还原敏感性界面交联的可降解聚合物胶束用于阿霉素的释放
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摘要
本论文设计、制备了还原敏感可逆交联的生物可降解的聚合物胶束。通过在聚乙二醇(PEG)和聚己内酯(PCL)之间引入可交联的基团,硫辛酸,在少量DTT的催化下,可在形成的胶束的界面发生交联,得到稳定的胶束,但在模拟体内还原环境中它很快解离,引起药物的触发释放。
(1)通过PEG-SH和PCL-丙烯酸酯的迈克尔加成反应,合成了中间含有DTT的PEG-DTT-PCL。然后,酯化反应把硫辛酸接到DTT的两个羟基上,从而得到在PEG和PCL界面上有两个硫辛酸功能团的嵌段聚合物PEG-L2-PCL。核磁氢谱和凝胶色谱测试显示PEG-L2-PCL嵌段聚合物具有可控的组成且聚合物分子量分布为1.36.在水溶液中PEG-L2-PCL形成胶束的粒径在20 -150 nm之间,临界胶束浓度为16 mg/L。加入硫辛酸官能团7.6%的DTT后,稀释、加入生理浓度盐和有机溶剂聚合物胶束仍然很稳定,但当加入10mM DTT后,聚合物胶束很快解交联。在体外释放研究显示,交联后胶束10h阿霉素仅释放了15%,未交联胶束在0.5h内释放了约80%,交联胶束在加入10mM DTT后,9h释放了75%.
(2)通过序贯RAFT聚合反应,合成了中间含有寡聚HEMA的三嵌段共聚物聚乙二醇(PEG)-P(HEMA)-P(HEMA-g-PLA)。然后,用同样的酯化反应把硫辛酸接到中间PHEMA链段上得到不同取代度的聚合物PEG-PHEMA-Lx-(PHEMA-g-PLA)。通过改变中间链段PHEMA上硫辛酸的取代度,研究了改变交联程度对胶束稳定性的影响。核磁氢谱和凝胶色谱测试显示PEG-PHEMA-Lx-(PHEMA-g-PLA)嵌段聚合物具有可控的组成且聚合物分子量分布较窄。在水溶液中PEG-PHEMA-Lx-(PHEMA-g-PLA)形成胶束的粒径在50 -150 nm之间,加入硫辛酸官能团10%的DTT后,稀释和有机溶剂后交联聚合物胶束仍然很稳定,但当加入10mM DTT后,聚合物胶束3h内解交联。
In this thesis, the reduction-sensitive reversibly interfacial crosslinked micelle was prepared. By introducing crosslinkably groups, lipoic acid, in between the biodegradable biocompatible PEG-PCL, the micelles can be reversibly crosslinked in the interface of the micelles as catalyzed by DTT. Thus crosslinked micelles demonstrated markedly enhanced stability, while they dissociated in mimicking intracellular reductive environment.
(1) In the first part, the block polymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) containing two lipoyl functional groups at their interface (PEG-L2-PCL) was synthesized. 1H NMR and gel permeation chromatography (GPC) measurements shows that PEG-L2-PCL block copolymer had a controlled composition and a polydispersity index (PDI) of 1.36. PEG-L2-PCL formed micelles with sizes ranging from 20 to 150 nm in aqueous solutions, wherein a critical micelle concentration (CMC) of 16 mg/L was determined. The micelles were readily crosslinked by adding 7.6 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution, physiological salt concentration and organic solvent. In the presence of 10 mM DTT, however, micelles were subject to rapid de-crosslinking. In vitro release studies showed minimal release of DOX from crosslinked micelles at a concentration of 10 mg/L (C < CMC), wherein less than 15 % DOX was released in 10 h. In contrast, rapid release of DOX was observed for DOX-loaded non-crosslinked micelles under otherwise the same conditions (ca. 80 % release in 0.5 h). In the presence of 10 mM DTT mimicking intracellular reductive environment, sustained release of DOX from crosslinked micelles was achieved, in which 75 % DOX was released in 9 h.
(2) In the second part, the block polymer of poly(ethylene glycol)-poly(2-Hydroxyethyl methacrylate)-poly(2-Hydroxyethyl methacrylate- g - polylactide) (PEG-PHEMA-P(HEMA-g-PLA)11 containing two lipoyl functional groups on the side chain (PEG-PHEMA-Lx-P(HEMA-g-PLA)11) was synthesized. 1H NMR and GPC measurements showed that PEG-PHEMA-P(HEMA-g-PLA) block copolymer had a controlled composition and a polydispersity index (PDI) of 1.12. PEG-PHEMA-Lx-P(HEMA-g-PLA)11 formed micelles with sizes ranging from 50 to 150 nm in aqueous solutions. The micelles were readily crosslinked by adding 10 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution and organic solvent. In the presence of 10 mM DTT mimicking intracellular reductive environment, the micelles de- crosslinked in 3h.
(1)通过PEG-SH和PCL-丙烯酸酯的迈克尔加成反应,合成了中间含有DTT的PEG-DTT-PCL。然后,酯化反应把硫辛酸接到DTT的两个羟基上,从而得到在PEG和PCL界面上有两个硫辛酸功能团的嵌段聚合物PEG-L2-PCL。核磁氢谱和凝胶色谱测试显示PEG-L2-PCL嵌段聚合物具有可控的组成且聚合物分子量分布为1.36.在水溶液中PEG-L2-PCL形成胶束的粒径在20 -150 nm之间,临界胶束浓度为16 mg/L。加入硫辛酸官能团7.6%的DTT后,稀释、加入生理浓度盐和有机溶剂聚合物胶束仍然很稳定,但当加入10mM DTT后,聚合物胶束很快解交联。在体外释放研究显示,交联后胶束10h阿霉素仅释放了15%,未交联胶束在0.5h内释放了约80%,交联胶束在加入10mM DTT后,9h释放了75%.
(2)通过序贯RAFT聚合反应,合成了中间含有寡聚HEMA的三嵌段共聚物聚乙二醇(PEG)-P(HEMA)-P(HEMA-g-PLA)。然后,用同样的酯化反应把硫辛酸接到中间PHEMA链段上得到不同取代度的聚合物PEG-PHEMA-Lx-(PHEMA-g-PLA)。通过改变中间链段PHEMA上硫辛酸的取代度,研究了改变交联程度对胶束稳定性的影响。核磁氢谱和凝胶色谱测试显示PEG-PHEMA-Lx-(PHEMA-g-PLA)嵌段聚合物具有可控的组成且聚合物分子量分布较窄。在水溶液中PEG-PHEMA-Lx-(PHEMA-g-PLA)形成胶束的粒径在50 -150 nm之间,加入硫辛酸官能团10%的DTT后,稀释和有机溶剂后交联聚合物胶束仍然很稳定,但当加入10mM DTT后,聚合物胶束3h内解交联。
In this thesis, the reduction-sensitive reversibly interfacial crosslinked micelle was prepared. By introducing crosslinkably groups, lipoic acid, in between the biodegradable biocompatible PEG-PCL, the micelles can be reversibly crosslinked in the interface of the micelles as catalyzed by DTT. Thus crosslinked micelles demonstrated markedly enhanced stability, while they dissociated in mimicking intracellular reductive environment.
(1) In the first part, the block polymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) containing two lipoyl functional groups at their interface (PEG-L2-PCL) was synthesized. 1H NMR and gel permeation chromatography (GPC) measurements shows that PEG-L2-PCL block copolymer had a controlled composition and a polydispersity index (PDI) of 1.36. PEG-L2-PCL formed micelles with sizes ranging from 20 to 150 nm in aqueous solutions, wherein a critical micelle concentration (CMC) of 16 mg/L was determined. The micelles were readily crosslinked by adding 7.6 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution, physiological salt concentration and organic solvent. In the presence of 10 mM DTT, however, micelles were subject to rapid de-crosslinking. In vitro release studies showed minimal release of DOX from crosslinked micelles at a concentration of 10 mg/L (C < CMC), wherein less than 15 % DOX was released in 10 h. In contrast, rapid release of DOX was observed for DOX-loaded non-crosslinked micelles under otherwise the same conditions (ca. 80 % release in 0.5 h). In the presence of 10 mM DTT mimicking intracellular reductive environment, sustained release of DOX from crosslinked micelles was achieved, in which 75 % DOX was released in 9 h.
