可生物降解碳酸酯共聚物与纳米抗癌药物的制备及性能研究
|
摘要
生物医用材料是用于生物系统疾病的诊断与治疗、生物体组织或器官的修复或者替换,增进或恢复其功能的材料。其中可生物降解的高分子材料已广泛地用作药物控制释放的载体的研究。由于纳米材料颗粒极小,生物相容性好,在体内不易作为异物受到排斥。因此以可生物降解高分子为载体的纳米胶束和微球药物控制释放体系已成为国内外药学领域的研究热点。
简要介绍可生物降解高分子的分类、合成以及应用,重点综述脂肪族聚碳酸酯和聚酯以及改性聚碳酸酯和聚酯在生物医用高分子材料中的应用。并概述了微波加热在高分子化学中的研究进展以及载药纳米胶束和微球的主要制备方法和药物控制释放系统的分类和发展现状。
将环状碳酸酯单体9-苯基-2,4,8,10-四氧螺[5,5]十一烷-3-酮(2-phenyl -5,5 - bis (hydroxyl-methyl) trimethylene carbonate)与ε-己内酯(ε-Caprolactone)进行了常规加热开环共聚反应,制备了一系列侧链含苄氧基的脂肪族聚碳酸酯,然后用10%Pd/C对聚合物进行氢化还原脱保护,得到侧链含部分羟基的聚碳酸酯。羟基功能基团的引入,不仅增加了聚碳酸酯的亲水性与降解速率,而且有利于化学结合肿瘤靶向基团与药物以及进行其他化学修饰。通过控制单体的投料比合成不同组成的碳酸酯共聚物,进一步调节聚碳酸酯的亲水-疏水性能与降解速率。对所得聚合物进行1H NMR、GPC、FT-IR、DSC、UV、Water Contact Angle等结构表征。体外降解实验表明部分脱保护的碳酸酯共聚物比未脱保护的碳酸酯共聚物有着更好的亲水性和较快的降解速率,两类共聚物都有稳定的释药速率和良好的药物控制释放性能,相对于未脱保护的共聚物来说,还原后的共聚物有更快的释药速率。
将PTC与CL采用微波加热方法进行微波开环共聚反应。研究了单体投料比,引发剂用量,微波聚合功率,微波聚合温度,微波辐照时间对聚合物的影响。对所得聚合物进行1H NMR、GPC、FT-IR、DSC、UV、Water Contact Angle等结构表征。体外降解实验表明共聚物降解缓慢,疏水性强。体外释药实验表明共聚物具有稳定的释药速率和良好的药物控制释放性能。
通过两步反应将肿瘤靶向基团磺胺嘧啶引入到可生物降解的部分还原的碳酸酯共聚物中,合成肿瘤靶向性药物载体。分别采用透析法和高压电场电雾化法制备纳米靶向抗癌药物。并对其形貌尺寸进行了表征,初步研究了纳米药物的体外控制释药性能。
Biomedical materials are used for the diagnosis and treatment of diseases, repairing and replacement of the tissue and organ, to improve or recover the function. The biodegradable polymer materials, can be widely used as the carriers of the drug controlled release systems. Recently, the nano-micelles and nano-particles drug delivery system based on the biodegradable polymers as the carriers have attracted the attention in the pharmacy filed, because nano materials possess the minimal particle size, good biocompatibility and can be reasily to pass through the organ and not be rejected as foreign body.
Briefly reports were done about the categories, synthesis and application of the biodegradable polymers in the first chapter. In addition, the application of aliphatic polycarbonate, polyester and modified polycarbonate and polyester in polymeric biomedical materials were reported subsequently, research progress of microwave heating in polymer chemistry was overviewed. The development trend of drug controlled release systems and the preparation methods of drug-loaded nano-micelles and nano-microparticles were described in detail here.
A series of polycarbonate copolymers were synthesized by the ring-opening bulk polymerization ofε-caprolactone (CL) and 2-phenyl-5,5-bis(hydroxymethyl) trimethylene carbonate (PTC) with Tin (II) 2-ethylhexanoate as an initiator. These polycarbonate copolymers were further reduced by the palladium/carbonate (Pd/C) catalyst to obtain the partly deprotected polycarbonate copolymers. These two type copolymers obtained were characterized by 1H NMR, FT-IR, UV, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and automatic contact angle meter. The influences of the feed molar ratio of monomers, initiator concentration and reaction time as well as reaction temperature on the copolymerization process were also studied. The copolymerization of CL and PTC monomers was a non-ideal copolymerization and the copolymerization reactivity ratio of CL was higher than that of PTC in the polymerization process. In vitro degradation tests indicated that partly deprotected polycarbonate copolymers possess the faster degradation rates and more hydrophilicity than those of unreduced polycarbonate copolymers. In vitro release profiles of 5-Fu from copolymers showed that these two type copolymers have the steady drug release rates and nice controlled release properties. Moreover, partly deprotected polycarbonate copolymers have faster drug release rates than those of unreduced polycarbonate copolymers.
