磁性纳米颗粒的研制及其肿瘤靶向磁热疗效应分析
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摘要
本文对天然高分子聚合物修饰的磁性纳米颗粒的制备方法及其应用进展进行了综述。通过大量实验研究了天然高分子聚合物修饰的磁性淀粉纳米颗粒的制备和生物学效应。实验从磁性纳米颗粒(γ-Fe_2O_3)入手,经天然的高分子聚合物淀粉包被,再经多聚赖氨酸和叶酸修饰,考察其理化性质,并进行了进一步的肿瘤细胞磁热疗方面的应用研究。
本文采用反相微乳液法制备了包裹磁流体的淀粉纳米颗粒(StNP@Fe_2O_3),再经多聚赖氨酸(PLL)和叶酸活性物质(FA-PEG-NH2)修饰,得到多聚赖氨酸-磁性淀粉纳米颗粒(PLL-StNP@Fe_2O_3)和叶酸-磁性淀粉纳米颗粒(FA-StNP@Fe_2O_3)。然后通过透射电子显微镜显示颗粒形貌,激光粒度分析仪检测显示所得颗粒平均粒径和电位大小。邻菲罗啉法检测颗粒的铁含量。经过改性的磁性纳米颗粒在交变磁场下作用30 min可使环境温度(37℃)升高到42~43℃,显示其具有一定的磁热效应。进一步将纳米颗粒与肿瘤细胞株Hela细胞共培养,经交变磁场作用后,进一步通过MTT实验、Hochest-PI双染色分析、流式细胞仪技术检测纳米颗粒在细胞水平的生物学效应,结果表明磁性纳米颗粒在未加磁场时,在一定浓度范围内对细胞的增殖无明显影响;而在一定交变磁场强度作用下则能有效地诱导细胞凋亡。普鲁士蓝染色实验中,在与正常细胞对比的情况下,显示了经过靶向修饰PLL和叶酸有助于纳米颗粒靶向识别肿瘤细胞。研究表明靶向修饰的纳米颗粒具有良好的肿瘤靶向磁热治疗效果,其中,FA-StNP@Fe_2O_3颗粒经过表面叶酸修饰后更能实现对肿瘤细胞的靶向识别和细胞内的富集,使肿瘤细胞凋亡显著,是一种很有潜力肿瘤靶向热疗载体,可望应用于肿瘤的靶向治疗。
This thesis describes current approaches for the preparation of biodegradable polymers nanoparticles and their applications research in medical field. Experimental magnetic nanoparticles start fromγ-Fe_2O_3, with natural starch polymer coating. And two kinds of natural macromolecules biodegradable polymers, Poly-L-lysine(PLL) and Folic acid (FA-PEG-NH2), were used in this experiments to modify starch magnetic nanoparticles. Study its physical and chemical properties, and further biological medical application for magnetic hyperthermia.
Modified magnetic starch nanoparticles (PLL-StNP@ Fe_2O_3&FA-StNP@ Fe_2O_3) were synthesized by conjugating PLL&FA-PEG-NH2 onto the surface of magnetic starch nanoparticles(StNP@ Fe_2O_3) prepared by reverse microemulsion method. The synthesized nanoparticles were investigated by transmission electron microscopy and zeta potential analysis. The average size of its well dispersed particles and the iron concentration detected by phenanthroline method were gained. Placing these nanoparticles in alternating magnetic field for 30 min could result in an increase in the suspension temperature from ambient temperature (37 oC) to a value between 42 and 43 oC. Co-cultured nanoparticles and Hela cell line or normal HUEC-12 cell line, and the biological effects at cellular level were investigated in alternating magnetic field using MTT assay, Hochest-PI double staining and flow cytometry analysis. Experimental results showed that functional nanoparticles within certain concentration range has no obvious effect on cell proliferation. When treated in magnetic field, apoptosis on Hela induced by these nanoparticles were obvious. Prussian blue staining analysis confirmed that the nanoparticles modified with PLL &FA had improved ability in tumor cell-targeting, compared with HUCE-12,and therefore, potential applications in biomedical and magnetocaloric areas. It is expected to be applied to tumor targeting therapy in the near future.
