摘要
恶性肿瘤是危害人类健康的重要因素,寻求有效的肿瘤诊断与治疗方法是全球科学家共同的目标。目前化疗还是治疗肿瘤的重要方法,但是其在杀伤肿瘤细胞的同时也损伤正常细胞,对患者造成严重的毒副作用。肿瘤的磁导靶向系统可以将化疗药物定向输送到肿瘤部位,提高对肿瘤的治疗效果,降低对人体的毒副作用,而选择合适的药物载体是磁导靶向给药系统关键的环节。核壳结构纳米金磁微粒由于粒径小,比表面积大,偶联容量高,表面易于功能化等特点使其成为靶向给药系统药物载体的理想选择。但水相存在的金磁微粒在环境(如介质盐离子浓度)发生变化时容易发生聚集,经过亲水性的葡聚糖对金磁微粒表面修饰,可以改善复合粒子在各种溶液中的稳定性,使其更适合作为药物载体。
本研究选用葡聚糖修饰金磁微粒(DGMNs),利用不同表征手段证实葡聚糖金磁复合微粒具有粒径大小均一,不易聚集,磁响应性好等特性,修饰后的纳米金磁微粒在注射用水,葡萄糖注射液,氯化钠注射液,PBS缓冲液以及血浆中的平均水合半径都在100nm左右,呈现优良的胶态稳定性。
选择化疗药物阿霉素,葡聚糖金磁复合微粒在体外的载药率达到14.3%,红外光谱表征确证了葡聚糖金磁复合微粒表面成功负载了阿霉素。体外释药曲线研究结果显示：在开始释药的2h大约有-40.7%的药物从磁粒表面释放,后续释药时间达到-120h,最大释药率是88.1%,表明药物是以缓慢稳定的方式释放。
利用MTT法测定葡聚糖金磁复合微粒对人肝癌细胞(HepG2)和小鼠肝癌细胞H22的毒性试验证实在磁粒浓度达到2000μg/mL时候,细胞存活率都大于80%,说明复合粒子安全无毒。载阿霉素的磁粒比游离阿霉素抑制HepG2和H22细胞能力更显著。
葡聚糖金磁复合微粒对小鼠的安全性试验证实,当载体浓度达到2g/kg体重时,其在动物体内仍是安全的。载药葡聚糖金磁复合微粒的体内试验结果证实：由于药物可以稳定缓释,大大降低了对动物的毒性作用,载阿霉素葡聚糖金磁复合微粒和游离阿霉素的半数致死量(LD50)分别为45.22mg/kg和15.60mg/kg,间接表明载体与阿霉素的结合,的确降低了药物对组织的伤害。脏器指数和器官病理分析的结果显示载药复合物促使阿霉素聚集在肝脏和脾脏部位,可降低对心脏的毒性。磁场在载药葡聚糖金磁复合微粒靶向定位时显示了很好的功效。
成功地建立了利用高效液相色谱法(HPLC)测定血浆中阿霉素含量方法,并利用此方法研究载阿霉素葡聚糖金磁复合微粒在SD大鼠体内的药代动力学。阿霉素、载阿霉素葡聚糖金磁复合微粒和加磁场组动物体内的药物代谢都是三室模型,其结果表明了载阿霉素葡聚糖金磁复合微粒和载阿霉素葡聚糖金磁复合微粒+磁场均能显著改变阿霉素的药代动力学特征,从而提高了生物利用度,降低峰浓度,减慢消除,有缓释、降低毒性的作用。
对H22荷瘤小鼠的药效学研究表明,采用不同治疗方案处理荷瘤小鼠,肿瘤生长的相对体积变化和体重抑制率都表明载阿霉素葡聚糖金磁复合微粒加磁场比游离阿霉素的效果更好。载阿霉素葡聚糖金磁复合微粒加磁场、载阿霉素葡聚糖金磁复合微粒、游离阿霉素以及对照作用于荷瘤小鼠的生存期分别为58.6±7.1,46.2±6.9,32.0±5.3和28.2±4.6天,载药磁粒加磁场组和载药磁粒组动物相对于对照组和阿霉素组明显延长了动物的生存期。小鼠的体重,饮食和饮水结果反映出载药葡聚糖金磁复合微粒相对于游离阿霉素,可以缓解化疗药物对动物本身的伤害。组织学研究表明载药葡聚糖金磁复合微粒加磁场组在各个治疗组中对肿瘤组织细胞的破坏力最大,从而使其治疗效果最好。
本文以葡聚糖金磁复合微粒为磁导靶向药物载体,阿霉素为药物模型,研究了其在在体内和体外肿瘤治疗中的作用,证实葡聚糖金磁复合微粒可以作为一个理想的药物载体,为磁导靶向输送药物提供了理论依据。
Malignant tumor remains one of the leading causes of death in the world. The seeking effective method of diagnosis and treatment is the common goal of the scientists. Chemotherapy kills tumor cells also damage normal cells as well as human body. The magnetically targeted drug delivery system (MT-DDS) may transport the chemotherapeutic drugs to the tumor site, then enhancing the therapeutic effect and reducing the toxic side effects on the human body. And the selection of appropriate drug-carrier is very important for MT-DDS. The GoldMag nanoparticles (GMNs) of core-shell structure have many advantages, such as large surface area, high capacity with drugs, easily functionalized surface, good magnetic response and so on. These characteristics make them ideal choices for MT-DDS drug carriers. However, the GMNs can easily cluster in the salt solution or plasma due to the great specific surface enery. The surface modification of GMNs with hydrophilic dextran may greatly improve their stability in various solutions, and make them more suitable as a drug carrier.