A series of polycarbonate copolymers were synthesized by microwave-assisted ring-opening polymerization ofε-caprolactone (CL) and 2-phenyl-5,5-bis(oxymethyl) trimethylene carbonate (PTC) with Tin (II) 2-ethylhexanoate as an initiator. These copolymers obtained were characterized by 1H NMR, FT-IR, UV, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and automatic contact angle meter. The influences of the feed molar ratio of monomers, initiator concentration, reaction time and reaction temperature, as well as microwave irradiation power on the copolymerization process were also studied. In vitro degradation tests indicated that these polycarbonate copolymers possess the slow degradation rates and strong hydrophobicity. In vitro release profiles of 5-Fu from copolymers showed that copolymers have the steady drug release rates and nice controlled release properties.
Sulfadiazine as the tumor targeting group was incorporated into the biodegradable partly deprotected polycarbonate copolymers to give the tumor-targeting drug delivery carriers. Drug-loaded polymer nano-micelles or nano-particles were prepared by the methods of dialysis and high voltage electric atomization. The particle size and morphology of drug-loaded nanometerials and drug release properties in vitro were also studied.
简要介绍可生物降解高分子的分类、合成以及应用,重点综述脂肪族聚碳酸酯和聚酯以及改性聚碳酸酯和聚酯在生物医用高分子材料中的应用。并概述了微波加热在高分子化学中的研究进展以及载药纳米胶束和微球的主要制备方法和药物控制释放系统的分类和发展现状。
将环状碳酸酯单体9-苯基-2,4,8,10-四氧螺[5,5]十一烷-3-酮(2-phenyl -5,5 - bis (hydroxyl-methyl) trimethylene carbonate)与ε-己内酯(ε-Caprolactone)进行了常规加热开环共聚反应,制备了一系列侧链含苄氧基的脂肪族聚碳酸酯,然后用10%Pd/C对聚合物进行氢化还原脱保护,得到侧链含部分羟基的聚碳酸酯。羟基功能基团的引入,不仅增加了聚碳酸酯的亲水性与降解速率,而且有利于化学结合肿瘤靶向基团与药物以及进行其他化学修饰。通过控制单体的投料比合成不同组成的碳酸酯共聚物,进一步调节聚碳酸酯的亲水-疏水性能与降解速率。对所得聚合物进行1H NMR、GPC、FT-IR、DSC、UV、Water Contact Angle等结构表征。体外降解实验表明部分脱保护的碳酸酯共聚物比未脱保护的碳酸酯共聚物有着更好的亲水性和较快的降解速率,两类共聚物都有稳定的释药速率和良好的药物控制释放性能,相对于未脱保护的共聚物来说,还原后的共聚物有更快的释药速率。
将PTC与CL采用微波加热方法进行微波开环共聚反应。研究了单体投料比,引发剂用量,微波聚合功率,微波聚合温度,微波辐照时间对聚合物的影响。对所得聚合物进行1H NMR、GPC、FT-IR、DSC、UV、Water Contact Angle等结构表征。体外降解实验表明共聚物降解缓慢,疏水性强。体外释药实验表明共聚物具有稳定的释药速率和良好的药物控制释放性能。
通过两步反应将肿瘤靶向基团磺胺嘧啶引入到可生物降解的部分还原的碳酸酯共聚物中,合成肿瘤靶向性药物载体。分别采用透析法和高压电场电雾化法制备纳米靶向抗癌药物。并对其形貌尺寸进行了表征,初步研究了纳米药物的体外控制释药性能。
Biomedical materials are used for the diagnosis and treatment of diseases, repairing and replacement of the tissue and organ, to improve or recover the function. The biodegradable polymer materials, can be widely used as the carriers of the drug controlled release systems. Recently, the nano-micelles and nano-particles drug delivery system based on the biodegradable polymers as the carriers have attracted the attention in the pharmacy filed, because nano materials possess the minimal particle size, good biocompatibility and can be reasily to pass through the organ and not be rejected as foreign body.
Briefly reports were done about the categories, synthesis and application of the biodegradable polymers in the first chapter. In addition, the application of aliphatic polycarbonate, polyester and modified polycarbonate and polyester in polymeric biomedical materials were reported subsequently, research progress of microwave heating in polymer chemistry was overviewed. The development trend of drug controlled release systems and the preparation methods of drug-loaded nano-micelles and nano-microparticles were described in detail here.