本文采用反相微乳液法制备了包裹磁流体的淀粉纳米颗粒(StNP@Fe_2O_3),再经多聚赖氨酸(PLL)和叶酸活性物质(FA-PEG-NH2)修饰,得到多聚赖氨酸-磁性淀粉纳米颗粒(PLL-StNP@Fe_2O_3)和叶酸-磁性淀粉纳米颗粒(FA-StNP@Fe_2O_3)。然后通过透射电子显微镜显示颗粒形貌,激光粒度分析仪检测显示所得颗粒平均粒径和电位大小。邻菲罗啉法检测颗粒的铁含量。经过改性的磁性纳米颗粒在交变磁场下作用30 min可使环境温度(37℃)升高到42~43℃,显示其具有一定的磁热效应。进一步将纳米颗粒与肿瘤细胞株Hela细胞共培养,经交变磁场作用后,进一步通过MTT实验、Hochest-PI双染色分析、流式细胞仪技术检测纳米颗粒在细胞水平的生物学效应,结果表明磁性纳米颗粒在未加磁场时,在一定浓度范围内对细胞的增殖无明显影响;而在一定交变磁场强度作用下则能有效地诱导细胞凋亡。普鲁士蓝染色实验中,在与正常细胞对比的情况下,显示了经过靶向修饰PLL和叶酸有助于纳米颗粒靶向识别肿瘤细胞。研究表明靶向修饰的纳米颗粒具有良好的肿瘤靶向磁热治疗效果,其中,FA-StNP@Fe_2O_3颗粒经过表面叶酸修饰后更能实现对肿瘤细胞的靶向识别和细胞内的富集,使肿瘤细胞凋亡显著,是一种很有潜力肿瘤靶向热疗载体,可望应用于肿瘤的靶向治疗。
This thesis describes current approaches for the preparation of biodegradable polymers nanoparticles and their applications research in medical field. Experimental magnetic nanoparticles start fromγ-Fe_2O_3, with natural starch polymer coating. And two kinds of natural macromolecules biodegradable polymers, Poly-L-lysine(PLL) and Folic acid (FA-PEG-NH2), were used in this experiments to modify starch magnetic nanoparticles. Study its physical and chemical properties, and further biological medical application for magnetic hyperthermia.
Modified magnetic starch nanoparticles (PLL-StNP@ Fe_2O_3&FA-StNP@ Fe_2O_3) were synthesized by conjugating PLL&FA-PEG-NH2 onto the surface of magnetic starch nanoparticles(StNP@ Fe_2O_3) prepared by reverse microemulsion method. The synthesized nanoparticles were investigated by transmission electron microscopy and zeta potential analysis. The average size of its well dispersed particles and the iron concentration detected by phenanthroline method were gained. Placing these nanoparticles in alternating magnetic field for 30 min could result in an increase in the suspension temperature from ambient temperature (37 oC) to a value between 42 and 43 oC. Co-cultured nanoparticles and Hela cell line or normal HUEC-12 cell line, and the biological effects at cellular level were investigated in alternating magnetic field using MTT assay, Hochest-PI double staining and flow cytometry analysis. Experimental results showed that functional nanoparticles within certain concentration range has no obvious effect on cell proliferation. When treated in magnetic field, apoptosis on Hela induced by these nanoparticles were obvious. Prussian blue staining analysis confirmed that the nanoparticles modified with PLL &FA had improved ability in tumor cell-targeting, compared with HUCE-12,and therefore, potential applications in biomedical and magnetocaloric areas. It is expected to be applied to tumor targeting therapy in the near future.
