磁性药物载体交联淀粉空白球制备和生物降解性能研究
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摘要
本文研究了作为药物载体的磁性交联淀粉纳米球的制备方法和性能。主要从以下几个方面展开研究：
研究了交联淀粉球的制备方法。在正交设计的基础上，采用反相微乳液法，控制不同的反应条件，制备出了粒径从微米级到纳米级可控的交联淀粉球，并通过多元线性回归的方法导出了预测淀粉球粒径的多项式回归方程。
采用傅立叶红外光谱分析、核磁共振氢谱和扫描电子显微镜对交联淀粉球的结构和性能做了详尽的研究。研究发现，交联度对交联淀粉的性质有着极大的影响。FTIR方面，共有3400cm~(-1)、1640cm~(-1)，1600 cm~(-1)、1250cm~(-1)～1269cm~(-1)的光谱带和1047cm~(-1)与1022cm~(-1)之间的比值对交联度的变化极为敏感，随着交联度的改变而有着不同的改变趋势。同时，交联度的变化也引起淀粉溶解性能和吸水性能的改变。高交联淀粉溶解性能降低，而吸水性能增强。交联反应的实质就是不断以交联键取代淀粉分子内的氢键。
为了考察交联淀粉的降解性，采用葡萄糖淀粉酶水解它。研究表明，在交联度分别为0、2、6、12、20的情况下，交联度为6的交联淀粉着有最好的降解性能。
应用原位法合成了平均粒径为60nm，比重1.37g／cm~3，比表面积为73.0m~2／g的磁性交联淀粉纳米球。球内铁氧体和交联淀粉之间以化学键连接，这种连接方式对磁性球的降解性能产生了影响。同时对磁性交联淀粉球的成核过程做了热力学上的推导。
As a drug carrier, study on nanometer magnetic crosslink starch sphere was reported in this paper as follows:
Firstly, a research of preparation of crosslink starch sphere had been conducted. Based on orthogonal design, crosslink starch sphere was synthesized whose mean diameter varied from micron to nanometer in inverse microemulsion through controlling reaction conditions. Also, we found a polynomial regression equation which could prognosticate the diameter of crosslink starch by multiple linear regression.
Secondly, it was studied in particular on structure and property of crosslink starch with FTIR, SEM and HNMR analysis. It was found that property of crosslink starch was very sensitive to its crosslink degree. In FTIR, around 3400cm-1?1640cm-1?1600 cm-1?from 1250cm-1 to 1269cm-1 and the ratio between 1047cm-1 and 1022 cm-1 were varied with crosslink degree changed. Meanwhile, dissolving and bibulous performance were also changed with crosslink degree. High crosslink starch nearly didn't dissolve in boiled water and could sop up more water. It was believed that substantially crosslink reaction substituted hydrogen bond for crosslink bond continually.
In order to observe the degradation performance of crosslink starch sphere, we designed a reaction with glucose amylase. The result of study indicated that crosslink starch with crosslink degree 6 had the best degradation performance in comparison with 0, 2, 12, 20.
Finally, magnetic crosslink starch was synthesized in situ. The particle size of it was around 60nm, density 1.37g/cm , specific surface area 73.0m2/g. Crosslink starch and ferrite were linked with chemical bond. The exist of such chemical bond had some effect on degradation performance of magnetic crosslink starch, that is, not as good as crosslink starch. The nucleus-form process of magnetic cross-linked starch microsphere was deduced on thermodynamics.
研究了交联淀粉球的制备方法。在正交设计的基础上，采用反相微乳液法，控制不同的反应条件，制备出了粒径从微米级到纳米级可控的交联淀粉球，并通过多元线性回归的方法导出了预测淀粉球粒径的多项式回归方程。
采用傅立叶红外光谱分析、核磁共振氢谱和扫描电子显微镜对交联淀粉球的结构和性能做了详尽的研究。研究发现，交联度对交联淀粉的性质有着极大的影响。FTIR方面，共有3400cm~(-1)、1640cm~(-1)，1600 cm~(-1)、1250cm~(-1)～1269cm~(-1)的光谱带和1047cm~(-1)与1022cm~(-1)之间的比值对交联度的变化极为敏感，随着交联度的改变而有着不同的改变趋势。同时，交联度的变化也引起淀粉溶解性能和吸水性能的改变。高交联淀粉溶解性能降低，而吸水性能增强。交联反应的实质就是不断以交联键取代淀粉分子内的氢键。
为了考察交联淀粉的降解性，采用葡萄糖淀粉酶水解它。研究表明，在交联度分别为0、2、6、12、20的情况下，交联度为6的交联淀粉着有最好的降解性能。
应用原位法合成了平均粒径为60nm，比重1.37g／cm~3，比表面积为73.0m~2／g的磁性交联淀粉纳米球。球内铁氧体和交联淀粉之间以化学键连接，这种连接方式对磁性球的降解性能产生了影响。同时对磁性交联淀粉球的成核过程做了热力学上的推导。
As a drug carrier, study on nanometer magnetic crosslink starch sphere was reported in this paper as follows:
Firstly, a research of preparation of crosslink starch sphere had been conducted. Based on orthogonal design, crosslink starch sphere was synthesized whose mean diameter varied from micron to nanometer in inverse microemulsion through controlling reaction conditions. Also, we found a polynomial regression equation which could prognosticate the diameter of crosslink starch by multiple linear regression.