A series of polycarbonate copolymers were synthesized by the ring-opening bulk polymerization ofε-caprolactone (CL) and 2-phenyl-5,5-bis(hydroxymethyl) trimethylene carbonate (PTC) with Tin (II) 2-ethylhexanoate as an initiator. These polycarbonate copolymers were further reduced by the palladium/carbonate (Pd/C) catalyst to obtain the partly deprotected polycarbonate copolymers. These two type copolymers obtained were characterized by 1H NMR, FT-IR, UV, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and automatic contact angle meter. The influences of the feed molar ratio of monomers, initiator concentration and reaction time as well as reaction temperature on the copolymerization process were also studied. The copolymerization of CL and PTC monomers was a non-ideal copolymerization and the copolymerization reactivity ratio of CL was higher than that of PTC in the polymerization process. In vitro degradation tests indicated that partly deprotected polycarbonate copolymers possess the faster degradation rates and more hydrophilicity than those of unreduced polycarbonate copolymers. In vitro release profiles of 5-Fu from copolymers showed that these two type copolymers have the steady drug release rates and nice controlled release properties. Moreover, partly deprotected polycarbonate copolymers have faster drug release rates than those of unreduced polycarbonate copolymers.
A series of polycarbonate copolymers were synthesized by microwave-assisted ring-opening polymerization ofε-caprolactone (CL) and 2-phenyl-5,5-bis(oxymethyl) trimethylene carbonate (PTC) with Tin (II) 2-ethylhexanoate as an initiator. These copolymers obtained were characterized by 1H NMR, FT-IR, UV, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and automatic contact angle meter. The influences of the feed molar ratio of monomers, initiator concentration, reaction time and reaction temperature, as well as microwave irradiation power on the copolymerization process were also studied. In vitro degradation tests indicated that these polycarbonate copolymers possess the slow degradation rates and strong hydrophobicity. In vitro release profiles of 5-Fu from copolymers showed that copolymers have the steady drug release rates and nice controlled release properties.
Sulfadiazine as the tumor targeting group was incorporated into the biodegradable partly deprotected polycarbonate copolymers to give the tumor-targeting drug delivery carriers. Drug-loaded polymer nano-micelles or nano-particles were prepared by the methods of dialysis and high voltage electric atomization. The particle size and morphology of drug-loaded nanometerials and drug release properties in vitro were also studied.
引文
[1] Griffith L G. Polymeric biomaterials [J]. Acta Mater 2000; 48: 263-277.
[2] Van M JA, Luyn R A, Cardiac tissue engineering: characteristics of in unison contracting two-and three-dimensional neonatal ratventricle cell (co)-cultures [J]. Biomaterials 2002; 24: 4793-4801.
[3] Chu P K, Chen J Y, Wang L P, Plasma surface modification of biomaterials [J]. Materials Science and Engineering-R-Reports 2002; 36(5-6): 143-206.
[4] Koji H, Naohide T, Takafumi Y, et al. Prospects for bone fixation-development of new cerclage fixation techniques [J]. Materials Science and Engineering 2001; 301: 27-32.
[5] Amaral M, Costa M A, Lopes M A, et al. Fernandes Si3N4-bio glass composites stimulate the proliferation of MG63 osteo blast-like cells and support the osteogenic differentiation of human bone marrow cell [J]. Biomaterials 2002; 24: 4897-4906.
[6] Lin F H, Lee Y H, Jian C H. A study of puriedmont morillonite intercalated with 5-Fluorouracil as drug carrier [J]. Biomaterials 2002; 23: 1981-1987.
[7] Rita C, Elisabetta E, Giovanni L. Claudio N. Production of lipospheres as carriers for bioactive compounds [J]. Biomaterials 2002; 23: 2283-2294.
[8] Ishihara M, Nakanishi K, Ono K, et al. Photo-crosslinkable chitosanas addressing for wound occlusion and acceleration healing process [J]. Biomaterials 2002; 23: 833-840.
[9] Chen C C, Chueh J Y, How Tseng, Haw Ming HS, Yang L. Preparation and characterization of biodegradable PLA polymeric blends [J]. Biomaterials 2003; 24: 1167-1173.
[10] Park J Y, Lee Y J, Chang S Y, Jeong M J. Radio isotope carrying polyethyleneoxide-poly caprolactone copolymer micells for targetable bone imaging [J]. Biomaterials 2002; 23: 873-879.
[11] Ramshaw JA M, Vaughan P R, Werkmeister J A. Applications of collagen in medical devices [J]. Biomed Eng Applications Basis Communications 2001; 13(1): 14-26.