Herein, Dextran coated GoldMag nanoparticles (DGMNs) were synthesized, characterized and demonstrated to be effective vehicles for targeted drug delivery. Characterization of DGMNs by different methods confirmed that they have uniformity sizes, good dispersibility and magnetic response. The result showed that the average hydrodynamic diameter of DGMNs was about100nm suspended in injection water, glucose injection, sodium chloride injection, PBS buffer and plasma, which showed a good stability of the colloid.
In vitro drug studies showed that the cancer drug-doxorubicin (Dox) binds effectively to DGMNs and the Fourier Transform Infrared Spectroscopy (FITR) spectra was used to confirm that the Dox was successfully loaded onto the surface of DGMNs. The kinetics doxorubicin release from Dox-DGMNs in vitro showed that the drug was steadily/controllably released from the particle surface in physiological conditions.
It is evident that DGMNs are not toxic to HepG2and H22cells by MTT assay in vitro, meanwhile the assessment of Dox-DGMNs showed that Dox-DGMNs killed HepG2and H22cells more effectively than Dox alone, which demonstrated that the drug was not only released from the particle surface but also probably near the cells in the culture well accounting for the increased toxicity
We did not observe any deleterious effects on animals at concentrations as high as2000mg/kg body weight (BW) in the experiments assessing the safety of DGMN particles in vivo, the results showed that DGMNs is enough safe as drug carriers. The results of animal experiments in vivo with Dox-DGMNs demonstrated that the drug may release slowly from particles surfaces and the carrier decreased toxic to animals relative to the free Dox. The LD50of Dox-DGMNs and free Dox were45.22mg/kg and15.60mg/kg, respectively. This indicated that the drug carrier may lower indeed the drug toxicity to tissues. Viscera index and pathological examination of various organs showed that the Dox from DGMNs surface concentrate on liver and spleen position and decreased the cardiotoxicity. Furthermore, Magnet localization of Dox-DGMNs in tissues showed DGMNs could be indeed localized in targeted position and ideal carrier of drugs for targeted tissues, such as treatment of liver tumor.
The method to measure Dox concerntration in the plasma was successfully established by High Performance Liquid Chromatography (HPLC), which was used to study the pharmacokinetics dynamics of Dox-DGMNs in SD rats. The results showed that Dox-DGMNs and Dox-DGMNs with external magnetic field (EMF) could significantly change the pharmacokinetic characteristics of Dox, enhance the bioavailability, slow eliminate rate and reduce the toxic effects.
To evaluate the therapeutic efficiency of Dox-DGMNs with EMF in vivo, the tumor-bearing mouse model was successfully established firstly. The pharmacodynamics in vivo showed Dox-DGMNs/EMF had the greatest antitumor efficacy with the different treatment protocols and significantly prolonged the life span of mice. The result illustrates that the high efficiency antitumor for Dox-DGMNs/EMF is because DGMNs enhance drug accumulation in tumor tissue.