(2) In the second part, the block polymer of poly(ethylene glycol)-poly(2-Hydroxyethyl methacrylate)-poly(2-Hydroxyethyl methacrylate- g - polylactide) (PEG-PHEMA-P(HEMA-g-PLA)11 containing two lipoyl functional groups on the side chain (PEG-PHEMA-Lx-P(HEMA-g-PLA)11) was synthesized. 1H NMR and GPC measurements showed that PEG-PHEMA-P(HEMA-g-PLA) block copolymer had a controlled composition and a polydispersity index (PDI) of 1.12. PEG-PHEMA-Lx-P(HEMA-g-PLA)11 formed micelles with sizes ranging from 50 to 150 nm in aqueous solutions. The micelles were readily crosslinked by adding 10 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution and organic solvent. In the presence of 10 mM DTT mimicking intracellular reductive environment, the micelles de- crosslinked in 3h.
引文
[1]张玥,赵弘韬,张丽芳,高分子载体药物.科技信息231.
[2]朱建华,周敬堂,聚合物胶束在医药领域中的新应用.中国西部科技7(33) (2008) 18-19.
[3] J. Torchilin, P. Vladimir, Drug targeting. Eur J Pharm Sci 11(2) (2000) 81-91.
[4] K. Letchford, H. Burt, A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes. European Journal of Pharmaceutics and Biopharmaceutics 65(3) (2007) 259-269.
[5]赵健,盛燕,单晓茜,章晓兰,袁媛,刘昌胜, 2008.生物医学工程学杂志25(1) 210-223.
[6]杨炳兴,成国祥,马林荣,生物可降解聚合物纳米微囊微球的制备与应用.胶体与聚合物21(1) (2003) 34-37.
[7] B.G. Fosh, J.G. Finch, M. Lea, Use of electrolysis as an adjunct to liverresection. Br J Surg 89(8) (2002) 999-1002.
[8]任晓慧,李莉,刘松财,张永亮,聚乳酸乳破乙醇破共豪物微球的研究进展.吉林畜牧兽医3 (2005) 13-15.
[9]袁建军,李英顺,李晓琴,聚苯乙烯-b-聚氧乙烯-b-聚苯乙烯三嵌段共聚物的自组装.高等学校化学学报24(2) (2003) 371-373.
[10]黎淳昭,张炜程,魏柳荷,规整链球型含C60聚(丙烯酸-β-羟乙酯)的合成及其在水中的自组装.高分子学报(1) (2002) 120-122.
[11] N.M. Sommerdijk, S.J. Holder, R.C. Morns, Self-assembled structures from an amphiphilic multiblock eopolymer containing rigid semi-conductor segment. Macromolecule 33(22) (2000) 8289-8294.
[12] T. Kunitake, Y. Okahata, M. Shimomura, Formation of stable bilayer assemblies in water from single-chain amphiphiles :Relationship behveen the amphiphile stnlcture and the agtg"egate morphology. J Am ChemSec 103(18) (1981) 5401-5413.
[13] S. Schrage, R. Sigel, H. Schlaad, Formation of amphiphilic polyion complex vesicles from mixtures of oppositely charged block ionomer. Macromolecules 36(5) (2003) 1417-1420.
[14] A. Harada, S. Cammas, K. Kataoka, Stabilized -helix sttuctures of poly(L-Lysine) -block-poly(ethylene glycol) in aqueous medium through supramolecular assembly. Macromolecule 29(19) (1996) 6183-6188.
[15] S. Cammas, A. Harada , Nagasakiy, Poly(ethylene oxide- co-β-benzyl-l-asparate) block copolymers:influence of the poly(ethylene oxide)block on the conformation ofthe poly(β-benzyl-l-asparate)segment in organic solvent. (1996).
[16] T.K. Bronich, M. Ouyang, K. V.A. Kabanoy, Synthesis of vesicles on polymers template. J Am Chem Soc 124(40) (2002) 11872-11873.
[17] E.A. Lysenk, T.K. Bronich, E.V. Slonkina, Block ionomer complexes with polystyrene core-forming block in selective solvents of vatious polarities.1.Solution behavior and self-assembly in aqueous media. Maeromolecules 35(16) (2002) 351-361.
[18] E.A. Lysenk, T.K. Bronich, E.V. Slonkina, Block ionomer complexes withpolystyrene core-form ing block in.selective solvents of vatious polarities.2.Solution behavior and self—assembly in nonpolar solven. Macromolecules 35(16) (2002) 6344-6250.
[19] J. Ding, G. Liu, Water-soluble hollow nmmsphel3~b as potential drug carrier. J Phys Chem B 102(31) (1998) 6106-6113.
[20] C. Naradin, T. Hirt, J. Ieukei, Polymerized ABA triblok copolymer vesicles. langmuir 16(3) (2000) 1035-1041.
[21] J. Du, Y. Chen, Y. Zhang, Organic/inorganic hybrid vesiclesbased on a reactive block copolyme. J Am Chem Soc 125(48) (2003) 1978-1983.
[22] N. Kimizuka, M. Tanaka, Bilayer membranes of four chained amlllonillnl amphiphil. Chem Letters(1) (1990) 29-32.
[23] T. Kunitake,N.N. Kimzuka,O. Higashi, Bilayer membranes of triple-chain ammonium amphiphile. J Am Chem Soc 106(7) (1984) 1978-1983.
[24] F.M. Menger,S.Marappan, Synthesis and properties of a polybolyte. Langmuir 16(17) (2000) 6763-6765.
[25] Y. Nagasakiy. K.Yasugi, Y. Yamamotoy, Sugar-installed block copolymer micelles : their preparation and specific interaction with lectin molecules. biomacromolecules 2(4) (2001) 1067-1070.
[26] W. Chen, F.H. Meng, F. Li, S.J. Ji, Z.Y. Zhong, pH-Responsive Biodegradable Micelles Based on Acid-Labile Polycarbonate Hydrophobe: Synthesis and Triggered Drug Release. Biomacromolecules 10(7) (2009) 1727-1735.
[27] K. Kataoka, A. Ishihara, A. Harada, Efect of the secondary structure of poly(L一Lysine)segmentts on the micellization in aqueous millieu of poly(ethylene glycol) -poly(L-Lysine)block copolymerpartically substituted with a hydrocirmamoyl group at the N -position. Macromolecule 31(18) (1998) 6071-6076.
[28]张晓君,王东凯,韩晓,聚合物胶束作为药物传递系统的研究进展.中国药剂学杂志7(3) (2009) 177-183.
[29] T. Shinobu,L. Mahesh,K.M. Patil, Development of new methods toward efficient immobilization of chiral catalysts. Tetrahedron 63(28) (2007) 6512-6528.
[30] N.L. Adams, Amphiphilic block copolymers for drug delivery. J Pharm Sci92(7) (2003) 1343-1354.
[31] W. Wang, X. Qu, A. Gray, Self-assembly of linear polyethylenimine to give micelles , vesicles , and dense nanoparticles. Macromolecule 37 (2004) 9114-9122.
[32] J.H. Jeong, T.G. Prak,Poly ( L-lysine)-g-poly ( D , L-lactic-co-glycolic acid) micelles for low cytotoxic biodegradable gene delivery carriers. Journal of Controlled Release 82 (2002) 159-166.
[33] E.S. Lee, K. Na, Y.H. Bae, Polymeric micelle for tumor pH and folate-mediated targeting. Journal of Controlled Release 91 (2003) 103-113.
[34] J. Leroux, E. Roux, D.L. Garrec, N-isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles. Journal of Controlled Release 72 (2001) 71-84.
[35] J.X. Zhang , L.Y. Qiu, Y. Jin, Physicochemical characterization of polymeric micelles constructed from novel amphiphilic polyphosphazene with poly ( N-isopropylacrylamide) and ethyl 4-aminobenzoate as side groups. Colloids and Surfaces B :Biointerfaces 43 (2005) 123-130.
[36] Y. Yamamoto, Y. Nagasakiy, Y. Kato, Long-circulating poly(ethylene glycol)-poly(DL-lactide)blockcopolymermicelles with modulated surface charge. journal of Controlled Release 77 (2001) 27-38.
[37] A.V. Kabanov, E.V. Batrakova, V.Y. Alakhov, Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release 82(2-3) (2002) 189-212.
[38] X. Zhang, J.K. Jackson, H.M. Burt, Development of amphiphilic diblock copolymers as micellar carriers of taxol. International Journal of Pharmaceutics 132(1-2) (1996) 195-206.
[39] H.M. Burt, X. Zhang, P. Toleikis, L. Embree, W.L. Hunter, Development of copolymers of poly(D,L-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel. Colloids and Surfaces B: Biointerfaces 16(1-4) (1999) 161-171.