[12] Singh D K, Ray A R, Biomedical applications of chitin, chitosan, and their derivatives [J]. J Macromol Sci Rev Macromol Chem Phys 2000; 40(C) (1): 69-83.
[13] Kohn J, Langer R. Polymerization reactions involving the side chains of L-amino Acids [J]. J Am Chem Soc, 1987, 109: 817-820.
[14] Deming T J. Living Polymerization of alpha-Amino Acid-N-Carboxyanhydrides [J]. J Polym Sci Polym Chem, 2000, 38: 3011-3018.
[15] Pitt C G. Poly (ε-Caprolactone) and its Copolymers [M]. In: polymeric biomaterial (Dumitriu Seel). New York: Marcel Dekker Inc. 1994, 71-119.
[16] Chen D R, Bei J Z, Wang S G. Polycaprolactone microparticles and their biodegradation [J]. Polymer Degradation and Stability, 2000, 12(4): 471-478.
[17] Shieh S J, Zimmerman M C, Parsons J R. Preliminary characterization of resorbable and non-resorbable synthetic fibers for repaired soft tissue [J]. J Biomed Mater Sci, 1990, 44: 789-808.
[18] Leong K W, Brotl B C, Langer R. Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation and release characteristics [J]. J Med. Biomed Mater Res, 1985, 19: 941-955.
[19] Domb A J, Gallardo C F, Langer R. Polyanhydrides based on aliphatic-aromatic diacids [J]. Macromolecules, 1989, 22: 3200.
[20] Leong K W, Mao H Q, Zhuo R X. The biodegradable polymerswith a phosphoryl-containing backbone: tissue engineering and controlled drug delivery application [J]. Chin J Polym Sci, 1995, 13: 289-314.
[21] Allcock H R, Austin P E, Neenan T X, et al. Phosphazene high polymers with bioactive substituent groups: Prospective Synesthetic Aminophosphazenes [J].Macromolecules, 1982, 15: 689-693.
[22] Potts, J.E.; Clendinnings, R.A.; Ackart, W.B.; Niegisch, W.D. The biodegradability of synthetic polymers [J]. Polym Sci. Technol. 1973, 3, 61-79.
[23] Diamond, M.J.; Freedman, B.; Galibaldi, J. A. Biodegradable polyester films [J]. Int. Biodetn. Bull.Ⅱ.1975, 127-132.
[24] Fields, R. D.; Rodriguez, F.; Finn, R. K. Microbial degradation of polyesters [J]. J. Appl. Polym. Sci. 1981, 26, 441-448.
[25] Tokiwa, Y.; Suzuki, T. Hydrolysis of copolyesters containing aromatic and aliphatic ester blocks by lipase [J]. J. Appl. Polym. Sci. 1981, 26, 441-448.
[26] Tokiwa, Y.; Suzuki, T. Hydrolysis of polyesters by lipases [J]. Nature, 1977, 270, 76-78.
[27] Schnell H. Chemistry and physics of polycarbonates [J]. Wiley, New York, 1964.
[28] Rokicki G. Aliphatic cyclic carbonates and spiroortho carbonates as monomers [J]. Prog Polym Sci, 2000, 25: 259-342.
[29] Yu, Z J; Liu, L J; Zhuo, R X. Microwave-improved polymerization ofε-caprolactone initiated by carboxylic acid [J]. J. Polym. Sci. Part A: Polym. Chem. 2003, 41, 13.
[30] Yu, Z J; Liu, L J; Song, Y.; Zhuo, R X. Microwave irradiation effect on the polymerization ofε-caprolactone with benzoic acid as initiator [J]. Polym. Prepr. 2003, 44, 868-867.
[31]张超.丙交酯和三亚甲基碳酸酯微波开环聚合初探[D].武汉:武汉大学,2002.
[32] Liu, L. J., Zhang, C., Liao, L. Q., Zhuo, R. X. Microwave-assisted polymerization of D, L-lactide with stannous octanoate as catalyst, Chin [J]. Chem. Lett. 2001, 12, 663.
[33] Zhang, C., Liu, L. J., Liao, L. Q, Zhuo, R. X. Microwave-assisted ring opening polymerization of trimethylcarbonat, Polym [J]. Prepr. 2003, 44, 674.
[34]傅杰,李世普.聚合物药物控制释放体系研究进展[J].材料导报.1999,13(6): 52-57.
[35]茹宗玲,杜慧.苯乙烯分散聚合反应制备均一粒径PS微球[J].安阳师范学院学报,2002,5:18-20.