In summary, the study provides some theoretical basis for targeted delivery of drugs to treat hepatic carcinoma. Of course, the further research is needed to make DGMNs be used to transport multiple kinds of drug to their desired targets, which will make them versatile therapeutic tools. The simple nanoparticles design and the drug delivery optimization may make them ideal candidates in targeted delivery in the near future.
引文
[1]Lubbe A. S., Alexion C., Bergemann C. Clinical application of magnetic drug targeting [J]. J Surg Res,2001,95(2):200-206
[2]Wu H. C., Chang D. K., Huang C. T. Targeted-therapy for cancer [J]. J Cancer Mol,2006, 2(2):57-66
[3]Kumari A., Yadav S. K., Yadav S. C. Biodegradable polymeric nanoparticles based drug delivery systems [J]. Colloid Surface B,2010,75(1):1-18
[4]Chen Y., Burton M. A., Codde J. P., ea al. Evaluation of ion-exchange microspheres as carrier for the anticancer drug Dox in vitro studies [J]. J Pharm Pharmacol,1992, 44:211-215
[5]Lu J. Y., Lowe D. A., Kennedy M. D., et al. Folate-targeted enzyme prodrug cancer therapy utilizing penicillin-vamidase and a doxorubicin prodrug [J]. J Drug Target,1999 7:43-53
[6]Neuberger T., Schopf B., Hofmann H., et al. Superparamagnetic nanoparticles for biomedical applications:Possibilities and limitations of a new drug delivery system [J]. J Magn Magn Mater,2005,293(1):483-96
[7]Liu Z., Ballinger J., Rauth M., et al. Delivery of an anticancer drug and a chemosensitizer to murine breast sarcoma by intratumoral injection of sulfopropyl dextran microspheres [J]. J Pharm Pharmacol,2003,55(8):1063-1073
[8]Langer R. Drug delivery and targeting [J]. Nature,1998,392:5-10
[9]Cheng R., Feng F., Meng F. H., et al. Glutathioneresponsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery [J]. J Control Release,2011, 152:2-12
[10]Pack D. W., Hoffman A. S., Pun S., et al. Design and development of polymers for gene delivery [J]. Nat Rev Drug Discov,2005,4:581-593
[11]Widder K. J., Senyei A. E.,Scarpelli D. G.,et al. Magnetic microshperes:A model system forsite specific drug delivery in vivo [J]. Proc Soc Exp BiolMed,1978,58:141-145
[12]Widder K. J., Senyei A. E., Ranney. D. F., et al. In vitro release of biologically active adriamycin by magnetically responsive albumin microspheres [J]. Cancer Res,1980,40: 3512-3517
[13]王浩红,李白成.征服肿瘤的定向导弹-磁性靶向药物简介[J].化学教学,2004,(1)：35-37
[14]Huang X., Jain P. K., El-Sayed I. H., et al. Plasmonic photothermal therapy (PPTT) using gold nanoparticles [J]. Laser Med Sci,2008,23(3):217-228
[15]DeNardo G. L., DeNardo S. J. Update:turning the heat on cancer [J]. Cancer Biother Radiopharm,2008,23(6):671-680
[16]Burke A., Ding X., Singh R., et al. Long-term survival following a single treatment of kidney tumors with multiwalled carbon nanotubes and near-infrared radiation [J]. P Natl Acad Sci,2009,106(31):12897-12902
[17]Yang K., Zhang S., Zhang G, et al. Graphene in mice:ultrahigh in vivo tumor uptake and efficient photothermal therapy [J]. Nano Lett,2010,10(9):3318-3323
[18]Li Y., Lu W., Huang Q., et al. Copper sulfide nanoparticles for photothermal ablation of tumor cells [J].Nanomedicine,2010,5(8):1161-1171
[19]李智铭.RGD偶联PAMAM树形分子—金纳米棒探针基础上的恶性黑素瘤在体靶向和光热治疗[D].合肥：安徽医科大学,2010：55-59
[20]Gobin A. M., Lee M. H., Halas N. J., et al. Near-infrared resonant nanoshells for combined optical imaging and photothermal cancer therapy [J]. Nano Lett,2007, 7(7):1929-1934
[21]Farrell D., Alper J., Ptak K., et al. Recent advances from the national cancer institute alliance for nanotechnology in cancer [J]. ACS Nano,2010,4:589-594