Secondly, it was studied in particular on structure and property of crosslink starch with FTIR, SEM and HNMR analysis. It was found that property of crosslink starch was very sensitive to its crosslink degree. In FTIR, around 3400cm-1?1640cm-1?1600 cm-1?from 1250cm-1 to 1269cm-1 and the ratio between 1047cm-1 and 1022 cm-1 were varied with crosslink degree changed. Meanwhile, dissolving and bibulous performance were also changed with crosslink degree. High crosslink starch nearly didn't dissolve in boiled water and could sop up more water. It was believed that substantially crosslink reaction substituted hydrogen bond for crosslink bond continually.
In order to observe the degradation performance of crosslink starch sphere, we designed a reaction with glucose amylase. The result of study indicated that crosslink starch with crosslink degree 6 had the best degradation performance in comparison with 0, 2, 12, 20.
Finally, magnetic crosslink starch was synthesized in situ. The particle size of it was around 60nm, density 1.37g/cm , specific surface area 73.0m2/g. Crosslink starch and ferrite were linked with chemical bond. The exist of such chemical bond had some effect on degradation performance of magnetic crosslink starch, that is, not as good as crosslink starch. The nucleus-form process of magnetic cross-linked starch microsphere was deduced on thermodynamics.
引文
[1] Aigner K R. Intra-arterial infusion: overview and novel approaches. Semin Surg Oncol, 1998,4(14):3,248-253
[2] Gupta A K, Curtis A S. Lactoferrin and ceruloplasmin derivatized superparamagnetic iron oxide nanoparticles for targeting cell surface receptors. Biomaterials, 2004, 25 (6) : 3029-3040
[3] Reubsaet, Jan L E, Pedersen-Bjergaard, Stig. Screening for central nervous system-stimulating drugs in human plasma by liquid chromatography with mass spectrometric detection. Journal of Chromatography A, 2004, 1031 (3): 203-211
[4] 高善民，孙树声，刘兆明．纳米材料在化工生产中的应用．化工技术经济，2000，18(5)：10-12
[5] 许海燕，孔桦．纳米材料及其在生物医学工程中的应用．国外医学生物医学工程分册，1998，21(5)：262-266
[6] Johnson B E. New targets and new treatments in non-small cell lung cancer. EJC Supplements, 2004, 2(3): 1-6
[7] Poruchynsky M S, Giannakakou P, Ward Y, et al. Accompanying protein alterations in malignant cells with a microtubule-polumerizing drug-resistance phemotype and a primary resistance mechanism. Biochem Pharmaclo, 2001, 62(11): 1469-1480
[8] Kuliopulos, A, Covic L. Blocking receptors on the inside: pepducin-based intervention of PAR signaling and thrombosis. Life Sciences, 2003, 74(12): 255-262
[9] Akuta K, Abe M, Kondo M, et al. Combined effects of hepatic arterial embolization using degradable starch microspheres (DSM) in hyperthermia for liver cancer. Int J Hyperthermia, 1991, 7(2): 231-242
[10] Allum W H, Jewkes A J, Lanchbury E, et al. Biodegradable emboli and antibody targeting of colorectal and gastric hepatic metastases: a pilot study. Eur J Cancer, 1990, 26(8): 876-879
[11] Amiet C C, Gadille E Microencapsulation of thizobacteria by spray-drying:
formulation and survival studies. J Microencapsul, 1998, 15(5): 639-659
[12] Arica M Y, Hasirei V, Alaeddinoglu NG. Govalent immobilization of alpha-amylase onto pHEMA microspheres: preparation and application to fixed bed reactor. Biomaterials, 1995, 16(10): 761-768
[13] Ball A B. Regional chemotherapy for colorectal hepatic metastases using degradable starch microspheres. A review Acta Oncol, 1991, 30(3): 303-313
[14] Pietzonka P, Rothen-Rutishauser B, Langguth P, el at. Transfer of lipophilic markers from PLGA and polystyrene nanoparticles to Caco-2 monolayers mimics particle uptake. Pharmaceutical Research, 2002,19(5):595-601.