[36]王雅琼,徐文林,吴昊.苯乙烯分散聚合工艺条件对转化率及微球尺寸的影响[J].化学反应工程于工艺.2002,18(2): 138-143.
[37]罗付生.功能型复合超微粒子的制备研究[D].博士学位论文.南京:南京理工大学.2002.
[38]郝广杰,申小义,梁志武,等.乳液法制备中空结构聚合物研究进展[J].石油化工,2003,32(6): 535-538.
[39]刘岚,卢保森,郑军军,等.种子溶胀聚合法制备新型分子烙印聚合物[J].中山大学学报(自然科学版), 2004, 43(3): 45-48.
[40] Guang Hui Ma, Hirotaka Sone, Shinzo Omi. Preparation of uniform-sized polystyrene polyacrylamide composite microspheres from a W/O/W emulsion by membrane emulsification technique and subsequent polymerization [J]. Macromolecules, 2004, 37: 2954-2964.
[41] LU X Y, WU J, Kim J S, et al. Self-assembly of mixtures of block copolymers of poly(styrene-b-acrylic acid) with random copolymers of poly(styrene-co-methacrylic acid) [J]. Langmuir, 2006, 22: 419-424.
[42] Guang HuiMa, Junichiro Fujiwara, Zhiguo Su, etal. Synthesisand characterization of crosslinked uniform polymeric microspheres containing polymide prepolymer by a new emulsification process [J]. J.Polym.Sci.Part A: Polym.Chem. 2003, 41(16): 2588-2598.
[43] Kubo S, Gu Z-Z, Takahashi K, et al. Control of optical band structure of liquid crystal-infiltrated inverse opal by a photoinduced nematic-iso-tropic phase transition [J]. J Am Chem Soc, 2002, 124: 10950-10951.
[44] Hu, B.; Yan, G. P.; Wu, Y.; Fan, C. L.; Zhuo, R. X. [J]. J. Appl. Polym. Scien. 2008, 107(5),3343.
[45] Mei, L. L.; Yan, G. P.; Yu, X. H.; Cheng, S. X.; Wu J. Y. [J]. J. Appl. Polym. Scien. 2008, 108,93.
[46] Bogdal D, Penczek P, Pielichowski J, Prociak A. Microwave assisted synthesis, crosslinking, and processing of polymeric materials [J]. Adv Polym Sci, 2003, 163: 193-263.
[47] Zong L, Zhou S, Sgriccia N, Hawley M C, Kempel L C. A review of microwave-assisted polymer chemistry (MAPC) [J]. J Microwave Power Electromagn Energy, 2003, 38: 49-74.
[48] Wiesbrock F, Hoogenboom R, Schubert U S. Microwave-assisted Polymer Synthesis: State-of-the-art and future perspectives [J]. Macromol Rapid Commun, 2004, 25: 1739-1764.
[49] Zhang C, Liao L Q, Gong S. Recent developments in microwave-assisted polymerization with a focus on ring-opening polymerization [J]. Green Chem, 2007, 9: 303-314.
[50] Hoogenboom R, Schubert U S. Microwave-assisted Polymer Synthesis: Recent developments in a rapidly expanding field of research [J]. Macromol Rapid Commun, 2007, 28: 368-386.
[51] Xu Z S, Deng Z W, Hu X X, Yi C F. Monodisperse polystyrene micropheres prepared by dispersion polymerization with microwave irradiation [J]. J Polym Sci Part A: Polym Chem, 2005, 43:2368-2376.
[52] Canadell J, Mantecon A, Cadiz V. Microwave-assisted synthesis of a novel phosphorus-containing spiroorthoester, characterization and cationic polymerization [J]. J Polym Sci Polym Chem, 2006, 44: 4722-4730.
[53] Zhu J, Zhu X L, Zhang Z B, Cheng Z P. Reversible addition-fragmentation chain transfer polymerization of styrene under microwave irradiation [J]. J Polym Sci Part A: Polym Chem, 2006, 44: 6810-6816.
[54] Liao L Q, Liu L J, Zhang C, He F, Zhuo R X. Microwave-assisted polycondensation of L-2-hydroxy-3-phenylpropanoic acid [J]. Chin Chem Lett, 2003, 12: 761-762.
[55] Sándor K, IldikóB, Jen? B, Gy?rgy D, Miklós D. A fast microwave-mediated bulk polycondensation of D, L-lactic acid [J]. Macromol Rapid Commun, 2001, 22: 1063-1065.
[56] Watanabe S, Hayama K, Imai Y. New microwave-assisted rapid synthesis of polyamides from nylon salts [J]. Macromol Rapid Commun, 1993, 14: 481-484.
