壳聚糖基缓释型药物载体的合成、表征及其性能研究
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摘要
本论文以乳糖酸作为导向基修饰壳聚糖,设计并合成了三个系列的壳聚糖基药物缓释载体,表征其结构,并以5-氟尿嘧啶为模型药物构建了载药缓释体系,研究了其在体外的释药行为。具体内容包括以下几个部分:
(1)设计并合成了3个系列的新型壳聚糖基药物缓释载体,分别是:i)二肽修饰的壳聚糖基药物缓释载体;ii)羧乙基修饰的壳聚糖基药物缓释载体;iii)赖氨酸修饰的壳聚糖基药物缓释载体。其中共得到8个新化合物,产物结构经IR、UV-Vis、LC/MS或1_H NMR表征。
(2)依据自组装原理运用透析法制备了分支状壳聚糖-5-氟尿嘧啶(6)的微球,用激光衍射法测定了微球粒径,用SEM测定了微球形态。微球的平均粒径为4μm,球形规整,分散性较好。
(3)对部分化合物的合成条件进行了优化:i)溴乙酰苯丙氨酸(1)的最佳合成条件: pH值10~11,温度-4℃,反应时间1.5h;ii)采用微波加热方式合成中间体N,N-二羧乙基壳聚糖,固定功率550W,微波加热最适宜时间为50 min,反应速率是常规加热的260倍,取代度为1.13;iii)研究了分支状壳聚糖-5-氟尿嘧啶(6)的合成条件,探讨了成交联副反应的机理,常温下最佳反应时间为24h。
(4)用UV-Vis测定了载药缓释体系的载药量及药物体外释放性能。i)分支状壳聚糖-5-氟尿嘧啶(6)的载药量(w/w)为10.60%,在碱性释放介质(pH为7.4的PBS溶液)和酸性释放介质(pH为1.2的盐酸氯化钾溶液)中,维持零级释放的时间分别为42h、34h,182h累计释药百分率分别为57.40%、77.86%;ii)分支状壳聚糖-5-氟尿嘧啶微球的载药量为13.21%,药物包封率为26.1%,在碱性和酸性释放介质中,分别在开始10h和6h有轻微突释现象,突释阶段累积释药百分含量分别为19.93%、23.82%,182h累计释药百分率分别为58.89%、79.33%;iii)分支状乳糖酰壳聚糖-5-氟尿嘧啶(7)的载药量为7.48%,在碱性和酸性释放介质中,维持零级释放的时间分别为34h、28h,182h累计释药百分率分别为65.45%、87.51%;iv)分支状壳聚糖赖氨酰-5-氟尿嘧啶(10)的载药量为9.17%;v)分支状四乳糖酰壳聚糖-5-氟尿嘧啶(13)的载药量为1.63%,在碱性和酸性释放介质中,维持零级释放的时间分别为64h、24h,184h累计释药百分率分别为71.97%和82.34%。
Three series of chitosan-based drug deliveries were designed and synthesized with lactose acid modified chitosan as guiding group and their structures were characterized in this thesis. The drug sustained releasing systems were constructed with 5-fluorouracil as model drug and their releasing behavior in vitro was studied. The main contents of this thesis include following:
(1) Three series of novel chitosan-based drug deliveries were designed and synthesized. They were: i) chitosan-based drug deliveries modified with dipeptide, ii) chitosan-based drug deliveries modified with carboxyethyl, iii) chitosan-based drug deliveries modified with lysine. A total of eight new compounds were obtained and their structures were characterized by IR, UV-Vis, LC/MS or 1_H NMR.
(2) Microspheres of dendritic chitosan -5 - fluorouracil (6) were prepared by the use of dialysis method based on principle of self-assembly. The diameter of microspheres was determined by laser diffraction and the configuration of microspheres was scanned using SEM. The results were the average diameter of microspheres of 4μm and regular spheres with good distribution.
(3) Some synthetic conditions were optimized. i) Optimum conditions of bromoacetyl phenylalanine(1) were pH value of 10~11, temperature of -4℃and reaction time of 1.5h. ii) N,N-dicarboxyethyl chitosan was synthesized by microwave heating. Optimum conditions with fixed power of 550W were heating time of 50 min, reaction rate of 260 times as conventional heating and the DS of N,N-dicarboxyethyl chitosan of 1.13. iii) Synthesis conditions of dendritic chitosan-5-fluorouracil(6) were resaerched and the mechanism of crosslinking side reactions was explored and the optimum reaction time was 24h under room temperature.
(4) The drug loading(w/w) and releasing properties in vitro of drug sustained releasing systems were determined with UV-Vis. i) Dendritic chitosan-5- fluorour- acil (6) was drug loading of 10.60%. In alkaline media (PBS solution, pH 7.4) and acid media (HCl/KCl solution, pH 1.2), its zero-order releasing time were 42h, 34h respectively and cumulative releasing percentage were 57.40%, 77.86% respectively in 182h. ii) Microspheres of dendritic chitosan -5 - fluorouracil were drug loading of 13.21% and encapsulation efficiency of 26.1%. In alkaline and acid media its slight burst release phenomenon appeared at the beginning of 10h and 6h respectively, cumulative releasing percentage of burst release were 19.93%, 23.82% respectively and cumulative releasing percentage were 58.89%, 79.33% respectively in 182h. iii) Dendritic galactosylated chitosan-5-fluorouracil (7) was drug loading of 7.48%. In alkaline and acid media, its zero-order releasing time were 34h, 28h respectively and cumulative releasing percentage were 65.45%, 87.51% respectively in 182h. iv) Dendritic chitosan lysyl-5-fluorouracil (10) was drug loading of 9.17%. v) Dendritic four-galactosylated chitosan-5 - fluorouracil (13) was drug loading of 1.63%. In alkaline and acid media, its zero-order releasing time were 64h, 24h respectively and cumulative releasing percentage were 71.97%, 82.34% respectively in 184h.
(1)设计并合成了3个系列的新型壳聚糖基药物缓释载体,分别是:i)二肽修饰的壳聚糖基药物缓释载体;ii)羧乙基修饰的壳聚糖基药物缓释载体;iii)赖氨酸修饰的壳聚糖基药物缓释载体。其中共得到8个新化合物,产物结构经IR、UV-Vis、LC/MS或1_H NMR表征。
(2)依据自组装原理运用透析法制备了分支状壳聚糖-5-氟尿嘧啶(6)的微球,用激光衍射法测定了微球粒径,用SEM测定了微球形态。微球的平均粒径为4μm,球形规整,分散性较好。
(3)对部分化合物的合成条件进行了优化:i)溴乙酰苯丙氨酸(1)的最佳合成条件: pH值10~11,温度-4℃,反应时间1.5h;ii)采用微波加热方式合成中间体N,N-二羧乙基壳聚糖,固定功率550W,微波加热最适宜时间为50 min,反应速率是常规加热的260倍,取代度为1.13;iii)研究了分支状壳聚糖-5-氟尿嘧啶(6)的合成条件,探讨了成交联副反应的机理,常温下最佳反应时间为24h。
(4)用UV-Vis测定了载药缓释体系的载药量及药物体外释放性能。i)分支状壳聚糖-5-氟尿嘧啶(6)的载药量(w/w)为10.60%,在碱性释放介质(pH为7.4的PBS溶液)和酸性释放介质(pH为1.2的盐酸氯化钾溶液)中,维持零级释放的时间分别为42h、34h,182h累计释药百分率分别为57.40%、77.86%;ii)分支状壳聚糖-5-氟尿嘧啶微球的载药量为13.21%,药物包封率为26.1%,在碱性和酸性释放介质中,分别在开始10h和6h有轻微突释现象,突释阶段累积释药百分含量分别为19.93%、23.82%,182h累计释药百分率分别为58.89%、79.33%;iii)分支状乳糖酰壳聚糖-5-氟尿嘧啶(7)的载药量为7.48%,在碱性和酸性释放介质中,维持零级释放的时间分别为34h、28h,182h累计释药百分率分别为65.45%、87.51%;iv)分支状壳聚糖赖氨酰-5-氟尿嘧啶(10)的载药量为9.17%;v)分支状四乳糖酰壳聚糖-5-氟尿嘧啶(13)的载药量为1.63%,在碱性和酸性释放介质中,维持零级释放的时间分别为64h、24h,184h累计释药百分率分别为71.97%和82.34%。
Three series of chitosan-based drug deliveries were designed and synthesized with lactose acid modified chitosan as guiding group and their structures were characterized in this thesis. The drug sustained releasing systems were constructed with 5-fluorouracil as model drug and their releasing behavior in vitro was studied. The main contents of this thesis include following:
(1) Three series of novel chitosan-based drug deliveries were designed and synthesized. They were: i) chitosan-based drug deliveries modified with dipeptide, ii) chitosan-based drug deliveries modified with carboxyethyl, iii) chitosan-based drug deliveries modified with lysine. A total of eight new compounds were obtained and their structures were characterized by IR, UV-Vis, LC/MS or 1_H NMR.
(2) Microspheres of dendritic chitosan -5 - fluorouracil (6) were prepared by the use of dialysis method based on principle of self-assembly. The diameter of microspheres was determined by laser diffraction and the configuration of microspheres was scanned using SEM. The results were the average diameter of microspheres of 4μm and regular spheres with good distribution.
(3) Some synthetic conditions were optimized. i) Optimum conditions of bromoacetyl phenylalanine(1) were pH value of 10~11, temperature of -4℃and reaction time of 1.5h. ii) N,N-dicarboxyethyl chitosan was synthesized by microwave heating. Optimum conditions with fixed power of 550W were heating time of 50 min, reaction rate of 260 times as conventional heating and the DS of N,N-dicarboxyethyl chitosan of 1.13. iii) Synthesis conditions of dendritic chitosan-5-fluorouracil(6) were resaerched and the mechanism of crosslinking side reactions was explored and the optimum reaction time was 24h under room temperature.