[15] Borissova R, Lammek B. Biodegradable microspheres: 16. Synthesis of primaquine-peptide for lysosomal release from starch microparticles. J Pharm Sci, 2002,84(2): 249-255
[16] Bremmer S, Mellgren A. Peritoneocele and enterocele. Formation and transformation during rectal evacuation as studied by means of defaeco-peritoneography. Acta Radiol, 1998,39(2): 167-175
[17] Carr B L, Zajko A, Bron K, et al. Phase Ⅱ study of Spherex (degradable starch microspheres) injected into the hepatic artery in conjunction with doxorubicin and cisplatin in the treatment of advanced-stage hepatocellular carcinoma interim analysis. Semin Oncol, 1997, 242(2) Suppl 6:S6-97-S6-99
[18] Cater R, Cooke T G, Hemingway D, et al. The combination of degradable starch microspheres and angiotensin Ⅱ in the manipulation of drug delivery in an animal model of colorectal metastasis, Br J Cancer, 1999, 65(1): 37-39
[19] Chadha H, Deluca P P. Effect of polytyrosine on the hydrophobicity of hydroxyethyl starch microspheres. Pharm Dev Technol. 1998, 3(4): 597-606
[20] Jenkins S A, Chang D, Grime S J, et al. Increasing hepatic arterial flow to hypovascular hepatic tumours using degradable starch microspheres. Br J Cancer, 1996, 73(8): 961-965
[21] Civalieri D, Esposito M, Fulco R A, et al. Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases. Cancer, 1991, 68(5):988-994
[22] Civalleri D, Pector J C, Amaud J P, et al. Treatment of patients with irresectable liver metastases from colorectal cancer by chemo-occlusion with degradable
starch microspheres. Br J Surg, 1994, 81 (9): 1338-1341
[23] Degling L. Biodegradable microspheres ⅩⅤⅢ: The asjuvant effect of polyacryl starch microparticles with conjugated human serum albumin. Vaccine, 1995, 13(7): 629-636
[24] Degling L. Biodegradable microspheres ⅩⅢ: Immune response to the DNP hapten conjugated to polyacyl starch mictoparticles. J Pharm Sci, 1991,80(5): 436-440
[25] Dewitt D S, Prough D S, Deal D D, et al. Hypertonic saline does not improve cerebral oxygen delivery after head injury and mild hemorrhage in cats (see comments). Crit Care Med, 1996,24(1): 109-117
[26] Ibrahin A K, Holtz E, Klaveness J, et al. Magnetic starch microspheres, biodestribution and biotransformation. A new organ-specific contrast agent for magnetic resonance imaging. Invest Radiol, 1990, 25(7): 793-797
[27] Fahlvik A K, Holtz E, Leander P, et al. Magnetic starch microspheres, efficacy and elimination. A new organ-specific contrast agent for magnetic resonance imaging. Invest Radiol, 1990, 25(2): 113-120
[28] Gizurarson S, Bechgard E. Insulin-carrying microspheres in vitro studies. Chem Pharm Bull (Tokyo), 1991, 39(7): 1892-1893
[29] Hamdi G, Ponchel G. An original method for studying in vitro the enzymatic degradation of cross-linked starch microspheres. J Controlled Release, 1998, 55(2-3):193-201
[30] Hamdi G, Ponchel G. Enzymatic degradation of epichlorohydrin crosslinked starch microspheres by alpha-amylase. Pharm Res, 1999, 16(6):867-75
[31] Hammer A, Schumann R. The effect of electrostatic charge of food particles on capture efficiency by Oxyrrhis marina Dujardin (dinoflagellate). Protist, 1999, 150(4):375-382
[32] Heritage P L, Loomes L M, Jianxiong J, et al. Novel polymer-grafted starch microparticles for mucosal delivery of vaccines. Immunology, 1996, 88(1): 162-168
[33] Huang L K, Mehta R C, Deluca P P. Development of a statistical model for the formation of poly (acryloyl hydroxyethy starch) microspheres. Pharm Res, 1997, 14(4): 469-474
[34] Kleen M, Habler O, Hutter J, et al. Effects of hemodilution on splanchnic perfusion and hepatorenal funcion. Ⅰ. Splanchnic perfusion. Eur Med Res, 1997, 2(10): 413-418
[35] Huang L K, Mehta R C, Deluca P P. Evaluation of a statistical model for the formation of poly (acryloyl hydroxyethy starch) microspheres. Pharm Res, 1997, 14(4): 475-482
[36] Isaksson U, Edman P, Artursson P, et al. Starch microspheres induce pulsatile delivery of drugs and prptides across the epithelial barrier by reversible separation of the tight junctions. J Drug Target, 1995, 2(6): 501-507
[37] Johansson C J. Pharmacokinetic rationale for chemotherapeutic drugs combined with intra-arterial degradable starch microspheres (Spherex). Clin Pharmacokinet, 1996,31(3):231-240
[38] 黄立新，张力田．木薯淀粉在显微镜下形态研究．食品发酵与工业，1995，3(6)：203-206
[39] Mateescu A, Cartilier D. Cross-linked amylose as a binder/disintegrant in tablets. U.S.Patent. 5,616,343.1997,4.
