative particle dynamics(DPD) simulations were employed to study the loading and release behaviors of anticancer drug doxorubicin(DOX) by drug delivery carrier polyamidoamine(PAMAM) dendrimers. A coarse-grained(CG) model for PAMAM dendrimers was first constructed, which reproduced the conformational properties of PAMAM dendrimers accurately. The effects of PAMAM dendrimer generation(G) on DOX loading and the environment pH on DOX release were investigated. Simulation results showed that PAMAM dendrimers mainly encapsulated DOX into their interior cavities through hydrophobic interaction. The encapsulation capacity of G6 and G7 PAMAM dendrimers were much better than PAMAM of lower generations, because there were more hydrophobic cavities inside G6 or G7 dendrimers for their high porosity. At low pH, PAMAM dendrimers underwent conformational changes, thus DOX molecule escaped from dendrimers quickly. Such phenomena are mainly caused by the protonation of primary amines and tertiary amines in PAMAM dendrimers and primary amines in DOX. The electrostatic repulsion between these charged groups will lead PAMAM dendrimers swelling immensely and the inner cavities being exposed, which promotes the release of DOX molecules. This work could provide useful guidance for the design and optimization of dendrimer-based drug delivery systems.
引文
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[25]LIN S T,MAITI P K,GODDARD W A.Dynamics and thermodynamics of water in PAMAM dendrimers at subnanosecond time scales[J].J.Phys.Chem.B,2005,109(18):8663-8672.
[26]WEN X F,LAN J L,CAI Z Q,et al.Dissipative particle dynamics simulation on drug loading/release in polyester-PEG dendrimer[J].J.Nanopart.Res.,2014,16(5):2403.
[27]GROOT R D,MADDEN T J.Dynamic simulation of diblock copolymer microphase separation[J].J.Chem.Phys.,1998,108(20):8713-8724.
[28]GROOT R D,RABONE K L.Mesoscopic simulation of cell membrane damage,morphology change and rupture by nonionic surfactants[J].Biophys.J.,2001,81(2):725-736.
[29]SEATON M A,ANDERSON R L,METZ S,et al.DL_MESO:highly scalable mesoscale simulations[J].Molecular Simulation,2013,39(10):796-821.
[30]RATHGEBER S,MONKENBUSCH M,KREITSCHMANN M,et al.Dynamics of star-burst dendrimers in solution in relation to their structural properties[J].J.Chem.Phys.,2002,117(8):4047-4062.
[31]MAITI P K,MESSINA R.Counterion distribution andζ-potential in PAMAM dendrimer[J].Macromolecules,2008,41(13):5002-5006.
[32]MAITI P K,CAGIN T,WANG G F,et al.Structure of PAMAM dendrimers:?generations 1 through 11[J].Macromolecules,2004,37(16):6236-6254.
[33]VOSS N R,GERSTEIN M,STEITZ T A,et al.The geometry of the ribosomal polypeptide exit tunnel[J].J.Mol.Biol.,2006,360(4):893-906.
[2]TOMALIA D A,BAKER H,DEWALD J,et al.A new class of polymers:starburst-dendritic macromolecules[J].Polym.J.,1985,17(1):117-132.
[3]WU P,FELDMAN A K,NUGENT A K,et al.Efficiency and fidelity in a click-chemistry route to triazole dendrimers by the copper(Ⅰ)-catalyzed ligation of azides and alkynes[J].Angew.Chem.Int.Ed.,2004,43(30):3928-3932.
[4]CARNAHAN M A,GRINSTAFF M W.Synthesis of generational polyester dendrimers derived from glycerol and succinic or adipic acid[J].Macromolecules,2006,39(2):609-616.
[5]ZHONG T P,AI P F,ZHOU J.Structures and properties of PAMAM dendrimer:a multi-scale simulation study[J].Fluid Phase Equilib.,2011,302(1/2):43-47.
[6]GILLIES E R,FRéCHET J M J.Dendrimers and dendritic polymers in drug delivery[J].Drug Discovery Today,2005,10(1):35-43.
[7]GUPTA U,AGASHE H B,ASTHANA A,et al.Dendrimers:?novel polymeric nanoarchitectures for solubility enhancement[J].Biomacromolecules,2006,7(3):649-658.
[8]CHENG Y Y,WANG J R,RAO T L,et al.Pharmaceutical applications of dendrimers:promising nanocarriers for drug delivery[J].Frontiers in Bioscience-Landmark,2008,13:1447-1471.
[9]YELLEPEDDI V K,VANGARA K K,PALAKURTHI S.Poly(amido)amine(PAMAM)dendrimer-cisplatin complexes for chemotherapy of cisplatin-resistant ovarian cancer cells[J].J.Nanopart.Res.,2013,15(9):1-15.
[10]OOYA T,LEE J,PARK K.Hydrotropic dendrimers of generations 4and 5:?synthesis,characterization,and hydrotropic solubilization of paclitaxel[J].Bioconjugate Chem.,2004,15(6):1221-1229.
[11]MARKATOU E,GIONIS V,CHRYSSIKOS G D,et al.Molecular interactions between dimethoxycurcumin and Pamam dendrimer carriers[J].International Journal of Pharmaceutics,2007,339(1/2):231-236.