(4) The drug loading(w/w) and releasing properties in vitro of drug sustained releasing systems were determined with UV-Vis. i) Dendritic chitosan-5- fluorour- acil (6) was drug loading of 10.60%. In alkaline media (PBS solution, pH 7.4) and acid media (HCl/KCl solution, pH 1.2), its zero-order releasing time were 42h, 34h respectively and cumulative releasing percentage were 57.40%, 77.86% respectively in 182h. ii) Microspheres of dendritic chitosan -5 - fluorouracil were drug loading of 13.21% and encapsulation efficiency of 26.1%. In alkaline and acid media its slight burst release phenomenon appeared at the beginning of 10h and 6h respectively, cumulative releasing percentage of burst release were 19.93%, 23.82% respectively and cumulative releasing percentage were 58.89%, 79.33% respectively in 182h. iii) Dendritic galactosylated chitosan-5-fluorouracil (7) was drug loading of 7.48%. In alkaline and acid media, its zero-order releasing time were 34h, 28h respectively and cumulative releasing percentage were 65.45%, 87.51% respectively in 182h. iv) Dendritic chitosan lysyl-5-fluorouracil (10) was drug loading of 9.17%. v) Dendritic four-galactosylated chitosan-5 - fluorouracil (13) was drug loading of 1.63%. In alkaline and acid media, its zero-order releasing time were 64h, 24h respectively and cumulative releasing percentage were 71.97%, 82.34% respectively in 184h.
引文
[1] Eva M Martín del Valle, Miguel A Galán, Ruben G Carbonell. Drug delivery technologies: the way forward in the new decade. Industrial and Engineering Chemistry Research, 2009, 48(5): 2475-2486.
[2] Ashish Dev, Binulal N S, Anitha A, et al. Preparation of poly(lactic acid)/chitosan nanoparticles for anti-HIV drug delivery applications. Carbohydrate Polymers, 2010, 80(3): 833-838
[3] Sarmila Sahoo, Abhisek Sasmal, Rajashree Nanda, et al. Synthesis of chitosan-polycaprolactone blend for control delivery of ofloxacin drug. Carbohydrate Polymers, 2010, 79(1): 106-113.
[4] Mourya V K, Nazma N Inamdar. Chitosan-modifications and applica- tions: Opportunities galore. Reactive & Functional Polymers, 2008, 68 (6): 1013-1051.
[5]Yasunori Maeda, Yoshiyuki Kimura. Antitumor effects of various low-molecu-larweight-chitosans are due to increased natural killer activity of intestinal intraepithelial lympho-cytes in sarcoma 180-bearing mice. Journal of Nutrition, 2004, 134 (4): 945-948.
[6] Thanou M, Verhoef J C, Junginger H E. Oral drug absorption enhancement by chitosan and its derivatives. Advanced Drug Delivery Reviews, 2001, 52(2): 117-126.
[7] Ravi Kumar M N V, Muzzarelli R A A, Muzzarelli C, et al. Chitosan chemistry and pharmaceutical perspectives. Chemical Reviews, 2004, 104 (12): 6017-6084.
[8] Bosch F X, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology, 2004, 127(Suppl): S5-16.
[9] Lai E C, Lau W Y. The continuing challenge of hepatic cancer in Asia. Surgeon, 2005, 3(3): 210-215.
[10] Zhang Yu-Jing, Li Haiyang, Wu Hui-Chen, et al. Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma. Cancer Letters, 2009, 275 (2): 277-284.
[11] Taghizadeh S M, Davari G. Preparation, characterization, and swelling behavior of N-acetylated and deacetylated chitosans. Carbohydrate Polymers, 2006, 64(1): 9-15.
[12]蒋挺大.壳聚糖,第二版.北京:化学工业出版社, 2006, 15-16.
[13] Lee M Y, Var F, Shin-ya Y, et al. Optimum conditions for the precipitation ofchitosan oligomers with DP 5-7 in concentrated hydrochloric acid at low temperature. Process Biochemistry , 1999, 34(5): 493-500.
[14] Mohamed E I Badawy, Entsar I Rabea, Tina M Rogge, et al. Synthesis and fungicidal activity of new N, O-Acyl chitosan derivatives. Biomacromolecules, 2004, 5 (2): 589-595.
[15] Masayuki Ishihara, Kuniaki Nakanishi, Katsuaki Ono, et al. Photocrosslinkable chitosan as a dressing for wound occlusion andaccelerator in healing process. Biomaterials, 2002, 23(3): 833-840.
[16] Harish Prashanth K V, Tharanathan R N. Chitin/chitosan: modifications and their unlimited application potential-an overview. Trends in Food Science & Technology, 2007, 18(3): 117-131.
[17] Jae Hyung Park, Gurusamy Saravanakumar, Kwangmeyung Kim, et al. Targeted delivery of low molecular drugs using chitosan and its derivatives. Advanced Drug Delivery Reviews, 2010, 62(1): 28-41.
[18]魏新林,夏文水.甲壳低聚糖的生理活性研究进展.中国药理学通报, 2003, 19(6): 614-617.
[19] Warayuth Sajomsang. Synthetic methods and applications of chitosan containing pyridylmethyl moiety and its quaternized derivatives: A review. Carbohydrate Polymers, 2010, 80(3): 631-647.
[20] Sashiwa H, Shigemasa Y. Chemical modification of chitin and chitosan 2: Prepar- ation and water soluble property of N-acylated or N-alkylated partially deacetylated chitins. Carbohydrate Polymers, 1999, 39(2): 127-138.
[21] Li Mingchun, Su Sheng, Xin Meihua, et al. Relationship between N,N-dialkyl chitosan monolayer and corresponding vesicle. Journal of Colloid and Interface Science, 2007, 311(1): 285-288.
[22] Zhang Can, Ding Ya, Ping Qineng, et al. Novel chitosan-derived nanomaterials and their micelle-forming properties. Journal of Agricultural and Food Chemistry, 2006, 54 (22): 8409-8416.
[23] Jiyoung M Dang, Daniel D N Sun, Yoshitsune Shin-Ya, et al. Temperature-responsive hydroxybutyl chitosan for the culture of mesenchymal stem cells and intervertebral disk cells. Biomaterials, 2006,27(3): 406-418.
[24] Jae Hyung Park, Seunglee Kwon, MinsuLee, et al. Self- assembled nanoparticles based on glycol chitosan bearing hydrophobic moieties as carriers for doxorubicin: In vivo biodistribution and anti-tumor activity. Biomaterials, 2006, 27(1): 119-126.
[25]隋卫平,杨秀利,杨倩等. (2-羟基-3-丁氧基)丙基-羟丙基壳聚糖的应用性质.应用化学, 2002,19(9): 890-893.
[26] Liu Chen-Guang, Kashappa Goud H. Desai, Chen Xi-Guang, et al. Preparation and characterization of nanoparticles containing trypsin based on hydrophobically modified chitosan. Journal of Agricultural and Food Chemistry, 2005, 53(5): 1728-1733.
[27] Mi Fwu-Long, Peng Chih-Kang, Huang Mei-Feng, et al. Preparation and charact- erization of N-acetylchitosan, N-propionylchitosan and N-butyrylchitosan microsph- eres for controlled release of 6-mercaptourine. Carbohydrate Polymers, 2005, 60 (2): 219-227.
[28] Zhu Aiping, Chen Tian, Yuan Lanhua, et al. Synthesis and characteri- zation of N-succinyl-chitosan and its self-assembly of nanospheres. Carbohydrate Polymers, 2006, 66(2): 274-279.
[29] Liu Xiao Fei, Guan Yun Lin , Yang Dong Zhi, et al. Antibacterial action of chitosan and carboxymethylated chitosan. Journal of Applied Polymer Science, 2000, 79(7): 1324 -1335.
[30] Yin Lichen, Fei Likun, Cui Fuying, et al. Superporous hydrogels containing poly (acrylic acid-co-acrylamide)/ O-carboxymethyl chitosan interpenetrating polymer networks. Biomaterials, 2007, 28(6):1258-1266.
[31] Kogana G, Skorik Y A, ?itňanováI, et al. Antioxidant and antimutagenic activity of N- (2-carboxyethyl) chitosan. Toxicology and Applied Pharmacology, 2004, 201 (3) 303-310.
[32] Maria J Cano-Cebrian1, Teodoro Zornoza1, Luis Granero1, et al. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: A target for drug delivery. Current Drug Delivery, 2005, 2(1): 9-22.
[33] Zhang Can, Ding Ya, Yu Liangli (Lucy), et al. Polymeric micelle systems of hydroxycamptothecin based on amphiphilic N-alkyl-N- trimethyl chitosan derivatives. Colloids and Surfaces B: Biointerfaces, 2007, 55(2): 192-199.
[34] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy. Highly convergent synthesis of dendrimerized chitosan-sialic acid hybrid. Macromolecules, 2001, 34(10): 3211-3214.
[35] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy. Chemical modification of chitosan 11: chitosan- dendrimer hybrid as a tree like molecule. Carbohydrate Polymers, 2002, 49(2): 195-205.
[36] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy. Chemical modification of chitosan 10.1: synthesis of dendronized chitosan-sialic acid hybrid using convergentgrafting of preassembled dendrons Built on gallic acid and tri(ethylene glycol) backbone. Macromolecules, 2001, 34 (12): 3905-3909.
[37] Mi Fwu-Long, Wu Yong-Yi, Chiu Ya-Lin. Synthesis of a novel glycoconjugated chitosan and preparation of its derived nanoparticles for targeting HepG2 cells. Biomacromolecules, 2007, 8 (3): 892-898.
[38] Maku?ka R, Gorochovceva N. Regioselective grafting of poly(ethylene glycol) onto chitosan through C-6 position of glucosamine units. Carbohydrate Polymers, 2006, 64(2): 319-327.
