Pluronic和PEG胆甾醇酯与磷脂单分子膜的相互作用的研究
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摘要
两亲共聚物结构上的特点为亲油部分和亲水部分不相容,易发生微相分离,因此表现出独特的表面性质,如两亲共聚物的亲油端或亲水端易发生表面富集等现象。
水溶性的聚氧乙烯—聚氧丙烯—聚氧乙烯嵌段共聚物(PEO-PPO-PEO)是一类重要的非离子型高分子表面活性剂,商品名为Pluronic,近年来,共聚物作为药物载体引起了人们广泛的重视。
本文利用Langmuir单分子膜法,从单层膜的角度来研究磷脂与Pluronic以及nPEG胆甾醇酯之间的相互作用。采用混合单分子膜和吸附单分子膜两种方法,通过热力学分析来阐述全二者的相互作用,得到如下结论：
1.研究了磷脂分子和胆固醇分子之间的相互作用,模拟天然脂质体双分子层中的一半空间,利用混合单分子膜的p～A曲线,并结合计算得到的过剩自由能,从热力学角度证明了两者的混溶性,说明在混合膜中,胆固醇增加了磷脂的流动性。
2.研究了一系列Pluronic的表面性质。表明在低的表面覆盖时,单分子膜的物理性质主要由PEO链决定,在高表面压时,单分子膜的物理性质主要由PPO链决定。
3.研究了Pluronic和磷脂分子间的相互作用。从混合铺展膜得出,PPO链越长,同磷脂分子之间的作用越大；PEO链越长,在高表面压时,同亚相水之间的作用就越大。吸附过程的研究表明,具有较高疏水性能的Pluronic表现出较高的渗透能力。
4.合成了mPEG胆甾醇酯,并对其进行表面性质的研究。同样采用混合铺展膜和吸附膜两种方法,研究了该产物和磷脂分子之间的相互作用。通过混合单分子膜的研究得到PEG链越长,与磷脂分子之间的作用力越强。而较长的PEG链反而影响了mPEG-chol在磷脂单分子膜中的吸附过程。
Amphiphilic copolymer possesses much particular specificity due to its special structures with hydrophilic and hydrophibic groups.
Aqueous amphiphilic copolymer PEO-PPO-PEO, commercially known as Pluronci, is a kind of important nonionic surfactant. Now Pluronic is extensively being studied as drug carrier because its amphiphilic characteristics can be tuned by changing the molecular architecture to meet specific application needs.
In this paper Langmuir Balance is used to study the interactions between phospholipid and Pluronic or synthesized mPEG ester. In order to systematically understand the interactions, the mixed monolayers and the absorbed monolayers were employed.
First, for simulating the half biomembrane, cholesterol/phospholipid mixed monolayers were studied. The mixed thermodynamics parameters, excess molecular area and excess Gibbs free energy were caculated from the p～A isotherms. The results show that phospholipid and cholesterol are miscible and cholesterol can increase the fluidity of phospholipid membrane.
Secondly, the interficial properties of Pluronics L61, L62, L64, F68, F108, L101, F127 and F88 were studied. The p-A isotherms indicate that, the physical properties of the films is mainly determined by the PEO chains at low cover density while PPO chains make the conformations and determine the monolayer properties at high surface pressure.
Thirdly, the inteactions between Pluronic and phospholipid were studied. By analysing the different mixed spreading monolayers, the conclusion we can be drawn that the longer the PPO chains of Pluronic, the stronger its interations with phospholipid. With the increase of the PEO chains, the interactions of Pluronic with subphase also increase at high surface pressure. The investigation of the phospholipid monolayers absorbed by Pluronics suggested that, Pluronics with higher hydrophbolicity manifested higher penetration ability to phospholipid monolayers.
Finnaly, three kinds of mPEG cholesterol esters with different molecular weight were synthesized and characterized. Their surfacial properties and the interactions between them and phospholipid were also studied by Langmuir Balance. It was found that the longer the PEG chains, the stronger interactions of mPEG cholesterol esters with phospholipids in the mPEG cholesterol esters/phospholipid mixed monolayers. But in the adsorption process, the long PEG chains may prevent the interactions of mPEG cholesterol esters with phospholipid.