[22]Ferrari M. Cancer nanotechnology:opportunities and challenges [J]. Nat Rev Cancer, 2005,5:161-171
[23]Rosi N. L., Mirkin C. A. Nanostructures in biodiagnostics [J]. Chem Rev,2005, 105:1547-1562
[24]Gunasekera U. A., Pankhurst Q. A., Douek M. Imaging applications of nanotechnology in cancer [J]. Target Oncol,2009,4:169-181
[25]Nel A. E., Maedler L., Velegol D., et al. Understanding biophysicochemical interactions at the nano-bio interface [J]. Nat Mater,2009,8:543-557
[26]Iyer A. K., Khaled G., Fang J., et al. Exploiting the enhanced permeability and retention effect for tumor targeting [J]. Drug Discov,2006,11:812-818
[27]Ghosh P., Han G., De M., et al. Gold nanoparticles in delivery applications [J]. Adv Drug Deliv Rev,2008,60:1307-1315
[28]Faraji A. H., Wipf P. Nanoparticles in cellular drug delivery [J]. Bioorg Med Chem,2009, 17:2950-2962
[29]Veiseh O., Gunn J. W., Zhang M. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging [J]. Adv Drug Deliv Rev,2010,62:284-304
[30]Husseini G. A., Pitt W. G. Micelles and nanoparticles for ultrasonic drug and gene delivery [J]. Adv Drug Deliv Rev,2008,60:1137-1152
[31]Liu Z., Jiao Y., Wang Y., et al. Polysaccharides-based nanoparticles as drug delivery systems [J]. Adv Drug Deliv Rev,2008,60:1650-1662
[32]Almelda A. J., Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins [J]. Adv Drug Deliv Rev,2007,59:478-490
[33]Sinha R., Kim G. J., Nie S., et al. Nanotechnology in cancer therapeutics:bioconjugated nanoparticles for drug delivery [J]. Mol Cancer Ther,2006,5:1909-1917
[34]Panyam J., Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue [J]. Adv Drug Deliv Rev,2003,55:329-347
[35]Xu H, Cheng L, Wang C, et al. Polymer encapsulated upconversion nanoparticle/iron oxide nanocomposites for multimodal imaging and magnetic targeted drug delivery [J]. Biomaterials,2011,32:9364-73
[36]Hua M. Y, Yang H. W., Chuang C. K., et al. Magnetic-nanoparticle-modified paclitaxel for targeted therapy for prostate cancer [J]. Biomaterials,2010,31:7355-7363
[37]Sun J. B., Duan J. H., Dai S. L., et al. In vitro and in vivo antitumor effects of doxorubicin loaded with bacterial magnetosomes (DBMs) on H22 cells:The magnetic bio-nanoparticles as drug carriers [J]. Cancer Lett,2007,258:109-117
[38]Zharov V. P., Letfullin R. R., Galitovskaya E. N. Microbubbles-overlapping mode for laser killing of cancer cells with absorbing nanoparticle clusters [J]. J Phys D:Appl Phys, 2005,38:2571-2581
[39]Panczyk T., Warzocha T. P., Camp P. J. A magnetically controlled molecular nanocontainer as a drug delivery dystem:The effects of carbon nanotube and magnetic nanoparticle parameters from monte carlo simulations [J]. J Phys Chem C,2010,114: 21299-22308
[40]Huang P., Li Z. M., Yang D. P., et al. Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magneto fluorescent imaging and targeting therapy [J]. Biomaterials 2011,32:3447-3458
[41]Park S. I., Lim J. H., Hwang Y. H., et al. In vivo and in vitro antitumor activity of doxorubicin-loaded magnetic fluids [J]. Physica Status Solidi (c),2007,4:4345-4351
[42]Santra S., Kaittanis C., Grimm J. Drug/Dye-Loaded, Multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging [J]. Small,2009,5:1862-1868
[43]Singh A., Dilnawaz F. Mewar S., et al. Composite polymeric magnetic nanoparticles for co-delivery of hydrophobic and hydrophilic anticancer drugs and MRI imaging for cancer therapy [J]. ACS Appl Mater Inter,2011,3:842-856
[44]Alexiou C., Arnold W., Klein R. J., et al. Locoregional cancer treatment with magnetic drug targeting [J]. Cancer Res,2000,60:6641-6648.