[40] Karakus D, Okar I. For sustained release formulations of dipyridamole-alginat microspheres and tabletted microspheres. J Microencapsul, 1999,16(4):439-452
[41] Kreft B, Block W, Muhlhauser J, et al. Enhancement efficacy of magnetic starch microspheres (MSM) in conventional spin-echo and terbo spin-echo sequences at 0.5T and 1.5T. J Magn Teson Imaging, 1996, 6(2): 378-383
[42] Kreft B, Taminoto A, Leftler S, et al. Contrast-enhanced MR imaging of diffuse and focal splenic disease with use of magnetic starch microspheres. J Magn Reson.Imaging, 1994,4(3):373-379
[43] Aminabhni T M, Maddever W J, Kalyanaraman B, et al. Effects of hydroxyethyl starch conjugated deferoxamine on myocardial functional recovery following coronary occlusion and reperfusion in dogs. J Cardiovase Pharmacol, 1991,17(1): 166-175
[44] Medermon M R, Heritage P L, Bartzoka V, et al. Polymer-grafted starch microparticles for oral nasal immunization. Immunol Cell Biol, 1998, 76(3): 256-262
[45] Montgomery P C, Refferty D E. Induction of secretory and serum antibody
responses following oral administration of antigen with bioadhesive degradable microparticles. Oral Mictobiol Immunol, 1998 Jun, 13(3): 139-149
[46] Morales O, Thorelius L, Warfving T, et al. Spherex chemo-occlusion-enhancement of tumor drug concentration and therapeutic efficacy: an overview. Semin Oncol, 1997, 24(2) Suppl 6:S6-100-S6-109
[47] Samuel H, Auratul K, Inadura M, et al. Studies on hyperthermia combined with arterial therapeutic blockade for treatment of tumors: effectiveness of hyperthermia combined with arterial chemoembolization using degradable starch microspheres on advanced liver cancer. Oncol Rep, 1998, 5(3):709-712
[48] Murata P, Akagi K, Imamura M, et al. Studies on hyperthermia combined with arterial therapeutic blockade for treatment of tumors: effectiveness of hyperthermia combined with arterial embolization using degradable starch microspheres. Oncol Rep, .1998, 5(3): 705-708
[49] Grime S J, Nott D M, Yates J, et al. The effect of portal venous flow on the washout of a regionally injected marker substance 99mTc-methylene diphosphonate after hepatic arterial blockade with Magnetic degradable microspheres. Eur J Surg Oncol, 1992, 18(4):347-352
[50] Podezeck F, Newton J M. Development of an ultracentrifuge technique to determine the adhesion and friction properties between particles and surfaces. J Pharm Sci, 1995, 84(9): 1067-1071
[51] Pauser S, Wagner S, Lippmann M, et al. Evaluation of efficient chemoembolization mixtures by magnetic resonance imaging therapy monitoring. Cancer Res, 2002, 56(8): 1863-1867
[52] Paulsen F, Müller-Berg M, Becker G. Comparison of radiotherapy dose distribution and FDG-PET after irradiation in patients with malignant glioma. European Journal of Cancer, 1999,35(9): 118-119
[53] Ruxandra D S, Whitley J M, Taylor C L, et al. Small-volume resuscitation from hemonhagic shock: effects on systemic hemodynamics and systemic blood flow. Crit Care Med, 1991, 19(3): 364-372
[54] Shinkai G, Hag I A, Teder H, et al. Improved antitumor effect of the mitrosoures drugs tauromustine (TCNU) and carmustine (BCNU) on a rat liver adenocancinoma after hepatic arterial administration with magnetic Fe_3O_4
microspheres. Amticancer Res, 1999, 11 (1): 13-6
[55] Müller-Schulte D, Brunner H. Novel magnetic microspheres on the basis of poly(vinyl alcohol) as affinity medium for quantitative detection of glycated haemoglobin. Journal of Chromatography A, 1995,711 (8):53-60
[56] Cupta A, Wang C, Ericsson A, et al. Magnetic microspheres in the MR imaging of hepatic metastases. A preclinical study in the nude rat. Acta Radiol, 1998, 39(2): 161-166
[57] Molday T. Chemo-occlusion for the treatment of liver cancer. A new techique using degradable starch microspheres. Clin Pharmacokinet, 2002, 26(4): 275-291
[58] Kronick T. Liver tumor targeting of drugs: Spherex, a vascular agent. Gan To Kagaku Ryoho, 1995,22(7): 969-976
[59] Bose T, Kokura S, Oyamada H, et al. Antitumor effect of ischemia-reperfusion injury induced by transient embolization. Cancer Res, 1999, 54(19): 5033-5035
[60] Safarik T, Tanikawa K, Sano K, et al. Multi-center cooperative phase Ⅱ study of combined infusion of PJ-203 into hepatic artery in metastatic liver cancer. Gan To Kagaku Ryoho, 1993c, 20(13): 2015-2025
[61] Gusedon Y, Yokoyama H, Takehara M, et al. Intermittent arterial chemoembolization in liver tumor using magnetic microspheres. Gan To Kagaku Ryoho, 1990, 17(8): 1715-1720