[39] Feng Hao, Dong Chang-Ming. Synthesis and characterization of phthaloyl-chitosan-g- poly(l-lactide) using an organic catalyst. Carbohydrate Polymers, 2007, 70(3): 258-264.
[40] Cai Kaiyong, Yao Kangde, Cui Yuanlu, et al. Surface modification of poly (D,L-lactic acid) with chitosan and its effects on the culture of osteoblasts in vitro. Journal of Biomedical Materials Research Part A, 2002, 60(3): 398-404.
[41] Chung Tze-Wen, Lu Ya-Fen, Wang Hsin-Ya, et al. Growth of human endothelial cells on different concentrations of Gly-Arg-Gly-Asp grafted chitosan surface. Artificial Organs, 2003, 27(2): 155-161.
[42] Jayanth Panyam, Vinod Labhasetwar. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Advanced Drug Delivery Reviews, 2003, 55(3): 329-347.
[43] Yoshiaki Kawashima. Nanoparticulate systems for improved drug delivery. Advanced Drug Delivery Reviews, 2001, 47(1): 1-2.
[44] Yuichi Ohya, Masahiro Shiratani, Hironao Kobayashi, et al. Release behavior of 5-fluorouracil from chitosan-gel nanospheres immobilizing 5-fluorouracil coated with polysaccharides and their cell specific cytotooxicity. Pure and Applied Chemistry, 1994, 31(5): 629-642.
[45]李和平,肖华伍,肖子丹等.磁性壳聚糖-5-氟尿嘧啶纳米粒的制备及体外释药性能.高分子材料科学与工程, 2007, 23(1): 189-191.
[46] Shu X Z, Zhu K J. Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure. International Journal of Pharmaceutics, 2002, 233(1-2): 217-225.
[47]应晓英,胡富强,袁弘.胰岛素壳聚糖纳米粒的制备.中国药学杂志, 2003, 38(12): 936-939.
[48] Lee K Y, Kim J H, Kwon I C, et al. Self-aggregates of deoxycholic acid-modified chitosan as a novel carrier of adriamycin. Colloid & Polymer Science, 2000, 278(12):1216-1219.
[49] Ping He, Stanley S. Davis, Lisbeth Illum. Chitosan microspheres prepared by spray drying. International Journal of Pharmaceutics, 1999, 187(1): 53-65.
[50]李和平,肖华伍,龙姝等.壳聚糖-5-氟尿嘧啶微球的制备.长沙理工大学学报(自然科学版), 2006, 3(4): 91-96.
[51]王毅超,邹全明,任建敏等.壳聚糖-海藻酸钠幽门螺杆菌全菌蛋白微球的制备及表征.华西药学杂志, 2005, 20(5): 375-377.
[52] Inouye K, Machida Y, Sannan T, et al. Buoyant sustained release tablets based on chitosan. Drug design and delivery, 1988, 2(3):165-75.
[53]刘祖雄,李晓东,汤韧等.壳聚糖-恶丙嗪缓释片的研制.中国药房, 2001, 12(9): 532-533
[54] Kwabena Ofori-Kwakye, John T Fell, Harbans L Sharma, et al. Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release. International Journal of Pharmaceutics, 2004, 270(1-2): 307-313
[55] Güng?r S, Y?ld?z A, ?zsoy Y, et al. Investigations on mefenamic acid sustained release tablets with water-insoluble gel. Il Farmaco, 2003, 58, (5): 397-401.
[56]杨红梅,葛为公,曾立威.烟酸占替诺壳聚糖缓释片的研制及释放度测定.广西医科大学学报, 2005, 22(3): 384-387.
[57] Kawashima Y, Handa T, Kasai A, et al. Novel method for the preparation of controlled-release theophylline granules coated with a polyelectrolyte complex of sodium polyphosphate-chitosan. Journal of Pharmaceutical Sciences, 1985, 74(3): 264-268.
[58] Wang Qun, Dong Zhanfeng, Du Yumin, et al. Controlled release of ciprofloxacin hydrochloride from chitosan/polyethylene glycol blend films. Carbohydrate Polymers, 2007, 69(2): 336-343.
[59] Mi Fwu-Long, Wu Yu-Bey, Shyu Shin-Shing, et al. Control of wound infections using a bilayer chitosan wound dressing with sustainable antibiotic delivery. Journal of Biomedical Materials Research Part A, 2002, 59 (3): 438-449.
[60] Emmanuel A. Ho, Vessela Vassileva, Christine Allen, et al. In vitro and in vivo characterization of a novel biocompatible polymer-lipid implant system for the sustained delivery of paclitaxel. Journal of Controlled Release, 2005, 104(1): 181-191.
[61]肖玲,涂依,李洁等.壳聚糖/壳聚糖季铵盐复合膜的性能研究.武汉大学学报(理学版), 2005, 51(2): 190-194.
[62] Makarand V Risbud, Anandwardhan A Hardikar, Sujata V. Bhat, et al.pH-sensitive freeze-dried chitosan–polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery. Journal of Controlled Release, 2000, 68(1): 23-30.
[63] Ruel-Gariépy E, Leclair G, Hildgen P, et al. Thermosensitive chitosan- based hydrogel containing liposomes for the delivery of hydrophilic molecules. Journal of Controlled Release, 2002, 82(2-3): 373-383.
[64] Ahmed A AL-Kahtani, Naik H S Bhojya, Sherigara B S. Synthesis and characterization of chitosan-based pH-sensitive semi-interpenetrating network microspheres for controlled release of diclofenac sodium. Carbohydrate Research, 2009, 344(5): 699-706.
[65]张维颖,樊东辉,徐政等.温敏性壳聚糖凝胶的阿霉素药物体外缓释研究.中国海洋药物杂志, 2005, 24(5): 50-53.
[66] Hideyuki Tozaki, Junta Komoike, Chika Tada, et al. Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon insulin absorption from the rat colon. Journal of Pharmaceutical Sciences, 1997, 86(9): 1016-1021.
[67] Liu Kun-Ho, Liu Ting-Yu, Chen San-Yuan, et al. Drug release behavior of chitosan-montmorillonite nanocomposite hydrogels following electrostimulation. Acta Biomaterialia, 2008, 4(4): 1038-1045.
[68] Davis S S, Illum L. Sustained release chitosan microspheres prepared by novel spray drying methods. Journal of Microencapsulation, 1999, 16(3): 343-355
[69] Hideyuki Tozaki, Tomokazu Odoriba, Naoki Okada, et al. Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. Journal of Controlled Release, 2002, 82(1): 51-61.
[70] Jain S K, Jain A, Gupta Y, et al. Targeted delivery of 5-ASA to colon using chitosan hydrogel microspheres. Journal of drug delivery science and technology, 2008, 18(5): 315-321.
[71] Lorenzo-Lamosa M L, Remu?án-López C, Vila-Jato J L, et al. Design of microencapsulated chitosan microspheres for colonic drug delivery. Journal of Controlled Release, 1998, 52(1-2): 109-118.
[72] Rubin B R, Talent J M, Pertusi R M, et al. Oral polymeric N-acetyl-D-glucosamine and osteoarthritis. Journal of the American Osteopathic Association, 2001, 101(6): 339-344.
[73] Setnikar I, Rovati L C. Absorption, distribution, metabolism and excretion ofglucosamine sulfate. A review. Arzneimittel-Forschung, 2001, 51(9): 699-725.
[74] Kenneth A Howard1, Sфen R Paludan, Mark A Behlke, et al. Chitosan/siRNA nanoparticle-mediated TNF-αknockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. The American Society of Gene Therapy, 2009, 17 (1): 162-168.
[75] Jia Wei-Tao, Zhang Xin, Luo Shi-Hua, et al. Novel borate glass/ chitosan composite as a delivery vehicle for teicoplanin in the treatment of chronic osteomyelitis. Acta Biomaterialia, 2010, 6(3): 812-819.
[76]莫名月,李国明,方雷.壳聚糖载药微囊的制备及应用研究进展.天津化工, 2005, 19(6): l-4.
[77] Tatsuro Ouchi, Toshio Banba, Mitsuo Fujimoto, et al. Synthesis and antitumor activity of chitosan carrying 5-fluorouracils. Die Makromolekulare Chemie, 1989, 190(8): 1817-1825.
[78] Zheng Yongli, Yang Wuli, Wang Changchun, et al. Nanoparticles based on the complex of chitosan and polyaspartic acid sodium salt: Preparation, characterization and the use for 5-fluorouracil delivery. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 67(3): 621-631.
[79] Liu Chenguang, Fan Wenwen, Chen Xiguang, et al. Self-assembled nanoparticles based on linoleic-acid modified carboxymethyl-chitosan as carrier of adriamycin (ADR). Current Applied Physics, 2007, 7(1): 125-129.
[80] Eunhye Lee, Jinju Lee, In-Hyun Lee, et al. Conjugated Chitosan as a Novel Platform for Oral Delivery of Paclitaxel. Journal of Medicinal Chemistry , 2008, 51 (20): 6442-6449.
[81]刘允怡,赖俊雄.肝癌治疗新进展.临床外科杂志, 2007, 15(1): 2.
[82] Maryvonne Daveau, Michel Scotte, Arnaud Fran?ois, et al. Hepatocyte growth factor, transforming growth factor and their receptors as combined markers of prognosis in hepatocellular carcinoma .Molecular Carcinogenesis, 2003, 36 (3): 130-141
[83]李瀚旻,晏雪生,明安萍等.脂质体介导姜黄素抑制Bel-740细胞增殖和诱导其凋亡的作用.中西医结合肝病杂志, 2005, 15 (4): 214-217.
[84] Qi Xian-Rong, Yan Wen-Wei, Shi Jing. Hepatocytes targeting of cationic liposomes modified with soybean sterylglucoside and polyethylene glycol. World Journal of Gastroenterology, 2005, 11(32): 4947-4952.