[12]KOJIMA C,KONO K,MARUYAMA K,et al.Synthesis of polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugs[J].Bioconjugate Chem.,2000,11(6):910-917.
[13]BHADRA D,BHADRA S,JAIN S,et al.A PEGylated dendritic nanoparticulate carrier of fluorouracil[J].International Journal of Pharmaceutics,2003,257(1/2):111-124.
[14]TANIS I,KARATASOS K.Association of a weakly acidic anti-inflammatory drug(ibuprofen)with a poly(amidoamine)dendrimer as studied by molecular dynamics simulations[J].J.Phys.Chem.B,2009,113(31):10984-10993.
[15]SHI X,LEE I,CHEN X,et al.Influence of dendrimer surface charge on the bioactivity of 2-methoxyestradiol complexed with dendrimers[J].Soft Matter,2010,6(11):2539-2545.
[16]ABDERREZAK A,BOURASSA P,MANDEVILLE J-S,et al.Dendrimers bind antioxidant polyphenols and cis-platin drug[J].PLo S ONE,2012,7(3):e33102.
[17]MAINGI V,KUMAR M V S,MAITI P K.PAMAM dendrimer-drug interactions:effect of p H on the binding and release pattern[J].J.Phys.Chem.B,2012,116(14):4370-4376.
[18]HOOGERBRUGGE P J,KOELMAN J M V A.Simulating microscopic hydrodynamic phenomena with dissipative particle dynamics[J].Europhys.Lett.,1992,19(3):155-160.
[19]郭泓雨,崔洁铭,孙德林,等.温敏性两亲嵌段共聚物相行为的耗散粒子动力学模拟[J].化工学报,2012,63(11):3707-3715.GUO H Y,CUI J M,SUN D L,et al.Dissipative particle dynamics simulation on phase behavior of thermo-responsive amphiphilic copolymer PCL-PNIPAM-PCL[J].CIESC Journal,2012,63(11):3707-3715.
[20]孙德林,周健.耗散粒子动力学模拟Nafion膜和PVA/Nafion共混膜的介观结构[J].物理化学学报,2012,28(4):909-916.SUN D L,ZHOU J.Dissipative particle dynamics simulations on mesoscopic structures of Nafion and PVA/Nafion blend membranes[J].Acta Physica-Chimica Sinica,2012,28(14):909-916.
[21]刘红艳,郭泓雨,周健.PLGA-PEG共聚物负载多西紫杉醇的药物输运体系的计算机模拟[J].化学学报,2012,70(23):2445-2450.LIU H Y,GUO H Y,ZHOU J.Computer simulations on the anticancer drug delivery system of docetaxel and PLGA-PEG copolymer[J].Acta Chimica Sinica,2012,70(23):2445-2450.
[22]GROOT R D,WARREN P B.Dissipative particle dynamics:bridging the gap between atomistic and mesoscopic simulation[J].J.Chem.Phys.,1997,107(11):4423-4435.
[23]GROOT R D.Electrostatic interactions in dissipative particle dynamics-simulation of polyelectrolytes and anionic surfactants[J].J.Chem.Phys.,2003,118(24):11265-11277.
[24]GONZ LEZ-MELCHOR M,MAYORAL E,VEL ZQUEZ M E,et al.Electrostatic interactions in dissipative particle dynamics using the Ewald sums[J].J.Chem.Phys.,2006,125(22):224107.
[25]LIN S T,MAITI P K,GODDARD W A.Dynamics and thermodynamics of water in PAMAM dendrimers at subnanosecond time scales[J].J.Phys.Chem.B,2005,109(18):8663-8672.
[26]WEN X F,LAN J L,CAI Z Q,et al.Dissipative particle dynamics simulation on drug loading/release in polyester-PEG dendrimer[J].J.Nanopart.Res.,2014,16(5):2403.
[27]GROOT R D,MADDEN T J.Dynamic simulation of diblock copolymer microphase separation[J].J.Chem.Phys.,1998,108(20):8713-8724.
[28]GROOT R D,RABONE K L.Mesoscopic simulation of cell membrane damage,morphology change and rupture by nonionic surfactants[J].Biophys.J.,2001,81(2):725-736.
[29]SEATON M A,ANDERSON R L,METZ S,et al.DL_MESO:highly scalable mesoscale simulations[J].Molecular Simulation,2013,39(10):796-821.
[30]RATHGEBER S,MONKENBUSCH M,KREITSCHMANN M,et al.Dynamics of star-burst dendrimers in solution in relation to their structural properties[J].J.Chem.Phys.,2002,117(8):4047-4062.
[31]MAITI P K,MESSINA R.Counterion distribution andζ-potential in PAMAM dendrimer[J].Macromolecules,2008,41(13):5002-5006.
[32]MAITI P K,CAGIN T,WANG G F,et al.Structure of PAMAM dendrimers:?generations 1 through 11[J].Macromolecules,2004,37(16):6236-6254.
[33]VOSS N R,GERSTEIN M,STEITZ T A,et al.The geometry of the ribosomal polypeptide exit tunnel[J].J.Mol.Biol.,2006,360(4):893-906.