[57] Imai Y, Hisashi N, Watanabe S, Masaki K. A new facile and rapid synthesis of aliphatic polyamides by microwave assisted polycondensation ofω-amino acids and nylon salts [J]. Polym J, 1996, 28: 256-260.
[58]廖工铁.靶向药物制剂[M].成都:四川科技出版社.1997.
[59] Harada A, Kataoka K. Formation of polyion complex micells in an aqueos milieu from a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments [J]. Macromolecules 1995; 28: 5294-5299.
[60] Leroux J C, Doelker E, Gurny R, et al. Pharmaco kinetics of anovel HIV-1 protease inhibitor in corporated into biodegradable or enteric nanoparticles following intravenous and oral adminstration to mice [J]. J pharm Sci 1995.
[61] Kawashima Y, Yamamoto H, Takeuchi H, et al. Pulmonary delivery of insulin with nebulized D, L-lactide/glycolide copolymer (PLGA) nanospheres to prolong hypoglycemic effect [J]. J Control Release 1999; 62: 279-287.
[62] Mauson S, Johnston KP, Comhes JR. Formation of poly(1,1,2,2-tetrahydroper fluorodecyl acrylate) submicron Fibers and particles from supercritical carbon dioxide solutions [J]. Macromolecules 1995; 28: 3128-31.
[2] Van M JA, Luyn R A, Cardiac tissue engineering: characteristics of in unison contracting two-and three-dimensional neonatal ratventricle cell (co)-cultures [J]. Biomaterials 2002; 24: 4793-4801.
[3] Chu P K, Chen J Y, Wang L P, Plasma surface modification of biomaterials [J]. Materials Science and Engineering-R-Reports 2002; 36(5-6): 143-206.
[4] Koji H, Naohide T, Takafumi Y, et al. Prospects for bone fixation-development of new cerclage fixation techniques [J]. Materials Science and Engineering 2001; 301: 27-32.
[5] Amaral M, Costa M A, Lopes M A, et al. Fernandes Si3N4-bio glass composites stimulate the proliferation of MG63 osteo blast-like cells and support the osteogenic differentiation of human bone marrow cell [J]. Biomaterials 2002; 24: 4897-4906.
[6] Lin F H, Lee Y H, Jian C H. A study of puriedmont morillonite intercalated with 5-Fluorouracil as drug carrier [J]. Biomaterials 2002; 23: 1981-1987.
[7] Rita C, Elisabetta E, Giovanni L. Claudio N. Production of lipospheres as carriers for bioactive compounds [J]. Biomaterials 2002; 23: 2283-2294.
[8] Ishihara M, Nakanishi K, Ono K, et al. Photo-crosslinkable chitosanas addressing for wound occlusion and acceleration healing process [J]. Biomaterials 2002; 23: 833-840.
[9] Chen C C, Chueh J Y, How Tseng, Haw Ming HS, Yang L. Preparation and characterization of biodegradable PLA polymeric blends [J]. Biomaterials 2003; 24: 1167-1173.
[10] Park J Y, Lee Y J, Chang S Y, Jeong M J. Radio isotope carrying polyethyleneoxide-poly caprolactone copolymer micells for targetable bone imaging [J]. Biomaterials 2002; 23: 873-879.
[11] Ramshaw JA M, Vaughan P R, Werkmeister J A. Applications of collagen in medical devices [J]. Biomed Eng Applications Basis Communications 2001; 13(1): 14-26.
[12] Singh D K, Ray A R, Biomedical applications of chitin, chitosan, and their derivatives [J]. J Macromol Sci Rev Macromol Chem Phys 2000; 40(C) (1): 69-83.
[13] Kohn J, Langer R. Polymerization reactions involving the side chains of L-amino Acids [J]. J Am Chem Soc, 1987, 109: 817-820.
[14] Deming T J. Living Polymerization of alpha-Amino Acid-N-Carboxyanhydrides [J]. J Polym Sci Polym Chem, 2000, 38: 3011-3018.
[15] Pitt C G. Poly (ε-Caprolactone) and its Copolymers [M]. In: polymeric biomaterial (Dumitriu Seel). New York: Marcel Dekker Inc. 1994, 71-119.
[16] Chen D R, Bei J Z, Wang S G. Polycaprolactone microparticles and their biodegradation [J]. Polymer Degradation and Stability, 2000, 12(4): 471-478.
[17] Shieh S J, Zimmerman M C, Parsons J R. Preliminary characterization of resorbable and non-resorbable synthetic fibers for repaired soft tissue [J]. J Biomed Mater Sci, 1990, 44: 789-808.