引文
[1] Lowe C R. Nanobiotechnogy: The fabrication and applications of chemical and biological nanostructures[J]. . Current Opinion in Chemical Biology, 2000 , (10): 428-434
[2]李凤林.纳米生物技术的研究进展及应用[J].发酵科技通讯, 2008, 37(4): 48-52
[3] Pankhurstq A, Connolly J, Jones S K, etal. Applications of magnetic nanoparticles in biomedicine[J]. J. Phys. D: PhyS, 2003, 36: 167-181
[4] Zimmermann U, V Ienken J , P Ilwat G. Development of drug carrier systems: Electrical field induced effects in cell membranes[J]. Bioelectrochem Bioenerg, 1980, 7 (3) : 553-574
[5] Kong G, Braumr, Dewh Irstm. Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size[J]. Cancer Research, 2000, 60: 4440-4445
[6] Schmeltzer R C, Sehmalenberg K E, Uhrich K E. Synthesis and cyto- toxicityofsalicylate-basedpoly (anhydrideesters) [J]. Biomacromolecules, 2005, 6(1): 359-367
[7] Somavarapul S, Pandit S, Gradassi G, eta1. Effect of vitamin E TPGS on immune response to nasally delivered diphtheria toxoid loaded poly (caprolactone) mieroparticles[J] . Int J Pharm, 2005, 298(2): 344-347
[8] Soga O, vall Nostrum C F, Fens M, eta1. Therm osensitive and biodegradable polymeric micelles for paelitaxel delivery[J]. J Contr Rel, 2005, 103(2): 341-353
[9]张阳德,李亚勇.纳米控释系统在肿瘤治疗中的应用研究[J].中国现代医学杂志, 2004, 14(14): 63-64
[10]杨菁,宋存先.纳米粒子作为药物输送和药物控释体系的应用前景[J].基础医学与临床, 2006, 26(7): 684-687
[11] Muller R H, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy Rationale for development and what we can expect for the future[J]. Advanced Drug Delivery Reviews, 2001, 47(1): 3-19
[12] Allemann E, Gury R, Doelker E. Drug-loaded nanoparticles preparation methods and drug targeting issue[J]. Eur J Pharm Biopharm, 1993, 39 (5) : 173
[13] Kreuter J. Nanoparticles and microparticles for drug and vaccine delivery[J]. J Anat, 1996, 189(1): 503-504
[14] Sinha V R, Trehan A. Biodegradable microspheres for protein delivery[J]. J Contr Rel, 2003, 90(3): 261-280
[15] Choi H, Choi S R, Zhou R, etal. Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor targeted delivery[J]. Acad Radiol, 2004, 11 (9) : 996
[16]任辉,张阳德纳米技术在生物系统领域的应用研究[J].中国实验诊断学, 2008, 12(7): 944-946
[17]张立德,牟季美.纳米材料和纳米结构[M].北京:科学出版社, 2001, 1-19
[18]高濂,郑珊,张青红.纳米氧化钛光催化材料及应用[M].北京:化学工业出版社, 2002
[19] Saini S, Sharma R, Baron R L, etal. Multicentre dose-ranging study on the efficacy of USPIO ferumoxtran-10 for liver MR imaging[J]. Clin Radiol, 2000, 55: 690-695
[20] Gupta A K, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications[J]. Biomaterials, 2005, 26(18): 3995-4021
[21] Soppimath K S,Aminabhavi T M,et a1. Biodegradable polymeric nanoparticles as drug delivery devices[J]. J Control Release, 2001, 70: 1-20
[22] Ravl Kumar. Nanoparticles and micmparticles as contFueddrug delivery devices[J]. J Pharm Sci, 2000, 3: 234-258
[23]徐晓雪,李莉,郑玉峰.生物医用磁性纳米颗粒的制备与表面改性[J].材料科学与工艺, 2008, 116(14) : 562-568