[45]Yang X. Q., Hong H., Grailer J. J., et al. cRGD-functionalized, DOX-conjugated, and (64)Cu-labeled superparamagnetic iron oxide nanoparticles for targeted anticancer drug delivery and PET/MR imaging [J]. Biomaterials,2011,32:4151-4160
[46]杨咏来,宁桂玲,吕秉玲.液相法制备纳米粉体时防团聚方法概述[J].材料导报,1998,12(2)：11
[47]Heng Y., Min C., Philip M., et al. Dumbbell-like Bifunctional Au-Fe3O4 Nano particles [J]. Nano Lett,2005,5(2):379-382
[48]刘祖黎,彭莉,姚凯伦,等.超小型Fe3O4/Au纳米复合微粒的制备征[J].功能材料,2005,36(2)：196-199
[49]Tartaj P., Gonzalez C. T., Serna C. J. Single-step nanoengineering of silica coated maghemite hollows pheres with tunable magnetic properties [J]. Adv Mater,2001,13(21)：1620-1624
[50]Lu Y, Yin Y, Mayers B. T., et al. Modifying the surface properties of superparamagnetic iron oxide nanoparticles through a Sol-Gel approach [J]. Nano Lett,2002,2:183-186
[51]Baer R., Neuhauser D., Weiss S. Enhanced absorption induced by a metallic nanoshell [J]. Nano Lett,2004,4(1):85-88
[52]Pradhan N., Pal A., Pal T. Catalytic reduction of aromatic nitro compounds by coinage metal nanoparticles [J].Langmuir,2001,17:1800-1802
[53]Taton T. A., Mirkin C. A., Letsinger R.L. Scanometric DNA array detection with nanoparticle probes [J]. Science,2000,289:1757-1760
[54]Lin J., Zhou W. L., Kumbhar A., et al, Gold-coated iron (Fe@Au) nanoparticles: synthesis, characterization, and magnetic field-induced self-assembly [J]. J Solid State Chem,2001,159:26-31
[55]Kinoshita T., Seinoa S., Okitsu K., et al. Magnetic evaluation of nanostructure of gold-iron composite particles synthesized by a reverse micelle method [J]. J Alloy Compd,2003,359:46-50
[56]Cho S. J., Idrobo J. C., Olamit J., et al. Growth mechanisms and oxidation resistance of gold-coated iron nanoparticles [J]. Chem Mater,2005,17:3181-3186
[57]Carpenter E. E., Kumbhar A., Wiemann J. A., et al. Synthesis and magnetic properties of gold-iron-gold nanocomposites [J]. Mater Sci Eng A,2000,286:81-86
[58]Lim J. K., Majetich S. A., Tilton R. D. Stabilization of superparamagnetic iron oxide core-gold shell nanoparticles in high ionic strength media [J]. Langmuir,2009,25: 13384-13393
[59]Yu H., Chen M., Rice P. M., et al. Dumbbell-like bifunctional Au-Fe3O4 nanoparticles [J]. Nano Lett,2005,5:379-382
[60]Cui Y. L., Hu D. D., Fang Y. Preparation and mechanism of Fe3O4/Au core/shell super-paramagnetic microsphere [J], Sci China Ser B,2001,44:404-410
[61]Cui Y. L., Wang Y. N., Hui W. L., et al The synthesis of GoldMag nano-particles and its application for antibody immobilization [J]. Biomed Microdevices,2005,7(2):153-156
[62]Cui Y. L., Hui W. L., Wang H. R., et al. Preparation and characterization of Fe3O4/Au composite particles. Sci China Ser B [J].2004,47(2):152-158
[63]Ren J., Zhang Z. L., Wang F., et al. MRI of prostate stem cell antigen expression in prostate tumor [J]. Nanomedicine,2012,7(5):691-703
[64]Xu Z. C., Hou Y. L., Sun S.H. J. Am. Magnetic core/shell Fe3O4/Au and Fe3O4/Au/Ag nanoparticles with tunable plasmonic properties [J]. Chem Soc,2007,129:8698-8699
[65]Chao X., Zhang Z. L., Guo L. L., et al. A novel magnetic nanoparticle drug carrier for enhanced cancer chemotherapy [J]. Plos One,2012,7 (10):e40388
[66]Hui W. L., Shi F., Yan K. P., et al. Fe3O4/Au/Fe3O4 nanoflowers exhibiting tunable saturation magnetization and enhanced bioconjugation [J]. Nanoscale,2011,4:747-51