[85] Jin Yong, Li Jun, Rong Long-Fu, et al. Anti- hepatocarcinoma effects of 5-fluorouracil encapsulated by galactosylceramide liposomes in vivo and in vitro.World Journal of Gastroenterology, 2005, 11(17): 2643-2646.
[86] Xiang Chen, Xianhuo Wang, Yongsheng Wang, et al. Improved tumor-targeting drug delivery and therapeutic efficacy by cationic liposome modified with truncated bFGF peptide. Journal of Controlled Release, 2010, 145(1): 17-25.
[87]连佳芳,秦葵,徐彪.靶向给药的研究进展.白求恩医学院学报, 2006, 4(2): 106-108.
[88]金义光,艾萍,佟丽等.新型靶向制剂阿昔洛韦药质体的家兔体内的研究.中华临床医药杂志, 2004, 5(22):1-3.
[89]于波涛,张志荣,曾仁杰.肝靶向氟尿嘧啶类脂纳米粒的研究.药学学报, 2000, 35(9): 700-705.
[90] Kramer W, Wess G. Bile acid transport systems as pharmaceutical targets. European journal of clinical investigation, 1996, 26(9): 715-732.
[91] Justin M. Saul, Ananth V. Annapragada, Ravi V. Bellamkonda. A dual-ligand approach for enhancing targeting selectivity of therapeutic nanocarriers. Journal of Controlled Release, 2006, 114(3): 277-287.
[92]高艳,李厚丽,吕青志等.主动转运途径在肝靶向给药系统中的应用.中国医药工业杂志, 2008, 39(7): 542-546.
[93]蔡春,苏敏,杨健等.肝靶向前药半乳糖化人血清白蛋白氟尿嘧啶偶联物的合成及靶向作用.中国药学杂志, 2006, 41(10): 786-789.
[94] Stefano G Di, Kratz F, Lanza M, et al. Doxorubicin coupled to lactosaminated human albumin remains confined within mouse liver cells after the intracellular release from the carrier. Digestive and Liver Disease, 2003, 35(6): 428-433.
[95] Mitsuru Hashida, Hideki Hirabayashi, Makiya Nishikawa, et al. Targeted delivery of drugs and proteins to the liver via receptor-mediated endocytosis. Journal of Controlled Release, 1997, 46(1-2): 129-137
[96] Gao Shuying, Chen Jiangning, Dong Lei, et al. Targeting delivery of oligonucleotide and plasmid DNA to hepatocyte via galactosylated chitosan vector European Journal of Pharmaceutics and Biopharmaceutics, 2005, 60(3): 327-334.
[97] Zhang Can, Cheng Yao, Qu Guowei, et al. Preparation and characterization of galactosylated chitosan coated BSA microspheres containing 5-fluorouracil. Carbohydrate Polymers, 2008, 72(3): 390-397.
[98] Sabine I Weiss, Nathalie Sieverling, Maren Niclasen, et al. Uronic acids functionalized polyethyleneimine (PEI)-polyethyleneglycol (PEG)- graft-copoly- mers as novel synthetic gene carriers. Biomaterials, 2006, 27(10): 2302-2312
[99]石艳,张惠斌,宗莉.靶向甘露糖受体的载体甘露糖化壳聚糖的全合成及其细胞毒性评价.药物生物技术, 2009, 16(3): 207-211.
[100] Peters G J, Backus H H J, Freemantle S, et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2002, 1587 (2-3): 195.
[101] Daniel B Longley, Harkin D Paul, Patrick G Johnston. 5-Fluorouracil: mechanisms of action and clinical strategies. Nature Reviews Cancer, 2003, 3, 330-338.
[102]魏嘉,王立峰,刘宝瑞. 5-FU相关的药物疗效及毒性预测分子研究进展.世界华人消化杂志, 2005, 13(15): 1889.
[103]卓仁禧,刘高伟,彭普平. 5-氟尿嘧啶N1-甲酰基氨基酸、短肽的合成及抗肿瘤活性.高等学校化学学报, 1991, 12(4): 555-559.
[104]刘学军,陈茹玉,杨媛媛. 5-氟尿嘧啶-1-基磷三肽化合物的合成及抗癌活性研究.高等学校化学学报, 2002, 23(7): 1299-1303.
[105] Yin Ping, Hu Mao-Lin, Hu Li-Chuan. Synthesis, structural characterization and anticarcinogenic activity of a new Gly-Gly dipeptide derivative: Methyl 2- (2- (5-fluoro-2, 4-dioxo-3, 4-dihydro- pyrimidin- 1(2H)-yl) acetamido) acetate. Journal of Molecular Structure, 2008, 882(1-3): 75-79.
[106]刘彦钦,张慧娟,韩士田. 5-氟尿嘧啶-卟啉化合物的合成及抗癌活性.有机化学, 2002, 22(4): 279-282.
[107] Shi Weimin, Zhang Gen, Dai Guifu, et al. Synthesis and in vitro PDT activity of miscellaneous porphyrins with amino acid and uracil. Bioorganic & Medicinal Chemistry, 2008, 16(10): 5665-5671.
[108]卓仁禧,陈衢生,刘高伟等.主链含5-氟尿嘧啶聚芳酯的合成.武汉大学学报(自然科学版), 1983, 74(1-3): 114-118.
[109]朱卡,汤谷平,陈启琪等. 5-氟尿嘧啶-聚α,β(2-羟乙基)-D L-天冬酰胺的合成及体内释放的研究.药学学报, 1998, 33(12): 906-909.
[110]张静夏,潘仕荣,王琴梅等.聚羟乙谷氨酰胺-5-氟尿嘧啶-1-乙酸的合成、表征与缓释性.应用化学, 2004, 21(10): 1057-1059.
[111] Yuan Fang, Chen Fu, Xiang Qing Yu, et al. Synthesis and characterization of HPMA copolymer-5-FU conjugates. Chinese Chemical Letters, 2008, 19(2): 137-140.
[112] Pohlen U, Reszka R, Schneider P, et al. Stealth liposomal 5-fluorouracil with or without degradable starch microspheres for hepatic arterial infusion in the treatment of liver metastases: an animal study in VX-2 liver tumor-bearing rabbits. Anticancer Research, 2004, 24(3a): 1699-1704.
[113]于波涛,张志荣,曾仁杰.肝靶向氟尿嘧啶类脂纳米粒的研究.药学学报, 2000, 35(9): 700-705.
[114] Krishnaiah Y S R, Satyanarayana V, Dinesh Kumar B, et al. In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets. European Journal of Pharmaceutical Sciences, 2003, 19(5): 355-362.
[115]李可欣,赵秀峰,庞大海等. 5-氟尿嘧啶结肠定位壳聚糖微球在大鼠体内的药物动力学及生物利用度考察.沈阳药科大学学报, 2008, 25(6): 439-443.
[116]李文献,黄国胜,徐正顺等.食管癌术中植入缓释氟尿嘧啶间质化疗的临床研究.陕西医学杂志, 2007, 36(5): 581-586.
[117] Katsuhiko Higuchi, Wasaburo Koizumi, Satoshi Tanabe, et al. A phase I trial of definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced esophageal carcinoma: Kitasato digestive disease & oncology group trial (KDOG 0501). Radiotherapy and Oncology, 2008, 87(3): 398-404.
[118]潘达超,谢忠.顺铂和5-氟尿嘧啶/醛氢叶酸双周疗法治疗晚期乳腺癌临床研究.肿瘤防治研究, 2002, 29(1): 69-70.
[119]刘敏,章文军,高宁.拼合原理及其在新药设计中的应用.化学试剂, 2009, 31(10): 795.
[120] Wei I-Chien, Tsao Ning, Huang Ya-Hui, et al. 99mTc-glycopeptide: Synthesis, biodistribution and imaging in breast tumor-bearing rodents. Applied Radiation and Isotopes, 2008, 66(3): 320-331.
[121] Chung Tze-Wen, Lu Ya-Fen, Wang Shoei-Shen, et al. Growth of human endothelial cells on photochemically grafted Gly-Arg-Gly-Asp (GRGD) chitosans. Biomaterials, 2002, 23(24): 4803-4809.
[122] Paula Gomes, Carlos A R Gomes, Mary K S Batista, et al. Synthesis, structural characterization and properties of water-soluble N-(γ-propanoyl-amino acid)-chitosans. Carbohydrate Polymers, 2008, 71(1): 54-65.
[123] Yu Cui-Yun, Zhang Xi-Chen, Zhou Fang-Zhou, et al. Sustained release of antineoplastic drugs from chitosan-reinforced alginate microparticle drug delivery systems.International Journal of Pharmaceutics, 2008, 357(1-2): 15-21.
[124]卢凤琦,庄昭霞,曹晶等.壳聚糖-5-氟尿嘧啶前药的合成与释放性研究.山东大学学报(医学版), 2004, 42(2): 226-228.
[125]李和平,阮建明,蔡红革等.壳聚糖-5-氟尿嘧啶高分子前药的合成与表征.长沙理工大学学报(自然科学版), 2005, 2(4): 84-88.
[126] Magdy W Sabaa, Nadia A Mohamed, Riham R Mohamed, et al. Synthesis,characterization and antimicrobial activity of poly (N-vinyl imidazole) grafted carboxymethyl chitosan. Carbohydrate Polymers, 2010, 79(4): 998-1005.
[127] Yury A Skorik, Carlos A R Gomes, M Teresa S D Vasconcelos, et al. N-(2- Carboxyethyl) chitosans: regioselective synthesis, characterisation and protolytic equilibria. Carbohydrate Research, 2003, 338 (3): 271-276.
[128] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy1. Novel N-Alkylation of chitosan via michael type reaction. Chemistry Letters, 2000, 29(8): 862-863.
[129] Karel Bezou?ka. Design, functional evaluation and biomedical applications of carbohydrate dendrimers (glycodendrimers). Reviews in Molecular Biotechnology, 2002, 90(3-4): 269-290.