[40] Jubo. Liu, Yuehua. Xiao, A. Christine, Polymer-drug compatibility: A guide to the development of delivery systems for the anticancer agent, ellipticine. Journal of Pharmaceutical Sciences 93(1) (2004) 132-143.
[41] S.Y. Kim, I.L.G. Shin, Y.M. Lee, C.S. Cho, Y.K. Sung, Methoxy poly(ethylene glycol) and [epsilon]-caprolactone amphiphilic block copolymeric micelle containing indomethacin.: II. Micelle formation and drug release behaviours. Journal of Controlled Release 51(1) (1998) 13-22.
[42] F. Kohori, M. Yokoyama, K. Sakai, T. Okano, Process design for efficient and controlled drug incorporation into polymeric micelle carrier systems. Journal of Controlled Release 78(1-3) (2002) 155-163.
[43] V.P. Sant, D. Smith, J.-C. Leroux, Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization. Journal of Controlled Release 97(2) (2004) 301-312.
[44] J. Yuan, Y. Li, X. Li, S. Cheng, L. Jiang, L. Feng, Z. Fan, The "crew-cut" aggregates of polystyrene-b-poly(ethylene oxide)-b-polystyrene triblock copolymers in aqueous media. European Polymer Journal 39(4) (2003) 767-776.
[45] L. Zhang, A. Eisenberg, Morphogenic Effect of Added Ions on Crew-Cut Aggregates of Polystyrene-b-poly(acrylic acid) Block Copolymers in Solutions. Macromolecules 29(27) (1996) 8805-8815.
[46]黄健,梅兴国,胶束纳米载体在药物投送系统中的应用前景.国际药学研究杂志34(6) (2007) 453-455.
[47]景遐斌,郑勇辉,柳时,高分子键合药靶向效应研究.高分子化学会议(2009).
[48] M.N. Iijima, Y. Okada, T. Kato, M. Kataoka, Core-polymerized reactive micelles from heterotelechelic amphiphilic block copolymers. macromolecules 32 (1999) 1140-1146.
[49] K. Emoto, Y. Nagasaki, K. Kataoka, Coating of Surfaces with Stabilized Reactive Micelles from Poly(ethylene glycol)-poly(dl-lactic acid) Block Copolymer. Langmuir 15(16) (1999) 5212-5218.
[50] K. Emoto, Y. Nagasaki, K. Kataoka, A Core-shell Structured Hydrogel Thin Layer on Surfaces by Lamination of a Poly(ethylene glycol)-b-poly(d,l-lactide) Micelle and Polyallylamine. Langmuir 16(13) (2000) 5738-5742.
[51] K. Emoto, M. Iijima, Y. Nagasaki, K. Kataoka, Functionality of PolymericMicelle Hydrogels with Organized Three-Dimensional Architecture on Surfaces. Journal of the American Chemical Society 122(11) (2000) 2653-2654.
[52] Y. Kakizawa, A.Harada, K. Kataoka, Glutathione-sensitive Glutathione -sensitive antisense DNA and thiolated poly(ethylene glycol)-block-poly(L-lysine): a potential carrier for systemic delivery of antisense DNA. Biomacromolecules 2 (2001) 491-497.
[53] Y. Kakizawa, A. Harada, K. Kataoka, Environment-Sensitive Stabilization of Core-shell Structured Polyion Complex Micelle by Reversible Cross-Linking of the Core through Disulfide Bond. Journal of the American Chemical Society 121(48) (1999) 11247-11248.
[54] K.B. Thurmond, T. Kowalewski, K.L.Wooley, Water-Soluble Knedel-Like Structures: The preparation of shell-crosslinked small particles. J. Am. Chem. Soc 118(30) (1996) 7239-7240.
[55] K. B. Thurmond,T. Kowalewski, K.L.Wooley, Shell Cross-linked Polymer Micelles: Stabilized Assemblies with Great Versatility and Potential. Colloids and Surfaces B 16 (1999) 45.
[56] K. Luo, J. Rzayev, Living Radical Polymerization of Bicyclic Dienes: Synthesis of Thermally Cross-Linkable Block Copolymers. Macromolecules 42(23) (2009) 9268-9274.
[57] S. Liu, Y. Ma, S.P. Armes, C. Perruchot, J.F. Watts, Direct Verification of the Core-shell Structure of Shell Cross-Linked Micelles in the Solid State Using X-ray Photoelectron Spectroscopy. Langmuir 18(21) (2002) 7780-7784.
[58] A.J. Convertine, R.G. Ezell, A. Heidenreich, Y. Li, C.L. McCormick, Responsive Nanoassemblies via Interpolyelectrolyte Complexation of Amphiphilic Block Copolymer Micelles. Macromolecules 39(25) (2006) 8594-8602.
[59] H. Huang, T. Kowalewski, E.E. Remsen, R. Gertzmann, K.L. Wooley, Hydrogel-Coated Glassy Nanospheres: A Novel Method for the Synthesis of Shell Cross-Linked Knedels. Journal of the American Chemical Society 119(48) (1997) 11653-11659.
[60] K.B. Thurmond, T. Kowalewski, K.L. Wooley, Shell Cross-LinkedKnedels: A Synthetic Study of the Factors Affecting the Dimensions and Properties of Amphiphilic Core-Shell Nanospheres. Journal of the American Chemical Society 119(28) (1997) 6656-6665.
[61] J. Ding, G. Liu, Polystyrene-block-poly(2-cinnamoylethyl methacrylate) Nanospheres with Cross-Linked Shells. Macromolecules 31(19) (1998) 6554-6558.
[62] E.S. Read, S.P. Armes, Recent advances in shell cross-linked micelles. Chem. Commun (2007) 3021–3035.
[63] V. Butun, K. L. Robinson, N. C. Billingham, and S. P. Armes, Synthesis of Shell Cross-Linked Micelles at High Solids in Aqueous Media. macromolecules 33 (2000) 1-3.
[64] S. Mayor, R.E. Pagano, Pathways of clathrin-independent endocytosis. Nature Reviews 8 (2007) 603-612.
[65] Z.G. Xie, X.L. Hu, X.S. Chen, G.J. Mo, J. Sun, X.B. Jing, A Novel Biodegradable and Light-Breakable Diblock Copolymer Micelle for Drug Delivery. Adv. Eng. Mater. 11(3) (2009) B7.
[66] Q. Shi, Y. Huang, X. Chen, M. Wu, J. Sun, X. Jing, Hemoglobin conjugated micelles based on triblock biodegradable polymers as artificial oxygen carriers. Biomaterials 30(28) (2009) 5077-5085.
[67]张丽裙,方晓玲,聚合物纳米粒和胶束的主动靶向研究进展.国外医学药学分册32 (2005) 399-404.
[1] A. Rosler, G. W. M. Vandermeulen, H.A. Klok, Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Adv Drug Deliv Rev(53) (2001) 95-108.
[2] K. Kataoka, A. Harada, Y. Nagasaki, Block copolymer micelles for drugdelivery: design, characterization and biological significance. Advanced Drug Delivery Reviews 47(1) (2001) 113-131.
[3] L. Y. Qiu, Y.H.Bae,Polymer architecture and drug delivery. Pharm. Res 23(1) (2006) 1-30.
[4] V.P. Torchilin, Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine. Pharm. Res 24(1) (2007) 1-16.
[5] Y. Kakizawa, K. Kataoka, Block copolymer micelles for delivery of gene and related compounds. Advanced Drug Delivery Reviews 54(2) (2002) 203-222.
[6] G.S. Kwon, T. Okano, Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews 21(2) (1996) 107-116.
[7] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release 65(1-2) (2000) 271-284.
[8] A.E. van der Ende, E.J. Kravitz, E. Harth, Approach to Formation of Multifunctional Polyester Particles in Controlled Nanoscopic Dimensions. J. Am. Chem. Soc 130(27) (2008) 8706-8713.
[9] C.J.F. Rijcken, O. Soga, W.E. Hennink, C.F.van Nostrum, Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery. Journal of Controlled Release 120(3) (2007) 131-148.
[10] R.T. Liggins, H.M. Burt, Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations. Advanced Drug Delivery Reviews 54(2) (2002) 191-202.
[11] K. Yasugi, T. Nakamura, Y. Nagasaki, M. Kato, K. Kataoka, Sugar-Installed Polymer Micelles: Synthesis and Micellization of Poly(ethylene glycol)-poly(d,l-lactide) Block Copolymers Having Sugar Groups at the PEG Chain End. macromolecules 32(24) (1999) 8024-8032.