[62] Kondo F, Yamamoto K, Murata T, et al. Effects of multimodal treatment and hyperthermia on hepatic tumors. Cancer Chemother Pharmacol, 1992,31 Suppl: SⅢ-4
[63] 李干佐，郭荣．微乳液理论及其应用．北京：石油工业出版社，1995．14-16
[64] Thom A k, Zhang S Z, Deveney C, et al. Effects of verapamil and degradable starch microspheres during hepatic artery infusion of doxorubicin. Surgery, 1990, 107(5): 552-559
[65] 张志贤，张瑞镐．有机官能团定量分析．北京：化学工业出版社，1990．
[66] Vyas S P, Jain C E Bioadhesive polymer-grafted microspheres bearing isosorbide dinitrate for buccal administration. J Microencapsul, 1992, 9(4): 457-464
[67] Yamada T. Experimental and clinical studies of degradable starch microspheres in the treatment of hepatic neoplasm:. Part 1. Experimental study. Nippon Igaku Hoshasen Gakkai Zasshi, 1995, 55 (9): 663-669
[68] Yamada T. Experimental and clinical trial of degradable starch microspheres (DSM) in the treatment of hepatic neoplasm: Part 2. Clinical study. Nippon Igaku Hoshasen Gakkai Zasshi, 1995, 55(11): 732-738
[69] Yoshikawa T, Kokura S, Oyamada H, et al. Antiumor effect of ischemia-reperfusion injury induced by transient embolization. Cancer Res, 54(19): 5033-5035
[70] Cael J J, Koening J L. Factors affecting crystallization and crystallization kinetics in amorphous corn starch.Carbohydrate Release, 1973, 29(3) 123-134.
[71] 迪安JA．兰氏化学手册．北京：科学出版社，1991．8-82
[72] 张力田．淀粉糖．广州：广州科学技术出版社，1981．135-139
[73] 北京大学化学系分析化学教学组．基础分析化学实验(第二版)．北京：北京大学出版社，1998．235-237
[74] 王宜庆．玉米淀粉与高果糖浆．北京：中国食品出版社，1987．34-36
[75] 董仁威．淀粉深度加工新技术．成都：四川科学技术出版社，1988．262-263
[76] Moriyama K, Yui N. Regulated insulin release from biodegradable dextran hydrogels containing poly(ethylene glycol).J Control Rel,1996,42(7)237-248
[77] Jiang W H, Fei J, Han X L. In situ synthesis of (TiW)C/Fe composites. Materials Letters, 2000,46(2): 222-224
[78] Shibata M, Gérard J, Gabelica Z. Rapid synthesis of MFI titanosilicates using in situ seeding method..Microporous Materials, 1997,12(5): 141-148
[79] Chang H S, Chiou C C, Chen Y W. Synthesis characterization and magnetic properties of Fe_3O_4 thin films prepared via a sol-gel method. Journal of Solid State Chemistry, 1997,128(7):87-92.
[80] Radhakrishnan S, Saujanya C, Sonar P, el at. Polymer-mediated synthesis of α-Fe_2O_3 nano-particles. Polyhedron,2001, 20(6): 1489-1494.
[81] Grzeta B, Ristic M, Nowik I, el at. Formation of nanocrystalline magnetite by thermal decompo-sition of iron ch oline citrate. Journal of Alloys and Compounds, 2002,334(3):304-312
[2] Gupta A K, Curtis A S. Lactoferrin and ceruloplasmin derivatized superparamagnetic iron oxide nanoparticles for targeting cell surface receptors. Biomaterials, 2004, 25 (6) : 3029-3040
[3] Reubsaet, Jan L E, Pedersen-Bjergaard, Stig. Screening for central nervous system-stimulating drugs in human plasma by liquid chromatography with mass spectrometric detection. Journal of Chromatography A, 2004, 1031 (3): 203-211
[4] 高善民，孙树声，刘兆明．纳米材料在化工生产中的应用．化工技术经济，2000，18(5)：10-12
[5] 许海燕，孔桦．纳米材料及其在生物医学工程中的应用．国外医学生物医学工程分册，1998，21(5)：262-266
[6] Johnson B E. New targets and new treatments in non-small cell lung cancer. EJC Supplements, 2004, 2(3): 1-6
[7] Poruchynsky M S, Giannakakou P, Ward Y, et al. Accompanying protein alterations in malignant cells with a microtubule-polumerizing drug-resistance phemotype and a primary resistance mechanism. Biochem Pharmaclo, 2001, 62(11): 1469-1480
[8] Kuliopulos, A, Covic L. Blocking receptors on the inside: pepducin-based intervention of PAR signaling and thrombosis. Life Sciences, 2003, 74(12): 255-262
[9] Akuta K, Abe M, Kondo M, et al. Combined effects of hepatic arterial embolization using degradable starch microspheres (DSM) in hyperthermia for liver cancer. Int J Hyperthermia, 1991, 7(2): 231-242
[10] Allum W H, Jewkes A J, Lanchbury E, et al. Biodegradable emboli and antibody targeting of colorectal and gastric hepatic metastases: a pilot study. Eur J Cancer, 1990, 26(8): 876-879
[11] Amiet C C, Gadille E Microencapsulation of thizobacteria by spray-drying:
formulation and survival studies. J Microencapsul, 1998, 15(5): 639-659
[12] Arica M Y, Hasirei V, Alaeddinoglu NG. Govalent immobilization of alpha-amylase onto pHEMA microspheres: preparation and application to fixed bed reactor. Biomaterials, 1995, 16(10): 761-768
[13] Ball A B. Regional chemotherapy for colorectal hepatic metastases using degradable starch microspheres. A review Acta Oncol, 1991, 30(3): 303-313
[14] Pietzonka P, Rothen-Rutishauser B, Langguth P, el at. Transfer of lipophilic markers from PLGA and polystyrene nanoparticles to Caco-2 monolayers mimics particle uptake. Pharmaceutical Research, 2002,19(5):595-601.