[130] Tomohiro Fukuda, Shunsuke Onogi, Yoshiko Miura. Dendritic sugar-microarrays by click chemistry. Thin Solid Films, 2009, 518(2): 880-888.
[131] Ben W Greatrex, Samuel J Brodie, Richard H Furneaux, et al. The synthesis and immune stimulating action of mannose-capped lysine-based dendrimers. Tetrahedron, 2009, 65(15): 2939-2950.
[132] Kenji Kono, Hitoshi Akiyama, Toshinari Takahashi, et al. Transfection activity of polyamidoamine dendrimers having hydrophobic amino acid residues in the periphery. Bioconjugate Chemistry, 2005, 16 (1): 208-214.
[133]扈靖,彦钦,韩士田. 5-氟尿嘧啶-1-基乙酸合成方法的改进.化学试剂, 2005, 27(8): 500-509.
[134] Green T W, Wuts P G M. Protective Groups in Organic Synthesis, New York: Wiley-Interscience, 1999, 604-607.
[135]丁文锋,李振南,韦静等.抗肝癌药物酪丝亮肽的工艺研究.医药导报, 2007, 26(10): 1024-1025.
[136] Martin Werle, Martin Hoffer. Glutathione and thiolated chitosan inhibit multidrug resistance. P-glycoprotein activity in excised small intestine. Journal of Controlled Release, 2006, 111(1-2):41-46.
[137] Shuqin Han, Takashi Yoshida, Toshiyuki Uryu. Synthesis of a new polylysine-dendritic oligosaccharide with alkyl spacer having peptide linkage. Carbohydrate Polymers, 2007, 69(3):436-444.
[138]张子涛.甲壳素脱乙酰化动力学及壳聚糖在抗菌染色中的应用研究: [东华大学博士学位论文].上海:东华大学化学化工与生物工程学院, 2003, 24-27.
[139]李美玲,许艳杰,姜丽琴等.三肽N-o-Ns-Gly-N-Me-D-Phe-L-Pro- OMe的合成.化学通报, 2006, 3: 179-180.
[140] Batista M K S, Pinto L F, Gomes C A R, et al. Novel highly-solublepeptide-chitosan polymers: Chemical synthesis and spectral characterization. Carbohydrate Polymers, 2006, 64, (2): 299-305.
[141] Jae Hyung Park, Yong Woo Cho, Hesson Chung, et al. Synthesis and characterization of sugar-bearing chitosan derivatives: aqueous solubility and biodegradability. Biomacromolecules, 2003, 4 (4): 1087-1091.
[142] Sun Lei, Dai Jinhua, Gregory L Baker, et al. High-capacity, protein-binding membranes based on polymer brushes grown in porous substrates. Chemistry of Materials, 2006, 18(17), 4033-4039.
[143] Krikor Torossian, Marie Audette, Richard Poulin. Substrate protection against inactivation of the mammalian polyaminetransport system by 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide. Biochemical Journal, 1996, 319(Pt 1): 21-26.
[144] Eduardo Fernandez-Megia, Ramn Novoa-Carballal, Emilio Quio, et al. Conjugation of bioactive ligands to PEG-grafted chitosan at the distal end of PEG. Biomacromolecules, 2007, 8 (3): 833-842.
[145] Yu Cui-Yun, Jia Li-Hui, Yin Bo-Cheng, et al. Fabrication of nanospheres and vesicles as drug carriers by self-assembly of alginate. Journal of Physical Chemistry C, 2008, 112 (43): 16774-16778.
[146] Yin Ping, Hu Mao-Lin, Hu Li-Chuan. Synthesis, structural characterization and anticarcin- ogenic activity of a new Gly-Gly dipeptide derivative: Methyl 2-(2-(5-fluoro-2,4-dioxo-3,4-dihydro- pyrimidin-1(2H)-yl)acetamido)acetate. Journal of Molecular Structure, 2008, 882(1-3):75-79.
[147] Yeh M-K, Tung S-M, Lu D-W, et a1. Formulation factors for preparing ocular biodegradable delivery system of 5-fluorouracil microparticles. Journal of Microencapsulation, 2001,18(4):507-519.
[148] Alf Lampreeht, Hiromitsu Yamamoto, HireFUmi Takeuchi, et a1. Microsphere designfor the colonic delivery of 5-fluoreuracil. Journal of Controlled Release, 2003, 90(3):313-322.
[149] Marija Glavas-Dodov, Emilija Fredre-Kumbaradi, Katerina Goracinova, et a1. 5-Fluorouracil in topical liposome gels for anticancer treatment formulation and evaluation. Acta Pharmaceutica, 2003, 53(4): 241-250.
[150] Rhongsheng Zhang, Mingguo Tang, Adrian Bowyer, et a1. A novel pH- and ionic-strength-sensitive carboxy methyl dextran hydrogel. Biomaterials, 2005, 26 (22): 4677-4683.
[151] Dean J A. Lange’s Handbook of Chemisry (15th ed). Beijing: McGraw- HillBook Co. Press, 1999, 7.80.
[152] Zhang Dan-Ying, Shen Xi-Zhong, Wang Ji-Yao, et a1. Preparation of chitosan-polyaspartic acid-5-fluorouracil nanoparticles and its anti- carcinoma effect on tumor growth in nude mice. World Journal of Gastroenterology, 2008 , 14(22): 3554-3562.
[153] Stefan Pichlmair, Manuel de Lera Ruiz, Kallol Basu, et a1. Evaluation of possible intramolecular [4+2] cycloaddition routes for assembling the central tetracyclic core of the potent marine antiinflammatory agent mangicol A. Tetrahedron, 2006, 62(22): 5178-5194.
[154] Payal Agrawal, Umesh Gupta, Jain N K. Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials, 2007, 28(22): 3349-3359.
[2] Ashish Dev, Binulal N S, Anitha A, et al. Preparation of poly(lactic acid)/chitosan nanoparticles for anti-HIV drug delivery applications. Carbohydrate Polymers, 2010, 80(3): 833-838
[3] Sarmila Sahoo, Abhisek Sasmal, Rajashree Nanda, et al. Synthesis of chitosan-polycaprolactone blend for control delivery of ofloxacin drug. Carbohydrate Polymers, 2010, 79(1): 106-113.
[4] Mourya V K, Nazma N Inamdar. Chitosan-modifications and applica- tions: Opportunities galore. Reactive & Functional Polymers, 2008, 68 (6): 1013-1051.
[5]Yasunori Maeda, Yoshiyuki Kimura. Antitumor effects of various low-molecu-larweight-chitosans are due to increased natural killer activity of intestinal intraepithelial lympho-cytes in sarcoma 180-bearing mice. Journal of Nutrition, 2004, 134 (4): 945-948.
[6] Thanou M, Verhoef J C, Junginger H E. Oral drug absorption enhancement by chitosan and its derivatives. Advanced Drug Delivery Reviews, 2001, 52(2): 117-126.
[7] Ravi Kumar M N V, Muzzarelli R A A, Muzzarelli C, et al. Chitosan chemistry and pharmaceutical perspectives. Chemical Reviews, 2004, 104 (12): 6017-6084.
[8] Bosch F X, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology, 2004, 127(Suppl): S5-16.
[9] Lai E C, Lau W Y. The continuing challenge of hepatic cancer in Asia. Surgeon, 2005, 3(3): 210-215.
[10] Zhang Yu-Jing, Li Haiyang, Wu Hui-Chen, et al. Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma. Cancer Letters, 2009, 275 (2): 277-284.
[11] Taghizadeh S M, Davari G. Preparation, characterization, and swelling behavior of N-acetylated and deacetylated chitosans. Carbohydrate Polymers, 2006, 64(1): 9-15.
[12]蒋挺大.壳聚糖,第二版.北京:化学工业出版社, 2006, 15-16.
[13] Lee M Y, Var F, Shin-ya Y, et al. Optimum conditions for the precipitation ofchitosan oligomers with DP 5-7 in concentrated hydrochloric acid at low temperature. Process Biochemistry , 1999, 34(5): 493-500.
[14] Mohamed E I Badawy, Entsar I Rabea, Tina M Rogge, et al. Synthesis and fungicidal activity of new N, O-Acyl chitosan derivatives. Biomacromolecules, 2004, 5 (2): 589-595.
[15] Masayuki Ishihara, Kuniaki Nakanishi, Katsuaki Ono, et al. Photocrosslinkable chitosan as a dressing for wound occlusion andaccelerator in healing process. Biomaterials, 2002, 23(3): 833-840.
[16] Harish Prashanth K V, Tharanathan R N. Chitin/chitosan: modifications and their unlimited application potential-an overview. Trends in Food Science & Technology, 2007, 18(3): 117-131.
[17] Jae Hyung Park, Gurusamy Saravanakumar, Kwangmeyung Kim, et al. Targeted delivery of low molecular drugs using chitosan and its derivatives. Advanced Drug Delivery Reviews, 2010, 62(1): 28-41.
[18]魏新林,夏文水.甲壳低聚糖的生理活性研究进展.中国药理学通报, 2003, 19(6): 614-617.
[19] Warayuth Sajomsang. Synthetic methods and applications of chitosan containing pyridylmethyl moiety and its quaternized derivatives: A review. Carbohydrate Polymers, 2010, 80(3): 631-647.
[20] Sashiwa H, Shigemasa Y. Chemical modification of chitin and chitosan 2: Prepar- ation and water soluble property of N-acylated or N-alkylated partially deacetylated chitins. Carbohydrate Polymers, 1999, 39(2): 127-138.
[21] Li Mingchun, Su Sheng, Xin Meihua, et al. Relationship between N,N-dialkyl chitosan monolayer and corresponding vesicle. Journal of Colloid and Interface Science, 2007, 311(1): 285-288.
[22] Zhang Can, Ding Ya, Ping Qineng, et al. Novel chitosan-derived nanomaterials and their micelle-forming properties. Journal of Agricultural and Food Chemistry, 2006, 54 (22): 8409-8416.