[12] H. Otsuka, Y. Nagasaki, K. Kataoka, Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications. Colloid and Interface Science 6(1) (2001) 3-10.
[13] T-Y. Kim, D.-W. Kim, J.-Y. Chung, S.- G. Shin, S.-C. Kim, D.S. Heo, N. K.Kim, Y.-J. Bang, Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies Clinical Cancer Research 10 (2004) 3708.
[14] T.H. Y Matsumura, T. Hamaguchi, T. Ura, K. Muro, Y. Yamada, Y. Shimada, K. Shirao, T. Okusaka, H. Ueno, M. Ikeda, N. Watanabe, Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. British Journal of Cancer 91(10) (2004) 1775-1781.
[15] E. S. Read, S.P. Armes, Recent advances in shell cross-linked micelles. Chem. Commun (2007) 3021-3035.
[16] T.K. Bronich, P.A. Keifer, L.S. Shlyakhtenko, A.V.Kabanov, Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc 127(23) (2005) 8236-8237.
[17] A. Lavasanifar, J. Samuel, G.S. Kwon, Poly(ethylene oxide)-block-poly(L-amino acid) micelles for drug delivery. Advanced Drug Delivery Reviews 54(2) (2002) 169-190.
[18] R.K. O’Reilly, C.J. Hawker, K. L. Wooley, Cross-linked Block Copolymer Micelles: Functional nanostructures of great potential and versatility. Chem. Soc. Rev 35(11) (2006) 1068-1083.
[19] K. B. Thurmond, H. Y. Huang, C. G. Clark, T. Kowalewski, K. L. Wooley, Shell Cross-linked Polymer Micelles: Stabilized Assemblies with Great Versatility and Potential. Colloids and Surfaces B 16 (1999) 45.
[20] H. Y. Huang, E. E. Remsen, K. L. Wooley, Amphiphilic Core-shell Nanospheres Obtained by Intramicellar Shell Crosslinking of Polymer Micelles with Poly(ethylene oxide) Linkers. Chem. Commun(13) (1998) 1415-1416.
[21] C. Cheng, K. Qi, D. S. Germack, E. Khoshdel, K. L. Wooley, Synthesis of Core-Crosslinked Nanoparticles with Controlled Cylindrical Shape and Narrowly-Dispersed Size via Core-Shell Brush Block Copolymer Templates. Adv. Mater. 19(19) (2007) 2830-2835.
[22] S. Harrisson, K. L. Wooley, Shell-crosslinked Nanostructures from Amphiphilic AB and ABA Block Copolymerss of Styrene-alt-(maleic anhydride) and Styrene: Polymerization, assembly and stabilization in one pot. Chem. Commun(26)(2005) 3259-3261.
[23] Q. Zhang, E. E. Remsen, K. L. Wooley, Shell Crosslinked Nanoparticles Containing Hydrolytically-degradable Crystalline Core Domains. J. Am. Chem. Soc 122(15) (2000) 3642-3651.
[24] C. J. Hawker, K.L. Wooley, The Convergence of Synthetic Organic and Polymer Chemistries. Science 309(5738) (2005) 1200-1205.
[25] Y.L. Li, W.J. Du, G.R. Sun, K.L. Wooley, pH-Responsive Shell Crosslinked Nanoparticles with Hydrolytically-labile Crosslinks. macromolecules 41 (2008) 6605-6607.
[26] Y. T. Li, B. S. Lokitz, S. P. Armes ,C. L. McCormick, Synthesis of Reversible Shell Cross-Linked Micelles for Controlled Release of Bioactive Agents. macromolecules 39 (2006) 2726.
[27] C.J. Rijcken, C.J. Snel, R.M. Schiffelers, C.F. van Nostrum, W.E. Hennink, Hydrolysable core-crosslinked thermosensitive polymeric micelles: Synthesis, characterisation and in vivo studies. Biomaterials 28(36) (2007) 5581-5593.
[28] X. T. Shuai, T. Merdan, A. K. Schaper, F. Xi, T. Kissel, Core-Cross-Linked Polymeric Micelles as Paclitaxel Carriers Bioconjugate Chemistry 15(3) (2004) 441-448.
[29] V. Butun, X.S.Wang, M.V.D. Banez , K. L. Robinson, N. C. Billingham, S. P. Armes, Synthesis of Shell Cross-Linked Micelles at High Solids in Aqueous Media. macromolecules 33 (2000) 1-3.
[30] X. Z. Jiang, S.Z.Luo, S.P. Armes, W.F. Shi, S.Y. Liu, UV irradiation-induced shell cross-linked micelles with pH-responsive cores using ABC triblock copolymers. Macromolecules 39 (2006) 5987.
[31] F.H. Meng, W.E. Hennink, Z.Y. Zhong, Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30(12) (2009) 2180-2198.
[32] J. Bustamante, J.K. Lodge, L. Marcocci, H.J. Tritschler, L. Packer, B.H. Rihn, [alpha]-Lipoic Acid in Liver Metabolism and Disease. Free Radical Biology and Medicine 24(6) (1998) 1023-1039.
[33] D.L. Elbert, J.A. Hubbell, Conjugate Addition Reactions Combined withFree-Radical Cross-Linking for the Design of Materials for Tissue Engineering. Biomacromolecules 2(2) (2001) 430-441.
[34] A. Sadownik, J. Stefely, S.L. Regen, Polymerized liposomes formed under extremely mild conditions. Journal of the American Chemical Society 108(24) (1986) 7789-7791.
[35] J. Stefely, M.A. Markowitz, S.L. Regen, Permeability characteristics of lipid bilayers from lipoic acid-derived phosphatidylcholines. Comparison of monomeric, crosslinked and noncrosslinked polymerized membranes. Journal of the American Chemical Society 110(22) (1988) 7463-7469.
[36] M. Balakirev, G. Schoehn, J. Chroboczek, Lipoic acid-derived amphiphiles for redox-controlled DNA delivery. Chemistry & Biology 7(10) (2000) 813-819.
[37] H.F. Xu, F.H. Meng, Z.Y. Zhong, Reversibly crosslinked temperature-responsive nano-sized polymersomes:synthesis and triggered drug release. Journal of Materials Chemistry 19 (2009) 4183-4190.
[38] A.V. Kabanov, E.V. Batrakova, V. Yu. Alakhov, An essential relationship between ATP depletion and chemosensitizing activity of Pluronic block copolymers. Journal of Controlled Release 91 (2003) 75-83.
[39] Y.J. Son, J.-S. Jang, Y.W. Cho, H. Chung, R.-W. Park, I.C. Kwon, I.-S. Kim, J.Y. Park, S.B. Seo, C.R. Park, S.Y. Jeong, Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol-chitosan nanoaggregates by EPR effect. Journal of Controlled Release 91(1-2) (2003) 135-145.
[40] B. Yechezkel, A. Shimon, G. Dorit, C. Rivka, G. Dan, S. Amram, B.G. Elisabeth, G. Alberto, Stability of liposomal doxorubicin formulations: Problems and prospects. Medicinal Research Reviews 13(4) (1993) 449-491.
[41] A. Gabizon, A. Dagan, D. Goren, Y. Barenholz, Z. Fuks, Liposomes as in Vivo Carriers of Adriamycin: Reduced Cardiac Uptake and Preserved Antitumor Activity in Micelles. Cancer Research 42 (1982) 4734-4739.
[1] A. Rosler, G. W. M. Vandermeulen, H.A. Klok, Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Adv Drug Deliv Rev(53) (2001) 95-108.
[2] K. Kataoka, A. Harada, Y. Nagasaki, Block copolymer micelles for drug delivery: design, characterization and biological significance. Advanced Drug Delivery Reviews 47(1) (2001) 113-131.
[3]L. Y. Qiu, Y. H. Bae, Polymer architecture and drug delivery. Pharm. Res 23(1) (2006) 1-30.
[4] V.P. Torchilin, Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine. Pharm. Res 24(1) (2007) 1-16.
[5] Y. Kakizawa, K. Kataoka, Block copolymer micelles for delivery of gene and related compounds. Advanced Drug Delivery Reviews 54(2) (2002) 203-222.
[6] G.S. Kwon, T. Okano, Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews 21(2) (1996) 107-116.
[7] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release 65(1-2) (2000) 271-284.
[8] E. S. Read, S.P. Armes, Recent advances in shell cross-linked micelles. Chem. Commun (2007) 3021-3035.
[9] K.P. Bronich TK, Shlyakhtenko LS, Kabanov AV., Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc 127(23) (2005) 8236-8237.