[67]Chao X., Guo L., Zhao Y, et al. PEG-modified GoldMag nanoparticles (PGMNs) combined with the magnetic field for local drug delivery [J]. J Drug Target,2011,19: 161-70
[68]Salehizadeh H., Hekmatian E., Sadeghi M.,et al. Synthesis and characterization of core-shell Fe3O4-gold-chitosan nanostructure[J]. J Nanobiotechnol,2012,10:1-7
[69]Zhao X., Hosmane N. S., Wu A. Ortho-Phenylenediamine:an effective spacer to build highly magnetic Fe3O4/Au nanocomposites [J]. Chemphyschem,2012,13(18): 4142-4147
[70]Zhao X., Cai Y, Wang T., et al. Preparation of alkanethiolate-functionalized core/shell Fe3O4@Au nanoparticles and its interaction with several typical target molecules [J]. Anal Chem,2008,80(23):9091-9096
[71]Lipka J., Semmler-Behnke M., Sperling R. A., et al. Biodistribution of PEG-modified gold nanoparticles following intratracheal instillation and intravenous injection [J]. Biomaterials,2010,31(25):6574-6581
[72]Mikhaylova M., Natalia D., Osmolowsky M., et al. Superparamagnetism of magnetite nanoparticles:dependence on surface modification [J]. Langmuir,2004,20:2472-2477
[73]Gupta A. K., Gupta M. Cytotoxicity suppression and cellular uptake enhancement of surface modified magnetic nanoparticles [J]. Biomaterials,2005,26:1565-1573
[74]Meng Y., Zou C., Madiyalakan R., et al. Water-soluble and biocompatible sono/photosensitizer nanoparticles for enhanced cancer therapy [J]. Nanomedicine,2010, 5:1559-1569
[75]Xu X. Q., Shen H., Xu J. R., et al. Core-shell structure and magnetic properties of magnetite magnetic fluids stabilized with dextran [J]. App Surf Sci,2005,252:494-500
[76]Mitra S., Gaur U., Ghosh P. C., et al. Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier [J]. J Control Release,2001,74:317-323
[77]Hreczuk-Hirst D., Chicco D., German L., et al. Dextrins as potential carriers for drug targeting:tailored rates of dextrin degradation by introduction of pendant groups [J]. Int J Pharmaceut,2001,230:57-66
[78]Tassa C., Shaw S. Y., Weissleder R. Dextran-coated iron oxide nanoparticles:a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy [J]. Accounts Chem Res,2011,44:842-52
[79]Scarberry K. E., Dickerson E. B., McDonald J. F., et al. Magnetic nanoparticle-peptide conjugates for in vitro and in vivo targeting and extraction of cancer cells [J]. J Am Chem Soc,2008,130:10258-10262
[80]Li X. B., Peng M. L., Raju P. A., et al. Dextran-coated GoldMag nanoparticles enhance the colloidal stability and controlled-release of doxorubicin [J]. IEEE T Magn,2013,49: 359-363
[81]Leakakos T., Ji C., Lawson G., et al. Intravesical administration of doxorubicin to swine bladder using magnetically targeted carriers [J]. Cancer Chemoth Pharm,2003,51 (6) 445-450
[82]Clement J. H., Schwalbe M., Buske N., et al. Differential interaction of magnetic nanoparticles with tumor cells and peripheral blood cells [J]. J Cancer Res Clin,2006, 132(5):287-292
[83]Tanimoto A., Kuribayashi S. Application of superparamagnetic iron oxide to imaging of hepatocellular carcinoma [J]. Eur J Radiol,2006,58(2):200-216
[84]陈伟,张绍祥,丁仕义,等.磁共振单克隆抗体免疫靶向对比剂McAb-PMP的制备 [J].中国医学影像技术,2002,18(9)：942-944
[85]Garnett M. C., Kallinteri P. Nanomedicines and nanotoxicology:some physiological principles [J]. Occupational Medicine-Oxford,2006,56:307-311
[86]Lacava L. M., Lacava Z. G, Da S., et al. Magnetic resonance of a dextran-coated magnetic fluid intravenously administered in mice [J]. Biophys J,2001,80:2483-2486