[15] Borissova R, Lammek B. Biodegradable microspheres: 16. Synthesis of primaquine-peptide for lysosomal release from starch microparticles. J Pharm Sci, 2002,84(2): 249-255
[16] Bremmer S, Mellgren A. Peritoneocele and enterocele. Formation and transformation during rectal evacuation as studied by means of defaeco-peritoneography. Acta Radiol, 1998,39(2): 167-175
[17] Carr B L, Zajko A, Bron K, et al. Phase Ⅱ study of Spherex (degradable starch microspheres) injected into the hepatic artery in conjunction with doxorubicin and cisplatin in the treatment of advanced-stage hepatocellular carcinoma interim analysis. Semin Oncol, 1997, 242(2) Suppl 6:S6-97-S6-99
[18] Cater R, Cooke T G, Hemingway D, et al. The combination of degradable starch microspheres and angiotensin Ⅱ in the manipulation of drug delivery in an animal model of colorectal metastasis, Br J Cancer, 1999, 65(1): 37-39
[19] Chadha H, Deluca P P. Effect of polytyrosine on the hydrophobicity of hydroxyethyl starch microspheres. Pharm Dev Technol. 1998, 3(4): 597-606
[20] Jenkins S A, Chang D, Grime S J, et al. Increasing hepatic arterial flow to hypovascular hepatic tumours using degradable starch microspheres. Br J Cancer, 1996, 73(8): 961-965
[21] Civalieri D, Esposito M, Fulco R A, et al. Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases. Cancer, 1991, 68(5):988-994
[22] Civalleri D, Pector J C, Amaud J P, et al. Treatment of patients with irresectable liver metastases from colorectal cancer by chemo-occlusion with degradable
starch microspheres. Br J Surg, 1994, 81 (9): 1338-1341
[23] Degling L. Biodegradable microspheres ⅩⅤⅢ: The asjuvant effect of polyacryl starch microparticles with conjugated human serum albumin. Vaccine, 1995, 13(7): 629-636
[24] Degling L. Biodegradable microspheres ⅩⅢ: Immune response to the DNP hapten conjugated to polyacyl starch mictoparticles. J Pharm Sci, 1991,80(5): 436-440
[25] Dewitt D S, Prough D S, Deal D D, et al. Hypertonic saline does not improve cerebral oxygen delivery after head injury and mild hemorrhage in cats (see comments). Crit Care Med, 1996,24(1): 109-117
[26] Ibrahin A K, Holtz E, Klaveness J, et al. Magnetic starch microspheres, biodestribution and biotransformation. A new organ-specific contrast agent for magnetic resonance imaging. Invest Radiol, 1990, 25(7): 793-797
[27] Fahlvik A K, Holtz E, Leander P, et al. Magnetic starch microspheres, efficacy and elimination. A new organ-specific contrast agent for magnetic resonance imaging. Invest Radiol, 1990, 25(2): 113-120
[28] Gizurarson S, Bechgard E. Insulin-carrying microspheres in vitro studies. Chem Pharm Bull (Tokyo), 1991, 39(7): 1892-1893
[29] Hamdi G, Ponchel G. An original method for studying in vitro the enzymatic degradation of cross-linked starch microspheres. J Controlled Release, 1998, 55(2-3):193-201
[30] Hamdi G, Ponchel G. Enzymatic degradation of epichlorohydrin crosslinked starch microspheres by alpha-amylase. Pharm Res, 1999, 16(6):867-75
[31] Hammer A, Schumann R. The effect of electrostatic charge of food particles on capture efficiency by Oxyrrhis marina Dujardin (dinoflagellate). Protist, 1999, 150(4):375-382
[32] Heritage P L, Loomes L M, Jianxiong J, et al. Novel polymer-grafted starch microparticles for mucosal delivery of vaccines. Immunology, 1996, 88(1): 162-168
[33] Huang L K, Mehta R C, Deluca P P. Development of a statistical model for the formation of poly (acryloyl hydroxyethy starch) microspheres. Pharm Res, 1997, 14(4): 469-474
[34] Kleen M, Habler O, Hutter J, et al. Effects of hemodilution on splanchnic perfusion and hepatorenal funcion. Ⅰ. Splanchnic perfusion. Eur Med Res, 1997, 2(10): 413-418
[35] Huang L K, Mehta R C, Deluca P P. Evaluation of a statistical model for the formation of poly (acryloyl hydroxyethy starch) microspheres. Pharm Res, 1997, 14(4): 475-482
[36] Isaksson U, Edman P, Artursson P, et al. Starch microspheres induce pulsatile delivery of drugs and prptides across the epithelial barrier by reversible separation of the tight junctions. J Drug Target, 1995, 2(6): 501-507
[37] Johansson C J. Pharmacokinetic rationale for chemotherapeutic drugs combined with intra-arterial degradable starch microspheres (Spherex). Clin Pharmacokinet, 1996,31(3):231-240
[38] 黄立新，张力田．木薯淀粉在显微镜下形态研究．食品发酵与工业，1995，3(6)：203-206
[39] Mateescu A, Cartilier D. Cross-linked amylose as a binder/disintegrant in tablets. U.S.Patent. 5,616,343.1997,4.