[10] A. Lavasanifar, J. Samuel, G.S. Kwon, Poly(ethylene oxide)-block- poly(L-amino acid) micelles for drug delivery. Advanced Drug Delivery Reviews 54(2) (2002) 169-190.
[11] R.K. O’Reilly, C.J. Hawker, K.L. Wooley, Cross-linked Block Copolymer Micelles: Functional nanostructures of great potential and versatility. Chem. Soc. Rev 35(11) (2006) 1068-1083.
[12] K. B. Thurmond, H. Y. Huang, C. G. Clark, T. Kowalewski, K. L. Wooley, Shell Cross-linked Polymer Micelles: Stabilized Assemblies with Great Versatility and Potential. Colloids and Surfaces B 16 (1999) 45.
[13] T.D. Dziubla, M.C. Torjman, J.I. Joseph, M. Murphy-Tatum, A.M. Lowman, Evaluation of porous networks of poly(2-hydroxyethyl methacrylate) as interfacial drug delivery devices. Biomaterials 22(21) (2001) 2893-2899.
[14] H. Daniel, L. Frantiscaronek, Rehark Vladim, S. Frantiscaronek, Porous polyHEMA beads prepared by suspension polymerization in aqueous medium. Journal of Applied Polymer Science 49(11) (1993) 2041-2050.
[15] C.D. Vianna-Soares, C.J. Kim, M.R. Borenstein, Borenstein M R,Manufacture of Porous Cross-Linked HEMA Spheres for Size Exclusion Packing Material Journal of Porous Materials 10(2) (2003) 123-130.
[16]张豪,褚良银,胡林, PHEMA多孔微球和微囊的制备及生物医药应用进展.化工进展27(2) (2008) 196-200.
[17] X.W. Xu, J.L. Huang, Synthesis and characterization of amphiphilic copolymer of linear poly(ethylene oxide) linked with [poly(styrene-co-2-hydroxyethyl methacrylate)-graft-poly(ε-caprolactone)] using sequential controlled polymerization. Journal of Polymer Science Part A: Polymer Chemistry 44(1) (2006) 467-476.
[18] H. Maude Le, L. Catherine, P.D. Thomas, H.S. Martina, B.-K. Christopher, Simultaneous reversible addition fragmentation chain transfer and ring-opening polymerization. Journal of Polymer Science Part A: Polymer Chemistry 46(9) (2008) 3058-3067.
[19] A. E. van der Ende, E. J. Kravitz, E. Harth, Approach to Formation of Multifunctional Polyester Particles in Controlled Nanoscopic Dimensions. J. Am. Chem. Soc 130(27) (2008) 8706-8713.
[20] C.J.F. Rijcken, O. Soga, W.E. Hennink, C.F.v. Nostrum, Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery. Journal of Controlled Release 120(3) (2007) 131-148.
[21] R.T. Liggins, H.M. Burt, Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations. Advanced Drug Delivery Reviews 54(2) (2002) 191-202.
[22] K. Yasugi, T. Nakamura, Y. Nagasaki, M. Kato, K. Kataoka, Sugar-Installed Polymer Micelles: Synthesis and Micellization of Poly(ethylene glycol)-poly(d,l-lactide) Block Copolymers Having Sugar Groups at the PEG Chain End. macromolecules 32(24) (1999) 8024-8032.
[23] H. Otsuka, Y. Nagasaki, K. Kataoka, Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications. Colloid and Interface Science 6(1) (2001) 3-10.
[24] J. Bustamante, J.K. Lodge, L. Marcocci, H.J. Tritschler, L. Packer, B.H. Rihn,α-Lipoic Acid in Liver Metabolism and Disease. Free Radical Biology andMedicine 24(6) (1998) 1023-1039.
[25] A. Sadownik, J. Stefely, S.L. Regen, Polymerized liposomes formed under extremely mild conditions. Journal of the American Chemical Society 108(24) (1986) 7789-7791.
[26] J. Stefely, M.A. Markowitz, S.L. Regen, Permeability characteristics of lipid bilayers from lipoic acid-derived phosphatidylcholines. Comparison of monomeric, crosslinked and noncrosslinked polymerized membranes. Journal of the American Chemical Society 110(22) (1988) 7463-7469.
[27] M. Balakirev, G. Schoehn, J. Chroboczek, Lipoic acid-derived amphiphiles for redox-controlled DNA delivery. Chemistry & Biology 7(10) (2000) 813-819.
[28] Y.M. Xu, F.H. Meng, R. Cheng, Z.Y. Zhong, Reduction-Sensitive Reversibly Crosslinked Biodegradable Micelles for Triggered Release of Doxorubicin. Macromolecular Bioscience 9 (2009) 1254-1261.
[2]朱建华,周敬堂,聚合物胶束在医药领域中的新应用.中国西部科技7(33) (2008) 18-19.
[3] J. Torchilin, P. Vladimir, Drug targeting. Eur J Pharm Sci 11(2) (2000) 81-91.
[4] K. Letchford, H. Burt, A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes. European Journal of Pharmaceutics and Biopharmaceutics 65(3) (2007) 259-269.
[5]赵健,盛燕,单晓茜,章晓兰,袁媛,刘昌胜, 2008.生物医学工程学杂志25(1) 210-223.
[6]杨炳兴,成国祥,马林荣,生物可降解聚合物纳米微囊微球的制备与应用.胶体与聚合物21(1) (2003) 34-37.
[7] B.G. Fosh, J.G. Finch, M. Lea, Use of electrolysis as an adjunct to liverresection. Br J Surg 89(8) (2002) 999-1002.
[8]任晓慧,李莉,刘松财,张永亮,聚乳酸乳破乙醇破共豪物微球的研究进展.吉林畜牧兽医3 (2005) 13-15.
[9]袁建军,李英顺,李晓琴,聚苯乙烯-b-聚氧乙烯-b-聚苯乙烯三嵌段共聚物的自组装.高等学校化学学报24(2) (2003) 371-373.
[10]黎淳昭,张炜程,魏柳荷,规整链球型含C60聚(丙烯酸-β-羟乙酯)的合成及其在水中的自组装.高分子学报(1) (2002) 120-122.
[11] N.M. Sommerdijk, S.J. Holder, R.C. Morns, Self-assembled structures from an amphiphilic multiblock eopolymer containing rigid semi-conductor segment. Macromolecule 33(22) (2000) 8289-8294.
[12] T. Kunitake, Y. Okahata, M. Shimomura, Formation of stable bilayer assemblies in water from single-chain amphiphiles :Relationship behveen the amphiphile stnlcture and the agtg"egate morphology. J Am ChemSec 103(18) (1981) 5401-5413.
[13] S. Schrage, R. Sigel, H. Schlaad, Formation of amphiphilic polyion complex vesicles from mixtures of oppositely charged block ionomer. Macromolecules 36(5) (2003) 1417-1420.
[14] A. Harada, S. Cammas, K. Kataoka, Stabilized -helix sttuctures of poly(L-Lysine) -block-poly(ethylene glycol) in aqueous medium through supramolecular assembly. Macromolecule 29(19) (1996) 6183-6188.
[15] S. Cammas, A. Harada , Nagasakiy, Poly(ethylene oxide- co-β-benzyl-l-asparate) block copolymers:influence of the poly(ethylene oxide)block on the conformation ofthe poly(β-benzyl-l-asparate)segment in organic solvent. (1996).
[16] T.K. Bronich, M. Ouyang, K. V.A. Kabanoy, Synthesis of vesicles on polymers template. J Am Chem Soc 124(40) (2002) 11872-11873.
[17] E.A. Lysenk, T.K. Bronich, E.V. Slonkina, Block ionomer complexes with polystyrene core-forming block in selective solvents of vatious polarities.1.Solution behavior and self-assembly in aqueous media. Maeromolecules 35(16) (2002) 351-361.
[18] E.A. Lysenk, T.K. Bronich, E.V. Slonkina, Block ionomer complexes withpolystyrene core-form ing block in.selective solvents of vatious polarities.2.Solution behavior and self—assembly in nonpolar solven. Macromolecules 35(16) (2002) 6344-6250.
[19] J. Ding, G. Liu, Water-soluble hollow nmmsphel3~b as potential drug carrier. J Phys Chem B 102(31) (1998) 6106-6113.
[20] C. Naradin, T. Hirt, J. Ieukei, Polymerized ABA triblok copolymer vesicles. langmuir 16(3) (2000) 1035-1041.