[18] Leong K W, Brotl B C, Langer R. Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation and release characteristics [J]. J Med. Biomed Mater Res, 1985, 19: 941-955.
[19] Domb A J, Gallardo C F, Langer R. Polyanhydrides based on aliphatic-aromatic diacids [J]. Macromolecules, 1989, 22: 3200.
[20] Leong K W, Mao H Q, Zhuo R X. The biodegradable polymerswith a phosphoryl-containing backbone: tissue engineering and controlled drug delivery application [J]. Chin J Polym Sci, 1995, 13: 289-314.
[21] Allcock H R, Austin P E, Neenan T X, et al. Phosphazene high polymers with bioactive substituent groups: Prospective Synesthetic Aminophosphazenes [J].Macromolecules, 1982, 15: 689-693.
[22] Potts, J.E.; Clendinnings, R.A.; Ackart, W.B.; Niegisch, W.D. The biodegradability of synthetic polymers [J]. Polym Sci. Technol. 1973, 3, 61-79.
[23] Diamond, M.J.; Freedman, B.; Galibaldi, J. A. Biodegradable polyester films [J]. Int. Biodetn. Bull.Ⅱ.1975, 127-132.
[24] Fields, R. D.; Rodriguez, F.; Finn, R. K. Microbial degradation of polyesters [J]. J. Appl. Polym. Sci. 1981, 26, 441-448.
[25] Tokiwa, Y.; Suzuki, T. Hydrolysis of copolyesters containing aromatic and aliphatic ester blocks by lipase [J]. J. Appl. Polym. Sci. 1981, 26, 441-448.
[26] Tokiwa, Y.; Suzuki, T. Hydrolysis of polyesters by lipases [J]. Nature, 1977, 270, 76-78.
[27] Schnell H. Chemistry and physics of polycarbonates [J]. Wiley, New York, 1964.
[28] Rokicki G. Aliphatic cyclic carbonates and spiroortho carbonates as monomers [J]. Prog Polym Sci, 2000, 25: 259-342.
[29] Yu, Z J; Liu, L J; Zhuo, R X. Microwave-improved polymerization ofε-caprolactone initiated by carboxylic acid [J]. J. Polym. Sci. Part A: Polym. Chem. 2003, 41, 13.
[30] Yu, Z J; Liu, L J; Song, Y.; Zhuo, R X. Microwave irradiation effect on the polymerization ofε-caprolactone with benzoic acid as initiator [J]. Polym. Prepr. 2003, 44, 868-867.
[31]张超.丙交酯和三亚甲基碳酸酯微波开环聚合初探[D].武汉:武汉大学,2002.
[32] Liu, L. J., Zhang, C., Liao, L. Q., Zhuo, R. X. Microwave-assisted polymerization of D, L-lactide with stannous octanoate as catalyst, Chin [J]. Chem. Lett. 2001, 12, 663.
[33] Zhang, C., Liu, L. J., Liao, L. Q, Zhuo, R. X. Microwave-assisted ring opening polymerization of trimethylcarbonat, Polym [J]. Prepr. 2003, 44, 674.
[34]傅杰,李世普.聚合物药物控制释放体系研究进展[J].材料导报.1999,13(6): 52-57.
[35]茹宗玲,杜慧.苯乙烯分散聚合反应制备均一粒径PS微球[J].安阳师范学院学报,2002,5:18-20.
[36]王雅琼,徐文林,吴昊.苯乙烯分散聚合工艺条件对转化率及微球尺寸的影响[J].化学反应工程于工艺.2002,18(2): 138-143.
[37]罗付生.功能型复合超微粒子的制备研究[D].博士学位论文.南京:南京理工大学.2002.
[38]郝广杰,申小义,梁志武,等.乳液法制备中空结构聚合物研究进展[J].石油化工,2003,32(6): 535-538.
[39]刘岚,卢保森,郑军军,等.种子溶胀聚合法制备新型分子烙印聚合物[J].中山大学学报(自然科学版), 2004, 43(3): 45-48.
[40] Guang Hui Ma, Hirotaka Sone, Shinzo Omi. Preparation of uniform-sized polystyrene polyacrylamide composite microspheres from a W/O/W emulsion by membrane emulsification technique and subsequent polymerization [J]. Macromolecules, 2004, 37: 2954-2964.
[41] LU X Y, WU J, Kim J S, et al. Self-assembly of mixtures of block copolymers of poly(styrene-b-acrylic acid) with random copolymers of poly(styrene-co-methacrylic acid) [J]. Langmuir, 2006, 22: 419-424.