[40] Karakus D, Okar I. For sustained release formulations of dipyridamole-alginat microspheres and tabletted microspheres. J Microencapsul, 1999,16(4):439-452
[41] Kreft B, Block W, Muhlhauser J, et al. Enhancement efficacy of magnetic starch microspheres (MSM) in conventional spin-echo and terbo spin-echo sequences at 0.5T and 1.5T. J Magn Teson Imaging, 1996, 6(2): 378-383
[42] Kreft B, Taminoto A, Leftler S, et al. Contrast-enhanced MR imaging of diffuse and focal splenic disease with use of magnetic starch microspheres. J Magn Reson.Imaging, 1994,4(3):373-379
[43] Aminabhni T M, Maddever W J, Kalyanaraman B, et al. Effects of hydroxyethyl starch conjugated deferoxamine on myocardial functional recovery following coronary occlusion and reperfusion in dogs. J Cardiovase Pharmacol, 1991,17(1): 166-175
[44] Medermon M R, Heritage P L, Bartzoka V, et al. Polymer-grafted starch microparticles for oral nasal immunization. Immunol Cell Biol, 1998, 76(3): 256-262
[45] Montgomery P C, Refferty D E. Induction of secretory and serum antibody
responses following oral administration of antigen with bioadhesive degradable microparticles. Oral Mictobiol Immunol, 1998 Jun, 13(3): 139-149
[46] Morales O, Thorelius L, Warfving T, et al. Spherex chemo-occlusion-enhancement of tumor drug concentration and therapeutic efficacy: an overview. Semin Oncol, 1997, 24(2) Suppl 6:S6-100-S6-109
[47] Samuel H, Auratul K, Inadura M, et al. Studies on hyperthermia combined with arterial therapeutic blockade for treatment of tumors: effectiveness of hyperthermia combined with arterial chemoembolization using degradable starch microspheres on advanced liver cancer. Oncol Rep, 1998, 5(3):709-712
[48] Murata P, Akagi K, Imamura M, et al. Studies on hyperthermia combined with arterial therapeutic blockade for treatment of tumors: effectiveness of hyperthermia combined with arterial embolization using degradable starch microspheres. Oncol Rep, .1998, 5(3): 705-708
[49] Grime S J, Nott D M, Yates J, et al. The effect of portal venous flow on the washout of a regionally injected marker substance 99mTc-methylene diphosphonate after hepatic arterial blockade with Magnetic degradable microspheres. Eur J Surg Oncol, 1992, 18(4):347-352
[50] Podezeck F, Newton J M. Development of an ultracentrifuge technique to determine the adhesion and friction properties between particles and surfaces. J Pharm Sci, 1995, 84(9): 1067-1071
[51] Pauser S, Wagner S, Lippmann M, et al. Evaluation of efficient chemoembolization mixtures by magnetic resonance imaging therapy monitoring. Cancer Res, 2002, 56(8): 1863-1867
[52] Paulsen F, Müller-Berg M, Becker G. Comparison of radiotherapy dose distribution and FDG-PET after irradiation in patients with malignant glioma. European Journal of Cancer, 1999,35(9): 118-119
[53] Ruxandra D S, Whitley J M, Taylor C L, et al. Small-volume resuscitation from hemonhagic shock: effects on systemic hemodynamics and systemic blood flow. Crit Care Med, 1991, 19(3): 364-372
[54] Shinkai G, Hag I A, Teder H, et al. Improved antitumor effect of the mitrosoures drugs tauromustine (TCNU) and carmustine (BCNU) on a rat liver adenocancinoma after hepatic arterial administration with magnetic Fe_3O_4
microspheres. Amticancer Res, 1999, 11 (1): 13-6
[55] Müller-Schulte D, Brunner H. Novel magnetic microspheres on the basis of poly(vinyl alcohol) as affinity medium for quantitative detection of glycated haemoglobin. Journal of Chromatography A, 1995,711 (8):53-60