[87]Babes L., Denzoit B., Tanguy G., et al. Synthesis of iron oxide nanoparticles used as MRI contrast agents:a parametric study [J]. J Colloid Interface Sci,1999,212:474-482
[88]Thoren L. The dextrans-clinical data [J]. Dev Biol Stand,1981,48:157-167
[89]R. Mehvar, Dextrans for targeted and sustained delivery of therapeutic and imaging agents [J]. J Control Release,2000,69:1-25
[90]Babincova M., Leszczynska D., Sourivong P., et al. Selective treatment of neoplastic cells using ferritin-mediated electromagnetic hyperthermia [J]. Med Hypoth,2000, 54(3):177-179
[91]Moore A., Marecos E. M., Bogdanov A., et al. Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model [J]. Radiology,2000, 214:568-574
[92]Berry C. C., Wells S., Charles S., et al. Cell response to dextran-derivatised iron oxide nanoparticles post internalization [J]. Biomaterials,2004,25(23):5405-5413
[93]Ding J., Tao K., Li J., et al. Cell-specific cytotoxicity of dextran-stabilized magnetite nanoparticles [J]. Colloid Surface B,2010,79(1):184-190
[94]Pradhan P., Giri J., Banerjee R., et al. Cellular interactions of lauric acid and dextran-coated magnetite nanoparticles [J]. J Magn Magn Mater,2007,311(1):282-287
[95]Berry C. C., Wells S., Charles S., et al. Dextran and albumin derivatised iron oxide nanoparticles:influence on fibroblasts in vitro [J]. Biomaterials,2003,24(25):4551-4557
[96]Liu H. L., Hou P., Zhang W. X., et al. Synthesis of monosized core-shell Fe3O4/Au multifunctional nanoparticles by PVP-assisted nanoemulsion process [J]. Colloid Surface A,2010,356:21-27
[97]Lin J., Zhou W. L., Kumbhar A., et al, Gold-coated iron (Fe@Au) nanoparticles: synthesis, characterization, and magnetic field-induced self-assembly [J]. J Solid State Chem,2001,159:26-31
[98]Kinoshita T., Seinoa S., Okitsu K., et al. Magnetic evaluation of nanostructure of gold-iron composite particles synthesized by a reverse micelle method [J]. J Alloy Compd,2003,359:46-50
[99]Park H. Y., Schadt M. J., Wang L., et al. Fabrication of magnetic core@shell Fe oxide@Au nanoparticles for interfacial bioactivity and bio-separation [J]. Langmuir, 2007,23:9050-9056
[100]Carpenter E. E., Kumbhar A., Wiemann J. A., et al. Synthesis and magnetic properties of gold-iron-gold nanocomposites [J]. Mater Sci Eng A,2000,286:81-86
[101]Lim J. K., Majetich S. A., Tilton R. D. Stabilization of superparamagnetic iron oxide core-gold shell nanoparticles in high ionic strength media [J]. Langmuir,2009,25: 13384-13393
[102]Garnett M. C., Kallinteri P. Nanomedicines and nanotoxicology:some physiological principles [J]. Occup Med (Lond),2006,56:307-311
[103]Sun C., Lee J., Zhang M. Magnetic nanoparticles in MR imaging and drug delivery [J] Adv Drug Del Rev,2008,60:1252-1265
[104]Wang L., Yang Z., Gao J., et al. A biocompatible method of decorporation: bisphosphonate-modified magnetite nanoparticles to remove uranyl ions from blood [J]. J Am Chem Soc,2006,128:13358-13359
[105]Goon I. Y., Lai L. M., Lim M., et al. Fabrication and dispersion of gold-shell-protected magnetite nanoparticles:systematic control using polyethyleneimine [J]. Chem Mater, 2009,21:673-681
[106]Morais P. C., Santos J. G., Silveira L. B., et al. Magnetic investigation of zero-field-cooled dextran-coated magnetite-based magnetic fluid [J]. J Magn Magn Mater,2005,289:174-176