[42] Guang HuiMa, Junichiro Fujiwara, Zhiguo Su, etal. Synthesisand characterization of crosslinked uniform polymeric microspheres containing polymide prepolymer by a new emulsification process [J]. J.Polym.Sci.Part A: Polym.Chem. 2003, 41(16): 2588-2598.
[43] Kubo S, Gu Z-Z, Takahashi K, et al. Control of optical band structure of liquid crystal-infiltrated inverse opal by a photoinduced nematic-iso-tropic phase transition [J]. J Am Chem Soc, 2002, 124: 10950-10951.
[44] Hu, B.; Yan, G. P.; Wu, Y.; Fan, C. L.; Zhuo, R. X. [J]. J. Appl. Polym. Scien. 2008, 107(5),3343.
[45] Mei, L. L.; Yan, G. P.; Yu, X. H.; Cheng, S. X.; Wu J. Y. [J]. J. Appl. Polym. Scien. 2008, 108,93.
[46] Bogdal D, Penczek P, Pielichowski J, Prociak A. Microwave assisted synthesis, crosslinking, and processing of polymeric materials [J]. Adv Polym Sci, 2003, 163: 193-263.
[47] Zong L, Zhou S, Sgriccia N, Hawley M C, Kempel L C. A review of microwave-assisted polymer chemistry (MAPC) [J]. J Microwave Power Electromagn Energy, 2003, 38: 49-74.
[48] Wiesbrock F, Hoogenboom R, Schubert U S. Microwave-assisted Polymer Synthesis: State-of-the-art and future perspectives [J]. Macromol Rapid Commun, 2004, 25: 1739-1764.
[49] Zhang C, Liao L Q, Gong S. Recent developments in microwave-assisted polymerization with a focus on ring-opening polymerization [J]. Green Chem, 2007, 9: 303-314.
[50] Hoogenboom R, Schubert U S. Microwave-assisted Polymer Synthesis: Recent developments in a rapidly expanding field of research [J]. Macromol Rapid Commun, 2007, 28: 368-386.
[51] Xu Z S, Deng Z W, Hu X X, Yi C F. Monodisperse polystyrene micropheres prepared by dispersion polymerization with microwave irradiation [J]. J Polym Sci Part A: Polym Chem, 2005, 43:2368-2376.
[52] Canadell J, Mantecon A, Cadiz V. Microwave-assisted synthesis of a novel phosphorus-containing spiroorthoester, characterization and cationic polymerization [J]. J Polym Sci Polym Chem, 2006, 44: 4722-4730.
[53] Zhu J, Zhu X L, Zhang Z B, Cheng Z P. Reversible addition-fragmentation chain transfer polymerization of styrene under microwave irradiation [J]. J Polym Sci Part A: Polym Chem, 2006, 44: 6810-6816.
[54] Liao L Q, Liu L J, Zhang C, He F, Zhuo R X. Microwave-assisted polycondensation of L-2-hydroxy-3-phenylpropanoic acid [J]. Chin Chem Lett, 2003, 12: 761-762.
[55] Sándor K, IldikóB, Jen? B, Gy?rgy D, Miklós D. A fast microwave-mediated bulk polycondensation of D, L-lactic acid [J]. Macromol Rapid Commun, 2001, 22: 1063-1065.
[56] Watanabe S, Hayama K, Imai Y. New microwave-assisted rapid synthesis of polyamides from nylon salts [J]. Macromol Rapid Commun, 1993, 14: 481-484.
[57] Imai Y, Hisashi N, Watanabe S, Masaki K. A new facile and rapid synthesis of aliphatic polyamides by microwave assisted polycondensation ofω-amino acids and nylon salts [J]. Polym J, 1996, 28: 256-260.
[58]廖工铁.靶向药物制剂[M].成都:四川科技出版社.1997.
[59] Harada A, Kataoka K. Formation of polyion complex micells in an aqueos milieu from a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments [J]. Macromolecules 1995; 28: 5294-5299.
[60] Leroux J C, Doelker E, Gurny R, et al. Pharmaco kinetics of anovel HIV-1 protease inhibitor in corporated into biodegradable or enteric nanoparticles following intravenous and oral adminstration to mice [J]. J pharm Sci 1995.
[61] Kawashima Y, Yamamoto H, Takeuchi H, et al. Pulmonary delivery of insulin with nebulized D, L-lactide/glycolide copolymer (PLGA) nanospheres to prolong hypoglycemic effect [J]. J Control Release 1999; 62: 279-287.
[62] Mauson S, Johnston KP, Comhes JR. Formation of poly(1,1,2,2-tetrahydroper fluorodecyl acrylate) submicron Fibers and particles from supercritical carbon dioxide solutions [J]. Macromolecules 1995; 28: 3128-31.