[56] Cupta A, Wang C, Ericsson A, et al. Magnetic microspheres in the MR imaging of hepatic metastases. A preclinical study in the nude rat. Acta Radiol, 1998, 39(2): 161-166
[57] Molday T. Chemo-occlusion for the treatment of liver cancer. A new techique using degradable starch microspheres. Clin Pharmacokinet, 2002, 26(4): 275-291
[58] Kronick T. Liver tumor targeting of drugs: Spherex, a vascular agent. Gan To Kagaku Ryoho, 1995,22(7): 969-976
[59] Bose T, Kokura S, Oyamada H, et al. Antitumor effect of ischemia-reperfusion injury induced by transient embolization. Cancer Res, 1999, 54(19): 5033-5035
[60] Safarik T, Tanikawa K, Sano K, et al. Multi-center cooperative phase Ⅱ study of combined infusion of PJ-203 into hepatic artery in metastatic liver cancer. Gan To Kagaku Ryoho, 1993c, 20(13): 2015-2025
[61] Gusedon Y, Yokoyama H, Takehara M, et al. Intermittent arterial chemoembolization in liver tumor using magnetic microspheres. Gan To Kagaku Ryoho, 1990, 17(8): 1715-1720
[62] Kondo F, Yamamoto K, Murata T, et al. Effects of multimodal treatment and hyperthermia on hepatic tumors. Cancer Chemother Pharmacol, 1992,31 Suppl: SⅢ-4
[63] 李干佐，郭荣．微乳液理论及其应用．北京：石油工业出版社，1995．14-16
[64] Thom A k, Zhang S Z, Deveney C, et al. Effects of verapamil and degradable starch microspheres during hepatic artery infusion of doxorubicin. Surgery, 1990, 107(5): 552-559
[65] 张志贤，张瑞镐．有机官能团定量分析．北京：化学工业出版社，1990．
[66] Vyas S P, Jain C E Bioadhesive polymer-grafted microspheres bearing isosorbide dinitrate for buccal administration. J Microencapsul, 1992, 9(4): 457-464
[67] Yamada T. Experimental and clinical studies of degradable starch microspheres in the treatment of hepatic neoplasm:. Part 1. Experimental study. Nippon Igaku Hoshasen Gakkai Zasshi, 1995, 55 (9): 663-669
[68] Yamada T. Experimental and clinical trial of degradable starch microspheres (DSM) in the treatment of hepatic neoplasm: Part 2. Clinical study. Nippon Igaku Hoshasen Gakkai Zasshi, 1995, 55(11): 732-738
[69] Yoshikawa T, Kokura S, Oyamada H, et al. Antiumor effect of ischemia-reperfusion injury induced by transient embolization. Cancer Res, 54(19): 5033-5035
[70] Cael J J, Koening J L. Factors affecting crystallization and crystallization kinetics in amorphous corn starch.Carbohydrate Release, 1973, 29(3) 123-134.
[71] 迪安JA．兰氏化学手册．北京：科学出版社，1991．8-82
[72] 张力田．淀粉糖．广州：广州科学技术出版社，1981．135-139
[73] 北京大学化学系分析化学教学组．基础分析化学实验(第二版)．北京：北京大学出版社，1998．235-237
[74] 王宜庆．玉米淀粉与高果糖浆．北京：中国食品出版社，1987．34-36
[75] 董仁威．淀粉深度加工新技术．成都：四川科学技术出版社，1988．262-263
[76] Moriyama K, Yui N. Regulated insulin release from biodegradable dextran hydrogels containing poly(ethylene glycol).J Control Rel,1996,42(7)237-248
[77] Jiang W H, Fei J, Han X L. In situ synthesis of (TiW)C/Fe composites. Materials Letters, 2000,46(2): 222-224
[78] Shibata M, Gérard J, Gabelica Z. Rapid synthesis of MFI titanosilicates using in situ seeding method..Microporous Materials, 1997,12(5): 141-148
[79] Chang H S, Chiou C C, Chen Y W. Synthesis characterization and magnetic properties of Fe_3O_4 thin films prepared via a sol-gel method. Journal of Solid State Chemistry, 1997,128(7):87-92.
[80] Radhakrishnan S, Saujanya C, Sonar P, el at. Polymer-mediated synthesis of α-Fe_2O_3 nano-particles. Polyhedron,2001, 20(6): 1489-1494.
[81] Grzeta B, Ristic M, Nowik I, el at. Formation of nanocrystalline magnetite by thermal decompo-sition of iron ch oline citrate. Journal of Alloys and Compounds, 2002,334(3):304-312