[23] Jiyoung M Dang, Daniel D N Sun, Yoshitsune Shin-Ya, et al. Temperature-responsive hydroxybutyl chitosan for the culture of mesenchymal stem cells and intervertebral disk cells. Biomaterials, 2006,27(3): 406-418.
[24] Jae Hyung Park, Seunglee Kwon, MinsuLee, et al. Self- assembled nanoparticles based on glycol chitosan bearing hydrophobic moieties as carriers for doxorubicin: In vivo biodistribution and anti-tumor activity. Biomaterials, 2006, 27(1): 119-126.
[25]隋卫平,杨秀利,杨倩等. (2-羟基-3-丁氧基)丙基-羟丙基壳聚糖的应用性质.应用化学, 2002,19(9): 890-893.
[26] Liu Chen-Guang, Kashappa Goud H. Desai, Chen Xi-Guang, et al. Preparation and characterization of nanoparticles containing trypsin based on hydrophobically modified chitosan. Journal of Agricultural and Food Chemistry, 2005, 53(5): 1728-1733.
[27] Mi Fwu-Long, Peng Chih-Kang, Huang Mei-Feng, et al. Preparation and charact- erization of N-acetylchitosan, N-propionylchitosan and N-butyrylchitosan microsph- eres for controlled release of 6-mercaptourine. Carbohydrate Polymers, 2005, 60 (2): 219-227.
[28] Zhu Aiping, Chen Tian, Yuan Lanhua, et al. Synthesis and characteri- zation of N-succinyl-chitosan and its self-assembly of nanospheres. Carbohydrate Polymers, 2006, 66(2): 274-279.
[29] Liu Xiao Fei, Guan Yun Lin , Yang Dong Zhi, et al. Antibacterial action of chitosan and carboxymethylated chitosan. Journal of Applied Polymer Science, 2000, 79(7): 1324 -1335.
[30] Yin Lichen, Fei Likun, Cui Fuying, et al. Superporous hydrogels containing poly (acrylic acid-co-acrylamide)/ O-carboxymethyl chitosan interpenetrating polymer networks. Biomaterials, 2007, 28(6):1258-1266.
[31] Kogana G, Skorik Y A, ?itňanováI, et al. Antioxidant and antimutagenic activity of N- (2-carboxyethyl) chitosan. Toxicology and Applied Pharmacology, 2004, 201 (3) 303-310.
[32] Maria J Cano-Cebrian1, Teodoro Zornoza1, Luis Granero1, et al. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: A target for drug delivery. Current Drug Delivery, 2005, 2(1): 9-22.
[33] Zhang Can, Ding Ya, Yu Liangli (Lucy), et al. Polymeric micelle systems of hydroxycamptothecin based on amphiphilic N-alkyl-N- trimethyl chitosan derivatives. Colloids and Surfaces B: Biointerfaces, 2007, 55(2): 192-199.
[34] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy. Highly convergent synthesis of dendrimerized chitosan-sialic acid hybrid. Macromolecules, 2001, 34(10): 3211-3214.
[35] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy. Chemical modification of chitosan 11: chitosan- dendrimer hybrid as a tree like molecule. Carbohydrate Polymers, 2002, 49(2): 195-205.
[36] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy. Chemical modification of chitosan 10.1: synthesis of dendronized chitosan-sialic acid hybrid using convergentgrafting of preassembled dendrons Built on gallic acid and tri(ethylene glycol) backbone. Macromolecules, 2001, 34 (12): 3905-3909.
[37] Mi Fwu-Long, Wu Yong-Yi, Chiu Ya-Lin. Synthesis of a novel glycoconjugated chitosan and preparation of its derived nanoparticles for targeting HepG2 cells. Biomacromolecules, 2007, 8 (3): 892-898.
[38] Maku?ka R, Gorochovceva N. Regioselective grafting of poly(ethylene glycol) onto chitosan through C-6 position of glucosamine units. Carbohydrate Polymers, 2006, 64(2): 319-327.
[39] Feng Hao, Dong Chang-Ming. Synthesis and characterization of phthaloyl-chitosan-g- poly(l-lactide) using an organic catalyst. Carbohydrate Polymers, 2007, 70(3): 258-264.
[40] Cai Kaiyong, Yao Kangde, Cui Yuanlu, et al. Surface modification of poly (D,L-lactic acid) with chitosan and its effects on the culture of osteoblasts in vitro. Journal of Biomedical Materials Research Part A, 2002, 60(3): 398-404.
[41] Chung Tze-Wen, Lu Ya-Fen, Wang Hsin-Ya, et al. Growth of human endothelial cells on different concentrations of Gly-Arg-Gly-Asp grafted chitosan surface. Artificial Organs, 2003, 27(2): 155-161.
[42] Jayanth Panyam, Vinod Labhasetwar. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Advanced Drug Delivery Reviews, 2003, 55(3): 329-347.
[43] Yoshiaki Kawashima. Nanoparticulate systems for improved drug delivery. Advanced Drug Delivery Reviews, 2001, 47(1): 1-2.
[44] Yuichi Ohya, Masahiro Shiratani, Hironao Kobayashi, et al. Release behavior of 5-fluorouracil from chitosan-gel nanospheres immobilizing 5-fluorouracil coated with polysaccharides and their cell specific cytotooxicity. Pure and Applied Chemistry, 1994, 31(5): 629-642.
[45]李和平,肖华伍,肖子丹等.磁性壳聚糖-5-氟尿嘧啶纳米粒的制备及体外释药性能.高分子材料科学与工程, 2007, 23(1): 189-191.
[46] Shu X Z, Zhu K J. Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure. International Journal of Pharmaceutics, 2002, 233(1-2): 217-225.
[47]应晓英,胡富强,袁弘.胰岛素壳聚糖纳米粒的制备.中国药学杂志, 2003, 38(12): 936-939.
[48] Lee K Y, Kim J H, Kwon I C, et al. Self-aggregates of deoxycholic acid-modified chitosan as a novel carrier of adriamycin. Colloid & Polymer Science, 2000, 278(12):1216-1219.
[49] Ping He, Stanley S. Davis, Lisbeth Illum. Chitosan microspheres prepared by spray drying. International Journal of Pharmaceutics, 1999, 187(1): 53-65.
[50]李和平,肖华伍,龙姝等.壳聚糖-5-氟尿嘧啶微球的制备.长沙理工大学学报(自然科学版), 2006, 3(4): 91-96.
[51]王毅超,邹全明,任建敏等.壳聚糖-海藻酸钠幽门螺杆菌全菌蛋白微球的制备及表征.华西药学杂志, 2005, 20(5): 375-377.
[52] Inouye K, Machida Y, Sannan T, et al. Buoyant sustained release tablets based on chitosan. Drug design and delivery, 1988, 2(3):165-75.
[53]刘祖雄,李晓东,汤韧等.壳聚糖-恶丙嗪缓释片的研制.中国药房, 2001, 12(9): 532-533
[54] Kwabena Ofori-Kwakye, John T Fell, Harbans L Sharma, et al. Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release. International Journal of Pharmaceutics, 2004, 270(1-2): 307-313
[55] Güng?r S, Y?ld?z A, ?zsoy Y, et al. Investigations on mefenamic acid sustained release tablets with water-insoluble gel. Il Farmaco, 2003, 58, (5): 397-401.
[56]杨红梅,葛为公,曾立威.烟酸占替诺壳聚糖缓释片的研制及释放度测定.广西医科大学学报, 2005, 22(3): 384-387.
[57] Kawashima Y, Handa T, Kasai A, et al. Novel method for the preparation of controlled-release theophylline granules coated with a polyelectrolyte complex of sodium polyphosphate-chitosan. Journal of Pharmaceutical Sciences, 1985, 74(3): 264-268.
[58] Wang Qun, Dong Zhanfeng, Du Yumin, et al. Controlled release of ciprofloxacin hydrochloride from chitosan/polyethylene glycol blend films. Carbohydrate Polymers, 2007, 69(2): 336-343.
[59] Mi Fwu-Long, Wu Yu-Bey, Shyu Shin-Shing, et al. Control of wound infections using a bilayer chitosan wound dressing with sustainable antibiotic delivery. Journal of Biomedical Materials Research Part A, 2002, 59 (3): 438-449.
[60] Emmanuel A. Ho, Vessela Vassileva, Christine Allen, et al. In vitro and in vivo characterization of a novel biocompatible polymer-lipid implant system for the sustained delivery of paclitaxel. Journal of Controlled Release, 2005, 104(1): 181-191.
[61]肖玲,涂依,李洁等.壳聚糖/壳聚糖季铵盐复合膜的性能研究.武汉大学学报(理学版), 2005, 51(2): 190-194.
[62] Makarand V Risbud, Anandwardhan A Hardikar, Sujata V. Bhat, et al.pH-sensitive freeze-dried chitosan–polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery. Journal of Controlled Release, 2000, 68(1): 23-30.
[63] Ruel-Gariépy E, Leclair G, Hildgen P, et al. Thermosensitive chitosan- based hydrogel containing liposomes for the delivery of hydrophilic molecules. Journal of Controlled Release, 2002, 82(2-3): 373-383.
[64] Ahmed A AL-Kahtani, Naik H S Bhojya, Sherigara B S. Synthesis and characterization of chitosan-based pH-sensitive semi-interpenetrating network microspheres for controlled release of diclofenac sodium. Carbohydrate Research, 2009, 344(5): 699-706.
[65]张维颖,樊东辉,徐政等.温敏性壳聚糖凝胶的阿霉素药物体外缓释研究.中国海洋药物杂志, 2005, 24(5): 50-53.
[66] Hideyuki Tozaki, Junta Komoike, Chika Tada, et al. Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon insulin absorption from the rat colon. Journal of Pharmaceutical Sciences, 1997, 86(9): 1016-1021.