[24] Lellouche JP, Perlman N, Joseph A, et al. New magnetically responsive polydicarbazole-magnetite nanoparticles[J]. Chem Commun , 2004 , (5) : 560-561
[25] Jolivet J P. Metal oxide chemistry and synthesis : From solutions to solid state[M] . New York : Wiley , 2000
[26]李文兵,周蓬蓬,余龙江等.生物相容Fe3O4磁性纳米颗粒的合成及应用[J].现代化工, 2006, 26: 322-326
[27] Tartaj P, Morales M, Veintemillas S, etal. The preparation of magnetic nanoparticles for applications in biomedicine[J]. J. Phys. D: Phys. , 2003, 36: 182-197
[28]何韶铮综述,吕国荣审校.纳米粒靶向治疗肝癌的研究进展[J].中国介入影像与治疗学, 2005, 2(1): 70-73
[29] Gupta A K, Curtis ASG. Lactoferrin and ceruloplasmin derivatized superparamagneticiron oxide nanoparticles for targeting cell surface receptors[J]. Biomaterials, 2004, 25 (15) : 3029-3040
[30] Shi Donglu, He Peng. Surface modifications of nanoparticles and nanotubes by p lasma polymerization[J]. Rev. Adv. Mater. Sci , 2004, (7): 97-107
[31] Kim D, Zhang Y, Kehr J, et al. Characterization and MR I study of surfactant-coater superparamagnetic nanoparticles administered into the rat brain[J]. J. Magn. Magn. Mater, 2001, 225: 256-261
[32]胡兴.纳米粒给药载体系统[J].怀化学院学报, 2003, 22(5): 56-59
[33]马勇杰,古宏晨.细胞内磁热疗研究概述[J].上海师范大学学报, 2005, 34(4): 65-69
[34]张阳德,张洋,潘一峰.磁性纳米颗粒靶向性肿瘤热疗的研究进展[J].中国医学工程, 2006, 14(2): 148-152
[35] Hergt R, Andra W, et al. Physical fimits of hyperthermia using magnetite fine particles[J]. IEEE Transactions on Magnetics, 1998,34(5) : 3745-3754
[36]赵强.热疗对肿瘤细胞MCF-7, Hela凋亡的影响:湖南大学学士学位论文.长沙:湖南大学, 2006
[37] Hildebrandt B , Wust P , Ahlers O , et al . The cellular and molecular basis of hperthermia[J] . Crit Rev Oncol Hematol , 2002 , 43(1) : 33– 56
[38] Cummings M. Increased c-fos expression associated with hyperthermia-induced apoptosis of a Burkit tlymphoma cell line[J]. Int J Radiat Biol , 1995 , 8(6): 687– 692
[39] Li JJ, Oberley LW. Overexpression of manganese-containing super oxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and or hypert hermia[J] . Cancer Res , 1997 , 57(10) : 1991-1998
[40] Gilchmst R K , Medal IL , Shorey W D, et a1. Selective inductive heating of lymph nodes[J]. Annals of Oncology, 1957, 146(4): 595-606
[41]张阳德.纳米生物技术学[M].北京:科学出版社, 2005:107
[42]张阳德,李浩.纳米载体肝靶向纳米药物研究进展[J].中国医学工程杂志, 2002, 11(6): 75-77
[43] Gordon RT, Hines JR, Gordon D, Med. A biophysical approach to cancer treatment via intracellular temperature and biophysical alterations[J]. Med Hypotheses , 1979, 5: 83-102
[44] Jordan A, Scholz R, Wust P, et al. Magnetic fluid hyperthermia (MFH): Cancer treatment with AC magnetic fieid induced excitation of biocompatible superparamagnetic nanoparticles[J]. Journal of Magnetism and MagneticMaterials, 1999, 201: 413-419
[45] Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in combined treatment of cancer[J]. The Lancet Oncology ,2002; 3:487–497.