[21] J. Du, Y. Chen, Y. Zhang, Organic/inorganic hybrid vesiclesbased on a reactive block copolyme. J Am Chem Soc 125(48) (2003) 1978-1983.
[22] N. Kimizuka, M. Tanaka, Bilayer membranes of four chained amlllonillnl amphiphil. Chem Letters(1) (1990) 29-32.
[23] T. Kunitake,N.N. Kimzuka,O. Higashi, Bilayer membranes of triple-chain ammonium amphiphile. J Am Chem Soc 106(7) (1984) 1978-1983.
[24] F.M. Menger,S.Marappan, Synthesis and properties of a polybolyte. Langmuir 16(17) (2000) 6763-6765.
[25] Y. Nagasakiy. K.Yasugi, Y. Yamamotoy, Sugar-installed block copolymer micelles : their preparation and specific interaction with lectin molecules. biomacromolecules 2(4) (2001) 1067-1070.
[26] W. Chen, F.H. Meng, F. Li, S.J. Ji, Z.Y. Zhong, pH-Responsive Biodegradable Micelles Based on Acid-Labile Polycarbonate Hydrophobe: Synthesis and Triggered Drug Release. Biomacromolecules 10(7) (2009) 1727-1735.
[27] K. Kataoka, A. Ishihara, A. Harada, Efect of the secondary structure of poly(L一Lysine)segmentts on the micellization in aqueous millieu of poly(ethylene glycol) -poly(L-Lysine)block copolymerpartically substituted with a hydrocirmamoyl group at the N -position. Macromolecule 31(18) (1998) 6071-6076.
[28]张晓君,王东凯,韩晓,聚合物胶束作为药物传递系统的研究进展.中国药剂学杂志7(3) (2009) 177-183.
[29] T. Shinobu,L. Mahesh,K.M. Patil, Development of new methods toward efficient immobilization of chiral catalysts. Tetrahedron 63(28) (2007) 6512-6528.
[30] N.L. Adams, Amphiphilic block copolymers for drug delivery. J Pharm Sci92(7) (2003) 1343-1354.
[31] W. Wang, X. Qu, A. Gray, Self-assembly of linear polyethylenimine to give micelles , vesicles , and dense nanoparticles. Macromolecule 37 (2004) 9114-9122.
[32] J.H. Jeong, T.G. Prak,Poly ( L-lysine)-g-poly ( D , L-lactic-co-glycolic acid) micelles for low cytotoxic biodegradable gene delivery carriers. Journal of Controlled Release 82 (2002) 159-166.
[33] E.S. Lee, K. Na, Y.H. Bae, Polymeric micelle for tumor pH and folate-mediated targeting. Journal of Controlled Release 91 (2003) 103-113.
[34] J. Leroux, E. Roux, D.L. Garrec, N-isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles. Journal of Controlled Release 72 (2001) 71-84.
[35] J.X. Zhang , L.Y. Qiu, Y. Jin, Physicochemical characterization of polymeric micelles constructed from novel amphiphilic polyphosphazene with poly ( N-isopropylacrylamide) and ethyl 4-aminobenzoate as side groups. Colloids and Surfaces B :Biointerfaces 43 (2005) 123-130.
[36] Y. Yamamoto, Y. Nagasakiy, Y. Kato, Long-circulating poly(ethylene glycol)-poly(DL-lactide)blockcopolymermicelles with modulated surface charge. journal of Controlled Release 77 (2001) 27-38.
[37] A.V. Kabanov, E.V. Batrakova, V.Y. Alakhov, Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release 82(2-3) (2002) 189-212.
[38] X. Zhang, J.K. Jackson, H.M. Burt, Development of amphiphilic diblock copolymers as micellar carriers of taxol. International Journal of Pharmaceutics 132(1-2) (1996) 195-206.
[39] H.M. Burt, X. Zhang, P. Toleikis, L. Embree, W.L. Hunter, Development of copolymers of poly(D,L-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel. Colloids and Surfaces B: Biointerfaces 16(1-4) (1999) 161-171.
[40] Jubo. Liu, Yuehua. Xiao, A. Christine, Polymer-drug compatibility: A guide to the development of delivery systems for the anticancer agent, ellipticine. Journal of Pharmaceutical Sciences 93(1) (2004) 132-143.
[41] S.Y. Kim, I.L.G. Shin, Y.M. Lee, C.S. Cho, Y.K. Sung, Methoxy poly(ethylene glycol) and [epsilon]-caprolactone amphiphilic block copolymeric micelle containing indomethacin.: II. Micelle formation and drug release behaviours. Journal of Controlled Release 51(1) (1998) 13-22.
[42] F. Kohori, M. Yokoyama, K. Sakai, T. Okano, Process design for efficient and controlled drug incorporation into polymeric micelle carrier systems. Journal of Controlled Release 78(1-3) (2002) 155-163.
[43] V.P. Sant, D. Smith, J.-C. Leroux, Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization. Journal of Controlled Release 97(2) (2004) 301-312.
[44] J. Yuan, Y. Li, X. Li, S. Cheng, L. Jiang, L. Feng, Z. Fan, The "crew-cut" aggregates of polystyrene-b-poly(ethylene oxide)-b-polystyrene triblock copolymers in aqueous media. European Polymer Journal 39(4) (2003) 767-776.
[45] L. Zhang, A. Eisenberg, Morphogenic Effect of Added Ions on Crew-Cut Aggregates of Polystyrene-b-poly(acrylic acid) Block Copolymers in Solutions. Macromolecules 29(27) (1996) 8805-8815.
[46]黄健,梅兴国,胶束纳米载体在药物投送系统中的应用前景.国际药学研究杂志34(6) (2007) 453-455.
[47]景遐斌,郑勇辉,柳时,高分子键合药靶向效应研究.高分子化学会议(2009).
[48] M.N. Iijima, Y. Okada, T. Kato, M. Kataoka, Core-polymerized reactive micelles from heterotelechelic amphiphilic block copolymers. macromolecules 32 (1999) 1140-1146.
[49] K. Emoto, Y. Nagasaki, K. Kataoka, Coating of Surfaces with Stabilized Reactive Micelles from Poly(ethylene glycol)-poly(dl-lactic acid) Block Copolymer. Langmuir 15(16) (1999) 5212-5218.
[50] K. Emoto, Y. Nagasaki, K. Kataoka, A Core-shell Structured Hydrogel Thin Layer on Surfaces by Lamination of a Poly(ethylene glycol)-b-poly(d,l-lactide) Micelle and Polyallylamine. Langmuir 16(13) (2000) 5738-5742.
[51] K. Emoto, M. Iijima, Y. Nagasaki, K. Kataoka, Functionality of PolymericMicelle Hydrogels with Organized Three-Dimensional Architecture on Surfaces. Journal of the American Chemical Society 122(11) (2000) 2653-2654.
[52] Y. Kakizawa, A.Harada, K. Kataoka, Glutathione-sensitive Glutathione -sensitive antisense DNA and thiolated poly(ethylene glycol)-block-poly(L-lysine): a potential carrier for systemic delivery of antisense DNA. Biomacromolecules 2 (2001) 491-497.
[53] Y. Kakizawa, A. Harada, K. Kataoka, Environment-Sensitive Stabilization of Core-shell Structured Polyion Complex Micelle by Reversible Cross-Linking of the Core through Disulfide Bond. Journal of the American Chemical Society 121(48) (1999) 11247-11248.
[54] K.B. Thurmond, T. Kowalewski, K.L.Wooley, Water-Soluble Knedel-Like Structures: The preparation of shell-crosslinked small particles. J. Am. Chem. Soc 118(30) (1996) 7239-7240.
[55] K. B. Thurmond,T. Kowalewski, K.L.Wooley, Shell Cross-linked Polymer Micelles: Stabilized Assemblies with Great Versatility and Potential. Colloids and Surfaces B 16 (1999) 45.
[56] K. Luo, J. Rzayev, Living Radical Polymerization of Bicyclic Dienes: Synthesis of Thermally Cross-Linkable Block Copolymers. Macromolecules 42(23) (2009) 9268-9274.
[57] S. Liu, Y. Ma, S.P. Armes, C. Perruchot, J.F. Watts, Direct Verification of the Core-shell Structure of Shell Cross-Linked Micelles in the Solid State Using X-ray Photoelectron Spectroscopy. Langmuir 18(21) (2002) 7780-7784.
[58] A.J. Convertine, R.G. Ezell, A. Heidenreich, Y. Li, C.L. McCormick, Responsive Nanoassemblies via Interpolyelectrolyte Complexation of Amphiphilic Block Copolymer Micelles. Macromolecules 39(25) (2006) 8594-8602.