水溶性的聚氧乙烯—聚氧丙烯—聚氧乙烯嵌段共聚物(PEO-PPO-PEO)是一类重要的非离子型高分子表面活性剂,商品名为Pluronic,近年来,共聚物作为药物载体引起了人们广泛的重视。
本文利用Langmuir单分子膜法,从单层膜的角度来研究磷脂与Pluronic以及nPEG胆甾醇酯之间的相互作用。采用混合单分子膜和吸附单分子膜两种方法,通过热力学分析来阐述全二者的相互作用,得到如下结论：
1.研究了磷脂分子和胆固醇分子之间的相互作用,模拟天然脂质体双分子层中的一半空间,利用混合单分子膜的p～A曲线,并结合计算得到的过剩自由能,从热力学角度证明了两者的混溶性,说明在混合膜中,胆固醇增加了磷脂的流动性。
2.研究了一系列Pluronic的表面性质。表明在低的表面覆盖时,单分子膜的物理性质主要由PEO链决定,在高表面压时,单分子膜的物理性质主要由PPO链决定。
3.研究了Pluronic和磷脂分子间的相互作用。从混合铺展膜得出,PPO链越长,同磷脂分子之间的作用越大；PEO链越长,在高表面压时,同亚相水之间的作用就越大。吸附过程的研究表明,具有较高疏水性能的Pluronic表现出较高的渗透能力。
4.合成了mPEG胆甾醇酯,并对其进行表面性质的研究。同样采用混合铺展膜和吸附膜两种方法,研究了该产物和磷脂分子之间的相互作用。通过混合单分子膜的研究得到PEG链越长,与磷脂分子之间的作用力越强。而较长的PEG链反而影响了mPEG-chol在磷脂单分子膜中的吸附过程。
Amphiphilic copolymer possesses much particular specificity due to its special structures with hydrophilic and hydrophibic groups.
Aqueous amphiphilic copolymer PEO-PPO-PEO, commercially known as Pluronci, is a kind of important nonionic surfactant. Now Pluronic is extensively being studied as drug carrier because its amphiphilic characteristics can be tuned by changing the molecular architecture to meet specific application needs.
In this paper Langmuir Balance is used to study the interactions between phospholipid and Pluronic or synthesized mPEG ester. In order to systematically understand the interactions, the mixed monolayers and the absorbed monolayers were employed.
First, for simulating the half biomembrane, cholesterol/phospholipid mixed monolayers were studied. The mixed thermodynamics parameters, excess molecular area and excess Gibbs free energy were caculated from the p～A isotherms. The results show that phospholipid and cholesterol are miscible and cholesterol can increase the fluidity of phospholipid membrane.
Secondly, the interficial properties of Pluronics L61, L62, L64, F68, F108, L101, F127 and F88 were studied. The p-A isotherms indicate that, the physical properties of the films is mainly determined by the PEO chains at low cover density while PPO chains make the conformations and determine the monolayer properties at high surface pressure.
Thirdly, the inteactions between Pluronic and phospholipid were studied. By analysing the different mixed spreading monolayers, the conclusion we can be drawn that the longer the PPO chains of Pluronic, the stronger its interations with phospholipid. With the increase of the PEO chains, the interactions of Pluronic with subphase also increase at high surface pressure. The investigation of the phospholipid monolayers absorbed by Pluronics suggested that, Pluronics with higher hydrophbolicity manifested higher penetration ability to phospholipid monolayers.
Finnaly, three kinds of mPEG cholesterol esters with different molecular weight were synthesized and characterized. Their surfacial properties and the interactions between them and phospholipid were also studied by Langmuir Balance. It was found that the longer the PEG chains, the stronger interactions of mPEG cholesterol esters with phospholipids in the mPEG cholesterol esters/phospholipid mixed monolayers. But in the adsorption process, the long PEG chains may prevent the interactions of mPEG cholesterol esters with phospholipid.
引文
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[2]Blodgett K B.Films built by depositing successive monomolecular layers on a solid surface [J]. J.Am.Chem.Soc.1935,57:10073～10079
[3]Blodgett K B. Built-Up Films of Barium Stearate and Their Optical Properties [J].Phys. Rev.B, 1937,51:964～970.
[4]隋森方,吴桦,王少鹏.LB膜天平[J].实验技术与管理,1991,8(5)：28-31.
[5]朱杰,孙润广.原子力显微镜的基本原理及其方法研究[J].生命科学仪器,2005,3(1)：22-26.
[6]Allen C., Maysinger D., Eisenberg A. Nano-engineering block copolymers aggregates for drug delivery[J]. Colloids Surf B,1999,16(1-4):3-27.
[7]Alexandridis, P.; Athanassiou, V.; Fukuda, S.; Hatton, T. A., Surface Activity of Poly(ethylene oxide)-block-Poly(propylene oxide)-block-Poly(ethylene oxide) Copolymers[J]. Langmuir 1994,10,2604-2612.
[8]Mu, Q. S., Lu, J. R., Ma, Y. H., Paz de Banez, M. V., Robinson, K. L., Armes, S. P., Lewis, A. L.Thomas, R. K. Neutron Reflection Study of a Water-Soluble Biocompatible Diblock Copolymer Adsorbed at the Air/Water Interface:The Effects of pH and Polymer Concentration[J]. Langmuir2006,22,6153-6160.