[46] Lafarik I, Lafarikova M. Magnetic nanoparticles and biosciences[J]. Monatshefte fürChemie , 2002 , 133 : 746-754
[47] FrankelRB. Biological permanent magnets[J]. HyperfineInteractions , 2003 , 151/ 152 : 145-153
[48] Tartaj P , Morales M P , Gonzalez-Carreìo T , et al . Advanced in magnetic nanoparticles for biotechnology applications[J]. J Mag Mag Mater , 2005 , 290-291 : 28-34
[49] Berry C C , Curtis A S G. Functionalisation of magnetic nanoparticles for applications in biomedicine[J]. J Phys D: Phys , 2003 , 36 : 198 -206
[50] Bazylinski D A. Magnetosome formation in prokaryotes[J]. Nat Rev Microbiol , 2004 , 2 : 217-230
[51]杨锦宗.变性淀粉的化学进展[J].造纸化学品, 1995, 7(2): 1-9
[52]冯国涛,单志华.变性淀粉的种类及其应用研究[J].皮革化工, 2005, 22(3): 25-28
[53]李德富,李宏利,林炜,等.改性淀粉的制备与应用研究进展[J].中国皮革, 2007, 36(1): 32-37
[54]钟森,温守明,张定凤,等.乳糖化多聚赖氨酸导向反义寡核苷酸抗乙型肝炎病毒的作用[J].中华实验和临床病毒学杂志, 2001 , 15 (2) : 150-153
[55]肖苏尧,童春义,刘选明,等.肿瘤靶向性药物载体叶酸-淀粉纳米颗粒的研制与应用[J].科学通报, 2006, 51(10): 1151-1155
[56]秦润华,刘宏英,姜炜.肿瘤治疗用磁流体研究进展[J].江苏化工,2003, 31(5): 8-11
[57] Wikingsson L D, Sj?holm I. Polyacryl starch microparticles as adjuvant in oral immunisation, inducing mucosal and systemic immune responses in mice[J]. Vaccine, 2002, 20(12): 3355-3363
[58] Pohja S, Suihko E, Vidgren M, et al. Starch acetate as a tablet matrix for sustained drug release[J]. J Control Release, 2004, 94(1): 293-302
[59] Tuovinen L, Ruhanen E, Kinnarinen T. Starch acetate microparticles for drug delivery into retinal pigment epithelium—in vitro study[J]. J Control Release, 2004, 98(1): 407-413
[60] He X, Shen B, Liu X. Production and applications on dialdehyde starch[J]. Chinese J Bioprocess Engineering, 2004, 2(3): 1-4
[61] Wongsagona R, Shobsngobb S, Varavinita S. Preparation and physicochemical properties of dialdehyde tapioca starch[J]. Starch/St?rke, 2005, 57(2): 166-172
[62]谢彩锋,杨连生,高群玉.纳米淀粉微球的制备及其在生物医药中的应用[J].现代化工, 2004, 24(9): 62-65
[63] PardoeH, Chua-anusorn W, St PierreT G, et al. StructuraI and magnetic properties of nanoscale iron oxide Particles synthesized in the Presence of dextran or Polyvinyl alcohol[J]. J. Magn. Mater. 2001, (225): 41-46
[64]肖苏尧,刘选明,童春义,等.多聚赖氨酸淀粉纳米颗粒基因载体的研制及应用[J].中国科学, 2004, 34 (6): 473-477
[65]郭毅,张爽男,康春生,等.纳米阳离子多聚物在基因载体系统的应用[J].高分子通报, 2005, 5: 142-146
[66] Weitman SD, Weinberg AG, Coney LR, et al. Cellularlocalization of the folate receptor: potential role in drug toxicity and folate homeostasis[J]. Cancer Res, 1992, 52: 6708-6711
[67] BagnoliM, Canevari S, FiginiM, et al. A step further in understanding the biology of the folate receptor in ovarian carcinoma[J]. GynecolOncol, 2003, 88: 140 -144
[68] Lu Y, Sega E, Leamon CP, et al. Folate recep tortargeted immunotherapy of cancer: mechanism and therapeutic potential[J]. Adv Drug Deliv Rev, 2004, 56: 1161-1176
[69] Sudimack J , Lee RJ. Targeted drug delivery via the foH late receptor[J]. Adv Drug Deliv Rev, 2000, 41: 147-162
[70]马勇杰,李红,鄢祝兵,等.细胞内磁热疗诱导人肺腺癌细胞PC-A1凋亡的体外实验研究[J].生物医学工程学杂志, 2007, 24 (6): 1305-1308