[59] H. Huang, T. Kowalewski, E.E. Remsen, R. Gertzmann, K.L. Wooley, Hydrogel-Coated Glassy Nanospheres: A Novel Method for the Synthesis of Shell Cross-Linked Knedels. Journal of the American Chemical Society 119(48) (1997) 11653-11659.
[60] K.B. Thurmond, T. Kowalewski, K.L. Wooley, Shell Cross-LinkedKnedels: A Synthetic Study of the Factors Affecting the Dimensions and Properties of Amphiphilic Core-Shell Nanospheres. Journal of the American Chemical Society 119(28) (1997) 6656-6665.
[61] J. Ding, G. Liu, Polystyrene-block-poly(2-cinnamoylethyl methacrylate) Nanospheres with Cross-Linked Shells. Macromolecules 31(19) (1998) 6554-6558.
[62] E.S. Read, S.P. Armes, Recent advances in shell cross-linked micelles. Chem. Commun (2007) 3021–3035.
[63] V. Butun, K. L. Robinson, N. C. Billingham, and S. P. Armes, Synthesis of Shell Cross-Linked Micelles at High Solids in Aqueous Media. macromolecules 33 (2000) 1-3.
[64] S. Mayor, R.E. Pagano, Pathways of clathrin-independent endocytosis. Nature Reviews 8 (2007) 603-612.
[65] Z.G. Xie, X.L. Hu, X.S. Chen, G.J. Mo, J. Sun, X.B. Jing, A Novel Biodegradable and Light-Breakable Diblock Copolymer Micelle for Drug Delivery. Adv. Eng. Mater. 11(3) (2009) B7.
[66] Q. Shi, Y. Huang, X. Chen, M. Wu, J. Sun, X. Jing, Hemoglobin conjugated micelles based on triblock biodegradable polymers as artificial oxygen carriers. Biomaterials 30(28) (2009) 5077-5085.
[67]张丽裙,方晓玲,聚合物纳米粒和胶束的主动靶向研究进展.国外医学药学分册32 (2005) 399-404.
[1] A. Rosler, G. W. M. Vandermeulen, H.A. Klok, Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Adv Drug Deliv Rev(53) (2001) 95-108.
[2] K. Kataoka, A. Harada, Y. Nagasaki, Block copolymer micelles for drugdelivery: design, characterization and biological significance. Advanced Drug Delivery Reviews 47(1) (2001) 113-131.
[3] L. Y. Qiu, Y.H.Bae,Polymer architecture and drug delivery. Pharm. Res 23(1) (2006) 1-30.
[4] V.P. Torchilin, Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine. Pharm. Res 24(1) (2007) 1-16.
[5] Y. Kakizawa, K. Kataoka, Block copolymer micelles for delivery of gene and related compounds. Advanced Drug Delivery Reviews 54(2) (2002) 203-222.
[6] G.S. Kwon, T. Okano, Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews 21(2) (1996) 107-116.
[7] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release 65(1-2) (2000) 271-284.
[8] A.E. van der Ende, E.J. Kravitz, E. Harth, Approach to Formation of Multifunctional Polyester Particles in Controlled Nanoscopic Dimensions. J. Am. Chem. Soc 130(27) (2008) 8706-8713.
[9] C.J.F. Rijcken, O. Soga, W.E. Hennink, C.F.van Nostrum, Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery. Journal of Controlled Release 120(3) (2007) 131-148.
[10] R.T. Liggins, H.M. Burt, Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations. Advanced Drug Delivery Reviews 54(2) (2002) 191-202.
[11] K. Yasugi, T. Nakamura, Y. Nagasaki, M. Kato, K. Kataoka, Sugar-Installed Polymer Micelles: Synthesis and Micellization of Poly(ethylene glycol)-poly(d,l-lactide) Block Copolymers Having Sugar Groups at the PEG Chain End. macromolecules 32(24) (1999) 8024-8032.
[12] H. Otsuka, Y. Nagasaki, K. Kataoka, Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications. Colloid and Interface Science 6(1) (2001) 3-10.
[13] T-Y. Kim, D.-W. Kim, J.-Y. Chung, S.- G. Shin, S.-C. Kim, D.S. Heo, N. K.Kim, Y.-J. Bang, Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies Clinical Cancer Research 10 (2004) 3708.
[14] T.H. Y Matsumura, T. Hamaguchi, T. Ura, K. Muro, Y. Yamada, Y. Shimada, K. Shirao, T. Okusaka, H. Ueno, M. Ikeda, N. Watanabe, Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. British Journal of Cancer 91(10) (2004) 1775-1781.
[15] E. S. Read, S.P. Armes, Recent advances in shell cross-linked micelles. Chem. Commun (2007) 3021-3035.
[16] T.K. Bronich, P.A. Keifer, L.S. Shlyakhtenko, A.V.Kabanov, Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc 127(23) (2005) 8236-8237.
[17] A. Lavasanifar, J. Samuel, G.S. Kwon, Poly(ethylene oxide)-block-poly(L-amino acid) micelles for drug delivery. Advanced Drug Delivery Reviews 54(2) (2002) 169-190.
[18] R.K. O’Reilly, C.J. Hawker, K. L. Wooley, Cross-linked Block Copolymer Micelles: Functional nanostructures of great potential and versatility. Chem. Soc. Rev 35(11) (2006) 1068-1083.
[19] K. B. Thurmond, H. Y. Huang, C. G. Clark, T. Kowalewski, K. L. Wooley, Shell Cross-linked Polymer Micelles: Stabilized Assemblies with Great Versatility and Potential. Colloids and Surfaces B 16 (1999) 45.
[20] H. Y. Huang, E. E. Remsen, K. L. Wooley, Amphiphilic Core-shell Nanospheres Obtained by Intramicellar Shell Crosslinking of Polymer Micelles with Poly(ethylene oxide) Linkers. Chem. Commun(13) (1998) 1415-1416.
[21] C. Cheng, K. Qi, D. S. Germack, E. Khoshdel, K. L. Wooley, Synthesis of Core-Crosslinked Nanoparticles with Controlled Cylindrical Shape and Narrowly-Dispersed Size via Core-Shell Brush Block Copolymer Templates. Adv. Mater. 19(19) (2007) 2830-2835.
[22] S. Harrisson, K. L. Wooley, Shell-crosslinked Nanostructures from Amphiphilic AB and ABA Block Copolymerss of Styrene-alt-(maleic anhydride) and Styrene: Polymerization, assembly and stabilization in one pot. Chem. Commun(26)(2005) 3259-3261.
[23] Q. Zhang, E. E. Remsen, K. L. Wooley, Shell Crosslinked Nanoparticles Containing Hydrolytically-degradable Crystalline Core Domains. J. Am. Chem. Soc 122(15) (2000) 3642-3651.
[24] C. J. Hawker, K.L. Wooley, The Convergence of Synthetic Organic and Polymer Chemistries. Science 309(5738) (2005) 1200-1205.
[25] Y.L. Li, W.J. Du, G.R. Sun, K.L. Wooley, pH-Responsive Shell Crosslinked Nanoparticles with Hydrolytically-labile Crosslinks. macromolecules 41 (2008) 6605-6607.
[26] Y. T. Li, B. S. Lokitz, S. P. Armes ,C. L. McCormick, Synthesis of Reversible Shell Cross-Linked Micelles for Controlled Release of Bioactive Agents. macromolecules 39 (2006) 2726.
[27] C.J. Rijcken, C.J. Snel, R.M. Schiffelers, C.F. van Nostrum, W.E. Hennink, Hydrolysable core-crosslinked thermosensitive polymeric micelles: Synthesis, characterisation and in vivo studies. Biomaterials 28(36) (2007) 5581-5593.
[28] X. T. Shuai, T. Merdan, A. K. Schaper, F. Xi, T. Kissel, Core-Cross-Linked Polymeric Micelles as Paclitaxel Carriers Bioconjugate Chemistry 15(3) (2004) 441-448.
[29] V. Butun, X.S.Wang, M.V.D. Banez , K. L. Robinson, N. C. Billingham, S. P. Armes, Synthesis of Shell Cross-Linked Micelles at High Solids in Aqueous Media. macromolecules 33 (2000) 1-3.
[30] X. Z. Jiang, S.Z.Luo, S.P. Armes, W.F. Shi, S.Y. Liu, UV irradiation-induced shell cross-linked micelles with pH-responsive cores using ABC triblock copolymers. Macromolecules 39 (2006) 5987.