[9]Sauer, B. B.; Yu, H.; Yazdanian, M.; Zografi, G.; Kim, M. W., An ellipsometric study of polymer monolayers at the air/water interface[J]. Macromolecules 1989,22, (5),2332-2337.
[10]Bingbing Li, Yitian Wu, Minghua Liu, and Alan R. Esker. Brester Angle Microscopy Study of Poly(ε-caprolactone) Crystal Growth in Langmiur Film at the Air/water Interface[J]. Langmuir,2006,22(11),4902-4905.
[11]Millicent A. Firestone, Amanda C.Wolf, and Sonke Seifert. Small Angle X-ray Scattering Study of the Interaction of Poly(ethylene oxide)-b-Poly(propylene oxide)-b-poly(ethlyene oxide) Triblock Copolyerms with Lipid Bilayers[J]. Biomaromolecules 2003,4,1539-1549.
[12]Sergiy Peleshanko, Kyle D.Anerson, Matthew Goodman, Michael D.Determan. Thermoresponsive Reversible Behavior of Multistimuli Pluronic-Based Pentablock Copolymer at the Air/water interface[J]. Langmuir 2007,23,25-30.
[13]Franck Pe'triat, Emmanuelle Roux, Jean Christophe Leroux, and Suzanne Giasson Study of
Molecular Interactions between a Phospholipidic Layer and a pH-Sensitive Polymer Using the Langmuir Balance Technique[J]. Langmuir 2004,20,1393-1400
[14]Alexander Wittemann, Tony Azzam, and Adi Eisenberg. Biocompatible Polymer Vesicles from Biamphiphilic Triblock Copolymers and Their Interaction with Bovine Serum Albumin[J]. Langmuir 2007,23,2224-2230
[15]Millicent A. Firestone and Sonke Seifert. Interaction of Nonionic PEO-PPO DiblockCopolymers with Lipid Bilayers[J].Biomacromolecules 2005,6,2678-2687
[16]S.M.Baker, K.A.Leach, C.E.Devereaux, and D.E.Gragson. Controlled patterning of diblock copolymers by monolayer langmuir-blodgett deposition[J]. Marcomolecules 2000,33, 5432-5436.
[17]de Gennes, P. G. Conformations of Polymers Attached to an Interface[J]. Macromolecules 1980,13, (5),1069-1075.
[18]Daniel J.Kuzmenka, and Sterve Granick. Collapse of polymer(ethylene oxide) monolayers[J]. Macromolecules,1998,21(3),779-782.
[19]M.Guzman,F.F.Garcia,J.Molpeceres and M.R.Aberturans, Polyoxyethylene-polyoxypropylene block copolymer gels as sustained release vehicles for subcutaneous drug administration[J]. International Journal of Pharmaceutics.1992,80,119-127.
[20]E. Gorter and F. Grendel. Arranged in a bimolecular leaflet. J. Expt. Med.1925,41439.
[21]A.V.Kaabanov, E.V.Batrakova, N.S.Melik- Nubarov, N.A.Fedoseev, T.Yu. Dorodnich, V.Yu. Alakbov, V.P.Chekhonin, I.R.Nazalova. A new class of drug carriers:micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microcontainers for drug targeting from blood in brain [J].Controlled Release,1992,22,141.
[22]Fang K,Zou, He P S,et al. Thermodynamic characterization of mixed monolayers of phosphatidylcholine and arachidic acid on different subphases [J]. Collids Surf A,2003, 224:53
[23]Davies J T, Rideal F K. Magnetic Resonance at High Pressure. New York:Academics Press, 1963,265
[24]王少鹏,隋森方.磷脂与胆固醇混合单分子层(LB膜)结构性质的研究.生物物理学报,1991(7)3.
[25]Chang, L.-C., Lin, C.-Y, Kuo, M.-W.; Gau, C.-S. Interactions of Pluronics with phospholipid monolayers at the air-water interface[J]. Journal of Colloid and Interface Science 2005,285, (2),640-652.
[26]A. Chonn, P.R. Cullis. Recent advances in liposomal drug-delivery systems. Current Opinion in Biotechnology.6,698-708.1995.
[27]Alexandridis, P.; Athanassiou, V.; Fukuda, S.; Hatton, T. A., Surface Activity of Poly(ethylene oxide)-block-Poly(propylene oxide)-block-Poly(ethylene oxide) Copolymers[J]. Langmuir 1994,10, (8),2604-2612.
[28]Nolan B.Holland, Z. X., Katanchalee Vacheethasanee, and Roger E.Marchant, Structuare of Poly(ehtylene oxide) Surfactant Polymers at Air-Water and Solid-Water Interfaces[J]. Macromolecules 2001,34,6424-6430.
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