[107]Lacava L. M., Garcia V., Kuckelhaus S., et al. Long-term retention of dextran-coated magnetite nanoparticles in the liver and spleen [J]. J Magn Magn Mater,2004, 272-276:2434-2435
[108]Yang J. H., Qi L. M., Zhang D. B., et al. Dextran-controlled crystallization of silver microcrystals with novel morphologies [J]. Cryst Growth Des,2004,4:1371-1375
[109]Tang M. H., Dou H. J., Sun K. One-step synthesis of dextran-based stable nanoparticles assisted by self-assembly [J]. Polymer,2006,47:728-734
[110]Xu X. Q., Shen H., Xu J. R., et al. Core-shell structure and magnetic properties of magnetite magnetic fluids stabilized with dextran [J]. Appl Surf Sci,2005,252: 494-500
[111]Gaur U., Sahoo S. K., De T. K. et al. Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system [J]. Int J Pharm,2002,202:1-10
[112]Allemann E., Leroux J. C., Gurny R. et al. In vitro extended release properties of drug-loaded poly(dl-lactic acid) nanoparticles produced by a salting-out procedure [J]. Pharm Res,1993,10:1732-1737
[113]Jason P., Peter M., Jing L., et al. PEGylated PLGA nanoparticles for the improved delivery of doxorubicin [J]. Nanomed:Nanotechnology,2009,5:410-418
[114]Yang J., Lee C. H., Ko H. J., et al. Multifunctional magneto-Polymeric nanohybrids for targeted detection and synergistic therapeutic effects on breast cancer [J]. Angew Chem Int Ed,2007,46:8836-8839
[115]Yang X. Y., Zhang X. Y, Liu Z. F., et al., High-efficiency loading and controlled release of doxorubicin hydrochloride on graphene oxide [J]. J Phys Chem C,2008,112: 17554-17558
[116]Garnett M. C., Kallinteri P. Nanomedicines and nanotoxicology:some physiological principles [J]. Occup Med (Lond),2006,56 (5):307-311
[117]Kagan V. E., Bayir H., Shvedova A. A. Nanomedicine and nanotoxicology:two sides of the same coin [J], Nanomedicine,2005,1 (4):313-316
[118]Figuerola A., Di Corato R., Manna L., et al. From iron oxide nanoparticles towards advanced iron-based inorganic materials designed for biomedical applications [J]. Pharmacol Res,2010,62(2):126-143
[119]Nel A., Xia T., Madler L., et al. Toxic potential of materials at the nanolevel [J], Science, 2006,311 (5761):622-627
[120]Li Y, Liu J., Zhong Y, et al. Biocompatibility of Fe3O4@Au composite magnetic nanoparticles in vitro and in vivo [J]. Int J Nanomed,2011,6:2805-2819
[121]Singh A., Dilnawaz F., Mewar S. Composite polymeric magnetic nanoparticles for co-delivery of hydrophobic and hydrophilic anticancer drugs and MRI imaging for cancer therapy[J]. ACS Appl Mater Interfaces,2011,3(3):842-856
[122]Alexiou C., Arnold W., Klein R. J., et al. Locoregional cancer treatment with magnetic drug targeting [J]. Cancer Res,2000,60(23):6641
[123]Yang X. Q., Hong H., Grailer J. J. et al. cRGD-functionalized, DOX-conjugated, and (64)Cu-labeled superparamagnetic iron oxide nanoparticles for targeted anticancer drug delivery and PET/MR imaging [J]. Biomaterials,2011,32:4151-4160
[124]Kim K., Kim J. H., Park H., et al. Tumor-homing multifunctional nanoparticles for cancer theragnosis:Simultaneous diagnosis, drug delivery, and therapeutic monitoring [J]. J Control Release,2010,146(2):219-227
[125]Park I., Lim J. H., Hwang Y. H., et al. In vivo and in vitro antitumor activity of doxorubicin-loaded magnetic fluids [J]. Phy Status Solidi C,2007,4(12):4345-4351