[71] Xiao X X, He Q Q, Huang K L, et al. Possible magnetic multifunctional nanoplatforms in medicine[J]. Med Hypotheses, 2007, 6(61): 680-682
[72] Nanz D, Weishaupt D, Quick H H, et al. TE-switched double-contrast enhanced visualization of vascular system and instruments for MR-guided interventions[J]. Magn Reson Med, 2000, 43: 645-648
[73] Zhang Y, Zhang J. Surface modification of monodisperse magnetite nanoparticles for improved intracellular uptake to breast cancer cells[J]. J Colloid Interface Sci, 2005, 283: 352-357
[2]李凤林.纳米生物技术的研究进展及应用[J].发酵科技通讯, 2008, 37(4): 48-52
[3] Pankhurstq A, Connolly J, Jones S K, etal. Applications of magnetic nanoparticles in biomedicine[J]. J. Phys. D: PhyS, 2003, 36: 167-181
[4] Zimmermann U, V Ienken J , P Ilwat G. Development of drug carrier systems: Electrical field induced effects in cell membranes[J]. Bioelectrochem Bioenerg, 1980, 7 (3) : 553-574
[5] Kong G, Braumr, Dewh Irstm. Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size[J]. Cancer Research, 2000, 60: 4440-4445
[6] Schmeltzer R C, Sehmalenberg K E, Uhrich K E. Synthesis and cyto- toxicityofsalicylate-basedpoly (anhydrideesters) [J]. Biomacromolecules, 2005, 6(1): 359-367
[7] Somavarapul S, Pandit S, Gradassi G, eta1. Effect of vitamin E TPGS on immune response to nasally delivered diphtheria toxoid loaded poly (caprolactone) mieroparticles[J] . Int J Pharm, 2005, 298(2): 344-347
[8] Soga O, vall Nostrum C F, Fens M, eta1. Therm osensitive and biodegradable polymeric micelles for paelitaxel delivery[J]. J Contr Rel, 2005, 103(2): 341-353
[9]张阳德,李亚勇.纳米控释系统在肿瘤治疗中的应用研究[J].中国现代医学杂志, 2004, 14(14): 63-64
[10]杨菁,宋存先.纳米粒子作为药物输送和药物控释体系的应用前景[J].基础医学与临床, 2006, 26(7): 684-687
[11] Muller R H, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy Rationale for development and what we can expect for the future[J]. Advanced Drug Delivery Reviews, 2001, 47(1): 3-19
[12] Allemann E, Gury R, Doelker E. Drug-loaded nanoparticles preparation methods and drug targeting issue[J]. Eur J Pharm Biopharm, 1993, 39 (5) : 173
[13] Kreuter J. Nanoparticles and microparticles for drug and vaccine delivery[J]. J Anat, 1996, 189(1): 503-504
[14] Sinha V R, Trehan A. Biodegradable microspheres for protein delivery[J]. J Contr Rel, 2003, 90(3): 261-280
[15] Choi H, Choi S R, Zhou R, etal. Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor targeted delivery[J]. Acad Radiol, 2004, 11 (9) : 996
[16]任辉,张阳德纳米技术在生物系统领域的应用研究[J].中国实验诊断学, 2008, 12(7): 944-946
[17]张立德,牟季美.纳米材料和纳米结构[M].北京:科学出版社, 2001, 1-19
[18]高濂,郑珊,张青红.纳米氧化钛光催化材料及应用[M].北京:化学工业出版社, 2002
[19] Saini S, Sharma R, Baron R L, etal. Multicentre dose-ranging study on the efficacy of USPIO ferumoxtran-10 for liver MR imaging[J]. Clin Radiol, 2000, 55: 690-695
[20] Gupta A K, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications[J]. Biomaterials, 2005, 26(18): 3995-4021
[21] Soppimath K S,Aminabhavi T M,et a1. Biodegradable polymeric nanoparticles as drug delivery devices[J]. J Control Release, 2001, 70: 1-20