[31] F.H. Meng, W.E. Hennink, Z.Y. Zhong, Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30(12) (2009) 2180-2198.
[32] J. Bustamante, J.K. Lodge, L. Marcocci, H.J. Tritschler, L. Packer, B.H. Rihn, [alpha]-Lipoic Acid in Liver Metabolism and Disease. Free Radical Biology and Medicine 24(6) (1998) 1023-1039.
[33] D.L. Elbert, J.A. Hubbell, Conjugate Addition Reactions Combined withFree-Radical Cross-Linking for the Design of Materials for Tissue Engineering. Biomacromolecules 2(2) (2001) 430-441.
[34] A. Sadownik, J. Stefely, S.L. Regen, Polymerized liposomes formed under extremely mild conditions. Journal of the American Chemical Society 108(24) (1986) 7789-7791.
[35] J. Stefely, M.A. Markowitz, S.L. Regen, Permeability characteristics of lipid bilayers from lipoic acid-derived phosphatidylcholines. Comparison of monomeric, crosslinked and noncrosslinked polymerized membranes. Journal of the American Chemical Society 110(22) (1988) 7463-7469.
[36] M. Balakirev, G. Schoehn, J. Chroboczek, Lipoic acid-derived amphiphiles for redox-controlled DNA delivery. Chemistry & Biology 7(10) (2000) 813-819.
[37] H.F. Xu, F.H. Meng, Z.Y. Zhong, Reversibly crosslinked temperature-responsive nano-sized polymersomes:synthesis and triggered drug release. Journal of Materials Chemistry 19 (2009) 4183-4190.
[38] A.V. Kabanov, E.V. Batrakova, V. Yu. Alakhov, An essential relationship between ATP depletion and chemosensitizing activity of Pluronic block copolymers. Journal of Controlled Release 91 (2003) 75-83.
[39] Y.J. Son, J.-S. Jang, Y.W. Cho, H. Chung, R.-W. Park, I.C. Kwon, I.-S. Kim, J.Y. Park, S.B. Seo, C.R. Park, S.Y. Jeong, Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol-chitosan nanoaggregates by EPR effect. Journal of Controlled Release 91(1-2) (2003) 135-145.
[40] B. Yechezkel, A. Shimon, G. Dorit, C. Rivka, G. Dan, S. Amram, B.G. Elisabeth, G. Alberto, Stability of liposomal doxorubicin formulations: Problems and prospects. Medicinal Research Reviews 13(4) (1993) 449-491.
[41] A. Gabizon, A. Dagan, D. Goren, Y. Barenholz, Z. Fuks, Liposomes as in Vivo Carriers of Adriamycin: Reduced Cardiac Uptake and Preserved Antitumor Activity in Micelles. Cancer Research 42 (1982) 4734-4739.
[1] A. Rosler, G. W. M. Vandermeulen, H.A. Klok, Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Adv Drug Deliv Rev(53) (2001) 95-108.
[2] K. Kataoka, A. Harada, Y. Nagasaki, Block copolymer micelles for drug delivery: design, characterization and biological significance. Advanced Drug Delivery Reviews 47(1) (2001) 113-131.
[3]L. Y. Qiu, Y. H. Bae, Polymer architecture and drug delivery. Pharm. Res 23(1) (2006) 1-30.
[4] V.P. Torchilin, Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine. Pharm. Res 24(1) (2007) 1-16.
[5] Y. Kakizawa, K. Kataoka, Block copolymer micelles for delivery of gene and related compounds. Advanced Drug Delivery Reviews 54(2) (2002) 203-222.
[6] G.S. Kwon, T. Okano, Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews 21(2) (1996) 107-116.
[7] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release 65(1-2) (2000) 271-284.
[8] E. S. Read, S.P. Armes, Recent advances in shell cross-linked micelles. Chem. Commun (2007) 3021-3035.
[9] K.P. Bronich TK, Shlyakhtenko LS, Kabanov AV., Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc 127(23) (2005) 8236-8237.
[10] A. Lavasanifar, J. Samuel, G.S. Kwon, Poly(ethylene oxide)-block- poly(L-amino acid) micelles for drug delivery. Advanced Drug Delivery Reviews 54(2) (2002) 169-190.
[11] R.K. O’Reilly, C.J. Hawker, K.L. Wooley, Cross-linked Block Copolymer Micelles: Functional nanostructures of great potential and versatility. Chem. Soc. Rev 35(11) (2006) 1068-1083.
[12] K. B. Thurmond, H. Y. Huang, C. G. Clark, T. Kowalewski, K. L. Wooley, Shell Cross-linked Polymer Micelles: Stabilized Assemblies with Great Versatility and Potential. Colloids and Surfaces B 16 (1999) 45.
[13] T.D. Dziubla, M.C. Torjman, J.I. Joseph, M. Murphy-Tatum, A.M. Lowman, Evaluation of porous networks of poly(2-hydroxyethyl methacrylate) as interfacial drug delivery devices. Biomaterials 22(21) (2001) 2893-2899.
[14] H. Daniel, L. Frantiscaronek, Rehark Vladim, S. Frantiscaronek, Porous polyHEMA beads prepared by suspension polymerization in aqueous medium. Journal of Applied Polymer Science 49(11) (1993) 2041-2050.
[15] C.D. Vianna-Soares, C.J. Kim, M.R. Borenstein, Borenstein M R,Manufacture of Porous Cross-Linked HEMA Spheres for Size Exclusion Packing Material Journal of Porous Materials 10(2) (2003) 123-130.
[16]张豪,褚良银,胡林, PHEMA多孔微球和微囊的制备及生物医药应用进展.化工进展27(2) (2008) 196-200.
[17] X.W. Xu, J.L. Huang, Synthesis and characterization of amphiphilic copolymer of linear poly(ethylene oxide) linked with [poly(styrene-co-2-hydroxyethyl methacrylate)-graft-poly(ε-caprolactone)] using sequential controlled polymerization. Journal of Polymer Science Part A: Polymer Chemistry 44(1) (2006) 467-476.
[18] H. Maude Le, L. Catherine, P.D. Thomas, H.S. Martina, B.-K. Christopher, Simultaneous reversible addition fragmentation chain transfer and ring-opening polymerization. Journal of Polymer Science Part A: Polymer Chemistry 46(9) (2008) 3058-3067.
[19] A. E. van der Ende, E. J. Kravitz, E. Harth, Approach to Formation of Multifunctional Polyester Particles in Controlled Nanoscopic Dimensions. J. Am. Chem. Soc 130(27) (2008) 8706-8713.
[20] C.J.F. Rijcken, O. Soga, W.E. Hennink, C.F.v. Nostrum, Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery. Journal of Controlled Release 120(3) (2007) 131-148.
[21] R.T. Liggins, H.M. Burt, Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations. Advanced Drug Delivery Reviews 54(2) (2002) 191-202.
[22] K. Yasugi, T. Nakamura, Y. Nagasaki, M. Kato, K. Kataoka, Sugar-Installed Polymer Micelles: Synthesis and Micellization of Poly(ethylene glycol)-poly(d,l-lactide) Block Copolymers Having Sugar Groups at the PEG Chain End. macromolecules 32(24) (1999) 8024-8032.
[23] H. Otsuka, Y. Nagasaki, K. Kataoka, Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications. Colloid and Interface Science 6(1) (2001) 3-10.
[24] J. Bustamante, J.K. Lodge, L. Marcocci, H.J. Tritschler, L. Packer, B.H. Rihn,α-Lipoic Acid in Liver Metabolism and Disease. Free Radical Biology andMedicine 24(6) (1998) 1023-1039.
[25] A. Sadownik, J. Stefely, S.L. Regen, Polymerized liposomes formed under extremely mild conditions. Journal of the American Chemical Society 108(24) (1986) 7789-7791.
[26] J. Stefely, M.A. Markowitz, S.L. Regen, Permeability characteristics of lipid bilayers from lipoic acid-derived phosphatidylcholines. Comparison of monomeric, crosslinked and noncrosslinked polymerized membranes. Journal of the American Chemical Society 110(22) (1988) 7463-7469.
[27] M. Balakirev, G. Schoehn, J. Chroboczek, Lipoic acid-derived amphiphiles for redox-controlled DNA delivery. Chemistry & Biology 7(10) (2000) 813-819.
[28] Y.M. Xu, F.H. Meng, R. Cheng, Z.Y. Zhong, Reduction-Sensitive Reversibly Crosslinked Biodegradable Micelles for Triggered Release of Doxorubicin. Macromolecular Bioscience 9 (2009) 1254-1261.