[67] Liu Kun-Ho, Liu Ting-Yu, Chen San-Yuan, et al. Drug release behavior of chitosan-montmorillonite nanocomposite hydrogels following electrostimulation. Acta Biomaterialia, 2008, 4(4): 1038-1045.
[68] Davis S S, Illum L. Sustained release chitosan microspheres prepared by novel spray drying methods. Journal of Microencapsulation, 1999, 16(3): 343-355
[69] Hideyuki Tozaki, Tomokazu Odoriba, Naoki Okada, et al. Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. Journal of Controlled Release, 2002, 82(1): 51-61.
[70] Jain S K, Jain A, Gupta Y, et al. Targeted delivery of 5-ASA to colon using chitosan hydrogel microspheres. Journal of drug delivery science and technology, 2008, 18(5): 315-321.
[71] Lorenzo-Lamosa M L, Remu?án-López C, Vila-Jato J L, et al. Design of microencapsulated chitosan microspheres for colonic drug delivery. Journal of Controlled Release, 1998, 52(1-2): 109-118.
[72] Rubin B R, Talent J M, Pertusi R M, et al. Oral polymeric N-acetyl-D-glucosamine and osteoarthritis. Journal of the American Osteopathic Association, 2001, 101(6): 339-344.
[73] Setnikar I, Rovati L C. Absorption, distribution, metabolism and excretion ofglucosamine sulfate. A review. Arzneimittel-Forschung, 2001, 51(9): 699-725.
[74] Kenneth A Howard1, Sфen R Paludan, Mark A Behlke, et al. Chitosan/siRNA nanoparticle-mediated TNF-αknockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. The American Society of Gene Therapy, 2009, 17 (1): 162-168.
[75] Jia Wei-Tao, Zhang Xin, Luo Shi-Hua, et al. Novel borate glass/ chitosan composite as a delivery vehicle for teicoplanin in the treatment of chronic osteomyelitis. Acta Biomaterialia, 2010, 6(3): 812-819.
[76]莫名月,李国明,方雷.壳聚糖载药微囊的制备及应用研究进展.天津化工, 2005, 19(6): l-4.
[77] Tatsuro Ouchi, Toshio Banba, Mitsuo Fujimoto, et al. Synthesis and antitumor activity of chitosan carrying 5-fluorouracils. Die Makromolekulare Chemie, 1989, 190(8): 1817-1825.
[78] Zheng Yongli, Yang Wuli, Wang Changchun, et al. Nanoparticles based on the complex of chitosan and polyaspartic acid sodium salt: Preparation, characterization and the use for 5-fluorouracil delivery. European Journal of Pharmaceutics and Biopharmaceutics, 2007, 67(3): 621-631.
[79] Liu Chenguang, Fan Wenwen, Chen Xiguang, et al. Self-assembled nanoparticles based on linoleic-acid modified carboxymethyl-chitosan as carrier of adriamycin (ADR). Current Applied Physics, 2007, 7(1): 125-129.
[80] Eunhye Lee, Jinju Lee, In-Hyun Lee, et al. Conjugated Chitosan as a Novel Platform for Oral Delivery of Paclitaxel. Journal of Medicinal Chemistry , 2008, 51 (20): 6442-6449.
[81]刘允怡,赖俊雄.肝癌治疗新进展.临床外科杂志, 2007, 15(1): 2.
[82] Maryvonne Daveau, Michel Scotte, Arnaud Fran?ois, et al. Hepatocyte growth factor, transforming growth factor and their receptors as combined markers of prognosis in hepatocellular carcinoma .Molecular Carcinogenesis, 2003, 36 (3): 130-141
[83]李瀚旻,晏雪生,明安萍等.脂质体介导姜黄素抑制Bel-740细胞增殖和诱导其凋亡的作用.中西医结合肝病杂志, 2005, 15 (4): 214-217.
[84] Qi Xian-Rong, Yan Wen-Wei, Shi Jing. Hepatocytes targeting of cationic liposomes modified with soybean sterylglucoside and polyethylene glycol. World Journal of Gastroenterology, 2005, 11(32): 4947-4952.
[85] Jin Yong, Li Jun, Rong Long-Fu, et al. Anti- hepatocarcinoma effects of 5-fluorouracil encapsulated by galactosylceramide liposomes in vivo and in vitro.World Journal of Gastroenterology, 2005, 11(17): 2643-2646.
[86] Xiang Chen, Xianhuo Wang, Yongsheng Wang, et al. Improved tumor-targeting drug delivery and therapeutic efficacy by cationic liposome modified with truncated bFGF peptide. Journal of Controlled Release, 2010, 145(1): 17-25.
[87]连佳芳,秦葵,徐彪.靶向给药的研究进展.白求恩医学院学报, 2006, 4(2): 106-108.
[88]金义光,艾萍,佟丽等.新型靶向制剂阿昔洛韦药质体的家兔体内的研究.中华临床医药杂志, 2004, 5(22):1-3.
[89]于波涛,张志荣,曾仁杰.肝靶向氟尿嘧啶类脂纳米粒的研究.药学学报, 2000, 35(9): 700-705.
[90] Kramer W, Wess G. Bile acid transport systems as pharmaceutical targets. European journal of clinical investigation, 1996, 26(9): 715-732.
[91] Justin M. Saul, Ananth V. Annapragada, Ravi V. Bellamkonda. A dual-ligand approach for enhancing targeting selectivity of therapeutic nanocarriers. Journal of Controlled Release, 2006, 114(3): 277-287.
[92]高艳,李厚丽,吕青志等.主动转运途径在肝靶向给药系统中的应用.中国医药工业杂志, 2008, 39(7): 542-546.
[93]蔡春,苏敏,杨健等.肝靶向前药半乳糖化人血清白蛋白氟尿嘧啶偶联物的合成及靶向作用.中国药学杂志, 2006, 41(10): 786-789.
[94] Stefano G Di, Kratz F, Lanza M, et al. Doxorubicin coupled to lactosaminated human albumin remains confined within mouse liver cells after the intracellular release from the carrier. Digestive and Liver Disease, 2003, 35(6): 428-433.
[95] Mitsuru Hashida, Hideki Hirabayashi, Makiya Nishikawa, et al. Targeted delivery of drugs and proteins to the liver via receptor-mediated endocytosis. Journal of Controlled Release, 1997, 46(1-2): 129-137
[96] Gao Shuying, Chen Jiangning, Dong Lei, et al. Targeting delivery of oligonucleotide and plasmid DNA to hepatocyte via galactosylated chitosan vector European Journal of Pharmaceutics and Biopharmaceutics, 2005, 60(3): 327-334.
[97] Zhang Can, Cheng Yao, Qu Guowei, et al. Preparation and characterization of galactosylated chitosan coated BSA microspheres containing 5-fluorouracil. Carbohydrate Polymers, 2008, 72(3): 390-397.
[98] Sabine I Weiss, Nathalie Sieverling, Maren Niclasen, et al. Uronic acids functionalized polyethyleneimine (PEI)-polyethyleneglycol (PEG)- graft-copoly- mers as novel synthetic gene carriers. Biomaterials, 2006, 27(10): 2302-2312
[99]石艳,张惠斌,宗莉.靶向甘露糖受体的载体甘露糖化壳聚糖的全合成及其细胞毒性评价.药物生物技术, 2009, 16(3): 207-211.
[100] Peters G J, Backus H H J, Freemantle S, et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2002, 1587 (2-3): 195.
[101] Daniel B Longley, Harkin D Paul, Patrick G Johnston. 5-Fluorouracil: mechanisms of action and clinical strategies. Nature Reviews Cancer, 2003, 3, 330-338.
[102]魏嘉,王立峰,刘宝瑞. 5-FU相关的药物疗效及毒性预测分子研究进展.世界华人消化杂志, 2005, 13(15): 1889.
[103]卓仁禧,刘高伟,彭普平. 5-氟尿嘧啶N1-甲酰基氨基酸、短肽的合成及抗肿瘤活性.高等学校化学学报, 1991, 12(4): 555-559.
[104]刘学军,陈茹玉,杨媛媛. 5-氟尿嘧啶-1-基磷三肽化合物的合成及抗癌活性研究.高等学校化学学报, 2002, 23(7): 1299-1303.
[105] Yin Ping, Hu Mao-Lin, Hu Li-Chuan. Synthesis, structural characterization and anticarcinogenic activity of a new Gly-Gly dipeptide derivative: Methyl 2- (2- (5-fluoro-2, 4-dioxo-3, 4-dihydro- pyrimidin- 1(2H)-yl) acetamido) acetate. Journal of Molecular Structure, 2008, 882(1-3): 75-79.
[106]刘彦钦,张慧娟,韩士田. 5-氟尿嘧啶-卟啉化合物的合成及抗癌活性.有机化学, 2002, 22(4): 279-282.
[107] Shi Weimin, Zhang Gen, Dai Guifu, et al. Synthesis and in vitro PDT activity of miscellaneous porphyrins with amino acid and uracil. Bioorganic & Medicinal Chemistry, 2008, 16(10): 5665-5671.
[108]卓仁禧,陈衢生,刘高伟等.主链含5-氟尿嘧啶聚芳酯的合成.武汉大学学报(自然科学版), 1983, 74(1-3): 114-118.
[109]朱卡,汤谷平,陈启琪等. 5-氟尿嘧啶-聚α,β(2-羟乙基)-D L-天冬酰胺的合成及体内释放的研究.药学学报, 1998, 33(12): 906-909.
[110]张静夏,潘仕荣,王琴梅等.聚羟乙谷氨酰胺-5-氟尿嘧啶-1-乙酸的合成、表征与缓释性.应用化学, 2004, 21(10): 1057-1059.
[111] Yuan Fang, Chen Fu, Xiang Qing Yu, et al. Synthesis and characterization of HPMA copolymer-5-FU conjugates. Chinese Chemical Letters, 2008, 19(2): 137-140.