[22] Ravl Kumar. Nanoparticles and micmparticles as contFueddrug delivery devices[J]. J Pharm Sci, 2000, 3: 234-258
[23]徐晓雪,李莉,郑玉峰.生物医用磁性纳米颗粒的制备与表面改性[J].材料科学与工艺, 2008, 116(14) : 562-568
[24] Lellouche JP, Perlman N, Joseph A, et al. New magnetically responsive polydicarbazole-magnetite nanoparticles[J]. Chem Commun , 2004 , (5) : 560-561
[25] Jolivet J P. Metal oxide chemistry and synthesis : From solutions to solid state[M] . New York : Wiley , 2000
[26]李文兵,周蓬蓬,余龙江等.生物相容Fe3O4磁性纳米颗粒的合成及应用[J].现代化工, 2006, 26: 322-326
[27] Tartaj P, Morales M, Veintemillas S, etal. The preparation of magnetic nanoparticles for applications in biomedicine[J]. J. Phys. D: Phys. , 2003, 36: 182-197
[28]何韶铮综述,吕国荣审校.纳米粒靶向治疗肝癌的研究进展[J].中国介入影像与治疗学, 2005, 2(1): 70-73
[29] Gupta A K, Curtis ASG. Lactoferrin and ceruloplasmin derivatized superparamagneticiron oxide nanoparticles for targeting cell surface receptors[J]. Biomaterials, 2004, 25 (15) : 3029-3040
[30] Shi Donglu, He Peng. Surface modifications of nanoparticles and nanotubes by p lasma polymerization[J]. Rev. Adv. Mater. Sci , 2004, (7): 97-107
[31] Kim D, Zhang Y, Kehr J, et al. Characterization and MR I study of surfactant-coater superparamagnetic nanoparticles administered into the rat brain[J]. J. Magn. Magn. Mater, 2001, 225: 256-261
[32]胡兴.纳米粒给药载体系统[J].怀化学院学报, 2003, 22(5): 56-59
[33]马勇杰,古宏晨.细胞内磁热疗研究概述[J].上海师范大学学报, 2005, 34(4): 65-69
[34]张阳德,张洋,潘一峰.磁性纳米颗粒靶向性肿瘤热疗的研究进展[J].中国医学工程, 2006, 14(2): 148-152
[35] Hergt R, Andra W, et al. Physical fimits of hyperthermia using magnetite fine particles[J]. IEEE Transactions on Magnetics, 1998,34(5) : 3745-3754
[36]赵强.热疗对肿瘤细胞MCF-7, Hela凋亡的影响:湖南大学学士学位论文.长沙:湖南大学, 2006
[37] Hildebrandt B , Wust P , Ahlers O , et al . The cellular and molecular basis of hperthermia[J] . Crit Rev Oncol Hematol , 2002 , 43(1) : 33– 56
[38] Cummings M. Increased c-fos expression associated with hyperthermia-induced apoptosis of a Burkit tlymphoma cell line[J]. Int J Radiat Biol , 1995 , 8(6): 687– 692
[39] Li JJ, Oberley LW. Overexpression of manganese-containing super oxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and or hypert hermia[J] . Cancer Res , 1997 , 57(10) : 1991-1998
[40] Gilchmst R K , Medal IL , Shorey W D, et a1. Selective inductive heating of lymph nodes[J]. Annals of Oncology, 1957, 146(4): 595-606
[41]张阳德.纳米生物技术学[M].北京:科学出版社, 2005:107
[42]张阳德,李浩.纳米载体肝靶向纳米药物研究进展[J].中国医学工程杂志, 2002, 11(6): 75-77
[43] Gordon RT, Hines JR, Gordon D, Med. A biophysical approach to cancer treatment via intracellular temperature and biophysical alterations[J]. Med Hypotheses , 1979, 5: 83-102
[44] Jordan A, Scholz R, Wust P, et al. Magnetic fluid hyperthermia (MFH): Cancer treatment with AC magnetic fieid induced excitation of biocompatible superparamagnetic nanoparticles[J]. Journal of Magnetism and MagneticMaterials, 1999, 201: 413-419
[45] Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in combined treatment of cancer[J]. The Lancet Oncology ,2002; 3:487–497.