[112] Pohlen U, Reszka R, Schneider P, et al. Stealth liposomal 5-fluorouracil with or without degradable starch microspheres for hepatic arterial infusion in the treatment of liver metastases: an animal study in VX-2 liver tumor-bearing rabbits. Anticancer Research, 2004, 24(3a): 1699-1704.
[113]于波涛,张志荣,曾仁杰.肝靶向氟尿嘧啶类脂纳米粒的研究.药学学报, 2000, 35(9): 700-705.
[114] Krishnaiah Y S R, Satyanarayana V, Dinesh Kumar B, et al. In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets. European Journal of Pharmaceutical Sciences, 2003, 19(5): 355-362.
[115]李可欣,赵秀峰,庞大海等. 5-氟尿嘧啶结肠定位壳聚糖微球在大鼠体内的药物动力学及生物利用度考察.沈阳药科大学学报, 2008, 25(6): 439-443.
[116]李文献,黄国胜,徐正顺等.食管癌术中植入缓释氟尿嘧啶间质化疗的临床研究.陕西医学杂志, 2007, 36(5): 581-586.
[117] Katsuhiko Higuchi, Wasaburo Koizumi, Satoshi Tanabe, et al. A phase I trial of definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced esophageal carcinoma: Kitasato digestive disease & oncology group trial (KDOG 0501). Radiotherapy and Oncology, 2008, 87(3): 398-404.
[118]潘达超,谢忠.顺铂和5-氟尿嘧啶/醛氢叶酸双周疗法治疗晚期乳腺癌临床研究.肿瘤防治研究, 2002, 29(1): 69-70.
[119]刘敏,章文军,高宁.拼合原理及其在新药设计中的应用.化学试剂, 2009, 31(10): 795.
[120] Wei I-Chien, Tsao Ning, Huang Ya-Hui, et al. 99mTc-glycopeptide: Synthesis, biodistribution and imaging in breast tumor-bearing rodents. Applied Radiation and Isotopes, 2008, 66(3): 320-331.
[121] Chung Tze-Wen, Lu Ya-Fen, Wang Shoei-Shen, et al. Growth of human endothelial cells on photochemically grafted Gly-Arg-Gly-Asp (GRGD) chitosans. Biomaterials, 2002, 23(24): 4803-4809.
[122] Paula Gomes, Carlos A R Gomes, Mary K S Batista, et al. Synthesis, structural characterization and properties of water-soluble N-(γ-propanoyl-amino acid)-chitosans. Carbohydrate Polymers, 2008, 71(1): 54-65.
[123] Yu Cui-Yun, Zhang Xi-Chen, Zhou Fang-Zhou, et al. Sustained release of antineoplastic drugs from chitosan-reinforced alginate microparticle drug delivery systems.International Journal of Pharmaceutics, 2008, 357(1-2): 15-21.
[124]卢凤琦,庄昭霞,曹晶等.壳聚糖-5-氟尿嘧啶前药的合成与释放性研究.山东大学学报(医学版), 2004, 42(2): 226-228.
[125]李和平,阮建明,蔡红革等.壳聚糖-5-氟尿嘧啶高分子前药的合成与表征.长沙理工大学学报(自然科学版), 2005, 2(4): 84-88.
[126] Magdy W Sabaa, Nadia A Mohamed, Riham R Mohamed, et al. Synthesis,characterization and antimicrobial activity of poly (N-vinyl imidazole) grafted carboxymethyl chitosan. Carbohydrate Polymers, 2010, 79(4): 998-1005.
[127] Yury A Skorik, Carlos A R Gomes, M Teresa S D Vasconcelos, et al. N-(2- Carboxyethyl) chitosans: regioselective synthesis, characterisation and protolytic equilibria. Carbohydrate Research, 2003, 338 (3): 271-276.
[128] Hitoshi Sashiwa, Yoshihiro Shigemasa, RenéRoy1. Novel N-Alkylation of chitosan via michael type reaction. Chemistry Letters, 2000, 29(8): 862-863.
[129] Karel Bezou?ka. Design, functional evaluation and biomedical applications of carbohydrate dendrimers (glycodendrimers). Reviews in Molecular Biotechnology, 2002, 90(3-4): 269-290.
[130] Tomohiro Fukuda, Shunsuke Onogi, Yoshiko Miura. Dendritic sugar-microarrays by click chemistry. Thin Solid Films, 2009, 518(2): 880-888.
[131] Ben W Greatrex, Samuel J Brodie, Richard H Furneaux, et al. The synthesis and immune stimulating action of mannose-capped lysine-based dendrimers. Tetrahedron, 2009, 65(15): 2939-2950.
[132] Kenji Kono, Hitoshi Akiyama, Toshinari Takahashi, et al. Transfection activity of polyamidoamine dendrimers having hydrophobic amino acid residues in the periphery. Bioconjugate Chemistry, 2005, 16 (1): 208-214.
[133]扈靖,彦钦,韩士田. 5-氟尿嘧啶-1-基乙酸合成方法的改进.化学试剂, 2005, 27(8): 500-509.
[134] Green T W, Wuts P G M. Protective Groups in Organic Synthesis, New York: Wiley-Interscience, 1999, 604-607.
[135]丁文锋,李振南,韦静等.抗肝癌药物酪丝亮肽的工艺研究.医药导报, 2007, 26(10): 1024-1025.
[136] Martin Werle, Martin Hoffer. Glutathione and thiolated chitosan inhibit multidrug resistance. P-glycoprotein activity in excised small intestine. Journal of Controlled Release, 2006, 111(1-2):41-46.
[137] Shuqin Han, Takashi Yoshida, Toshiyuki Uryu. Synthesis of a new polylysine-dendritic oligosaccharide with alkyl spacer having peptide linkage. Carbohydrate Polymers, 2007, 69(3):436-444.
[138]张子涛.甲壳素脱乙酰化动力学及壳聚糖在抗菌染色中的应用研究: [东华大学博士学位论文].上海:东华大学化学化工与生物工程学院, 2003, 24-27.
[139]李美玲,许艳杰,姜丽琴等.三肽N-o-Ns-Gly-N-Me-D-Phe-L-Pro- OMe的合成.化学通报, 2006, 3: 179-180.
[140] Batista M K S, Pinto L F, Gomes C A R, et al. Novel highly-solublepeptide-chitosan polymers: Chemical synthesis and spectral characterization. Carbohydrate Polymers, 2006, 64, (2): 299-305.
[141] Jae Hyung Park, Yong Woo Cho, Hesson Chung, et al. Synthesis and characterization of sugar-bearing chitosan derivatives: aqueous solubility and biodegradability. Biomacromolecules, 2003, 4 (4): 1087-1091.
[142] Sun Lei, Dai Jinhua, Gregory L Baker, et al. High-capacity, protein-binding membranes based on polymer brushes grown in porous substrates. Chemistry of Materials, 2006, 18(17), 4033-4039.
[143] Krikor Torossian, Marie Audette, Richard Poulin. Substrate protection against inactivation of the mammalian polyaminetransport system by 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide. Biochemical Journal, 1996, 319(Pt 1): 21-26.
[144] Eduardo Fernandez-Megia, Ramn Novoa-Carballal, Emilio Quio, et al. Conjugation of bioactive ligands to PEG-grafted chitosan at the distal end of PEG. Biomacromolecules, 2007, 8 (3): 833-842.
[145] Yu Cui-Yun, Jia Li-Hui, Yin Bo-Cheng, et al. Fabrication of nanospheres and vesicles as drug carriers by self-assembly of alginate. Journal of Physical Chemistry C, 2008, 112 (43): 16774-16778.
[146] Yin Ping, Hu Mao-Lin, Hu Li-Chuan. Synthesis, structural characterization and anticarcin- ogenic activity of a new Gly-Gly dipeptide derivative: Methyl 2-(2-(5-fluoro-2,4-dioxo-3,4-dihydro- pyrimidin-1(2H)-yl)acetamido)acetate. Journal of Molecular Structure, 2008, 882(1-3):75-79.
[147] Yeh M-K, Tung S-M, Lu D-W, et a1. Formulation factors for preparing ocular biodegradable delivery system of 5-fluorouracil microparticles. Journal of Microencapsulation, 2001,18(4):507-519.
[148] Alf Lampreeht, Hiromitsu Yamamoto, HireFUmi Takeuchi, et a1. Microsphere designfor the colonic delivery of 5-fluoreuracil. Journal of Controlled Release, 2003, 90(3):313-322.
[149] Marija Glavas-Dodov, Emilija Fredre-Kumbaradi, Katerina Goracinova, et a1. 5-Fluorouracil in topical liposome gels for anticancer treatment formulation and evaluation. Acta Pharmaceutica, 2003, 53(4): 241-250.
[150] Rhongsheng Zhang, Mingguo Tang, Adrian Bowyer, et a1. A novel pH- and ionic-strength-sensitive carboxy methyl dextran hydrogel. Biomaterials, 2005, 26 (22): 4677-4683.
[151] Dean J A. Lange’s Handbook of Chemisry (15th ed). Beijing: McGraw- HillBook Co. Press, 1999, 7.80.
[152] Zhang Dan-Ying, Shen Xi-Zhong, Wang Ji-Yao, et a1. Preparation of chitosan-polyaspartic acid-5-fluorouracil nanoparticles and its anti- carcinoma effect on tumor growth in nude mice. World Journal of Gastroenterology, 2008 , 14(22): 3554-3562.
[153] Stefan Pichlmair, Manuel de Lera Ruiz, Kallol Basu, et a1. Evaluation of possible intramolecular [4+2] cycloaddition routes for assembling the central tetracyclic core of the potent marine antiinflammatory agent mangicol A. Tetrahedron, 2006, 62(22): 5178-5194.
[154] Payal Agrawal, Umesh Gupta, Jain N K. Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials, 2007, 28(22): 3349-3359.