[46] Lafarik I, Lafarikova M. Magnetic nanoparticles and biosciences[J]. Monatshefte fürChemie , 2002 , 133 : 746-754
[47] FrankelRB. Biological permanent magnets[J]. HyperfineInteractions , 2003 , 151/ 152 : 145-153
[48] Tartaj P , Morales M P , Gonzalez-Carreìo T , et al . Advanced in magnetic nanoparticles for biotechnology applications[J]. J Mag Mag Mater , 2005 , 290-291 : 28-34
[49] Berry C C , Curtis A S G. Functionalisation of magnetic nanoparticles for applications in biomedicine[J]. J Phys D: Phys , 2003 , 36 : 198 -206
[50] Bazylinski D A. Magnetosome formation in prokaryotes[J]. Nat Rev Microbiol , 2004 , 2 : 217-230
[51]杨锦宗.变性淀粉的化学进展[J].造纸化学品, 1995, 7(2): 1-9
[52]冯国涛,单志华.变性淀粉的种类及其应用研究[J].皮革化工, 2005, 22(3): 25-28
[53]李德富,李宏利,林炜,等.改性淀粉的制备与应用研究进展[J].中国皮革, 2007, 36(1): 32-37
[54]钟森,温守明,张定凤,等.乳糖化多聚赖氨酸导向反义寡核苷酸抗乙型肝炎病毒的作用[J].中华实验和临床病毒学杂志, 2001 , 15 (2) : 150-153
[55]肖苏尧,童春义,刘选明,等.肿瘤靶向性药物载体叶酸-淀粉纳米颗粒的研制与应用[J].科学通报, 2006, 51(10): 1151-1155
[56]秦润华,刘宏英,姜炜.肿瘤治疗用磁流体研究进展[J].江苏化工,2003, 31(5): 8-11
[57] Wikingsson L D, Sj?holm I. Polyacryl starch microparticles as adjuvant in oral immunisation, inducing mucosal and systemic immune responses in mice[J]. Vaccine, 2002, 20(12): 3355-3363
[58] Pohja S, Suihko E, Vidgren M, et al. Starch acetate as a tablet matrix for sustained drug release[J]. J Control Release, 2004, 94(1): 293-302
[59] Tuovinen L, Ruhanen E, Kinnarinen T. Starch acetate microparticles for drug delivery into retinal pigment epithelium—in vitro study[J]. J Control Release, 2004, 98(1): 407-413
[60] He X, Shen B, Liu X. Production and applications on dialdehyde starch[J]. Chinese J Bioprocess Engineering, 2004, 2(3): 1-4
[61] Wongsagona R, Shobsngobb S, Varavinita S. Preparation and physicochemical properties of dialdehyde tapioca starch[J]. Starch/St?rke, 2005, 57(2): 166-172
[62]谢彩锋,杨连生,高群玉.纳米淀粉微球的制备及其在生物医药中的应用[J].现代化工, 2004, 24(9): 62-65
[63] PardoeH, Chua-anusorn W, St PierreT G, et al. StructuraI and magnetic properties of nanoscale iron oxide Particles synthesized in the Presence of dextran or Polyvinyl alcohol[J]. J. Magn. Mater. 2001, (225): 41-46
[64]肖苏尧,刘选明,童春义,等.多聚赖氨酸淀粉纳米颗粒基因载体的研制及应用[J].中国科学, 2004, 34 (6): 473-477
[65]郭毅,张爽男,康春生,等.纳米阳离子多聚物在基因载体系统的应用[J].高分子通报, 2005, 5: 142-146
[66] Weitman SD, Weinberg AG, Coney LR, et al. Cellularlocalization of the folate receptor: potential role in drug toxicity and folate homeostasis[J]. Cancer Res, 1992, 52: 6708-6711
[67] BagnoliM, Canevari S, FiginiM, et al. A step further in understanding the biology of the folate receptor in ovarian carcinoma[J]. GynecolOncol, 2003, 88: 140 -144
[68] Lu Y, Sega E, Leamon CP, et al. Folate recep tortargeted immunotherapy of cancer: mechanism and therapeutic potential[J]. Adv Drug Deliv Rev, 2004, 56: 1161-1176
[69] Sudimack J , Lee RJ. Targeted drug delivery via the foH late receptor[J]. Adv Drug Deliv Rev, 2000, 41: 147-162
[70]马勇杰,李红,鄢祝兵,等.细胞内磁热疗诱导人肺腺癌细胞PC-A1凋亡的体外实验研究[J].生物医学工程学杂志, 2007, 24 (6): 1305-1308
[71] Xiao X X, He Q Q, Huang K L, et al. Possible magnetic multifunctional nanoplatforms in medicine[J]. Med Hypotheses, 2007, 6(61): 680-682
[72] Nanz D, Weishaupt D, Quick H H, et al. TE-switched double-contrast enhanced visualization of vascular system and instruments for MR-guided interventions[J]. Magn Reson Med, 2000, 43: 645-648
[73] Zhang Y, Zhang J. Surface modification of monodisperse magnetite nanoparticles for improved intracellular uptake to breast cancer cells[J]. J Colloid Interface Sci, 2005, 283: 352-357