脑靶向高分子聚合物纳米药物载体的制备、表征和应用
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摘要
药物能够高效转染神经细胞，且可透过血脑屏障（BBB）入脑，对脑部疾病的基础研究和临床治疗具有重要意义。本文的研究目标是开发出能够携带药物高效转染神经细胞和透过BBB入脑的纳米药物载体。
以聚（乳酸-羟基乙酸）共聚物（PLGA）、聚乙二醇（PEG）、乳铁蛋白（Lf）和二油酰磷脂酰乙醇胺（DOPE）等为主要原料，采用水/油/水（W/O/W）复乳法制得了Lf-PEG-PLGA/DOPE纳米载体，借助FTIR、~1H-NMR、XRD、TGA、UV-vis、DLLS和TEM等分析手段对该载体进行了鉴定和表征。以血红素加氧酶-1（HO-1）质粒为模型基因药物，考察了载体对药物的荷载效果，并将其在神经细胞转染和透过BBB入脑方面进行了初步应用。结果表明：Lf通过PEG以共价键与PLGA成功接枝；Lf-PEG-PLGA/DOPE纳米载体呈无定型结构，热稳定性较好，平均粒径为142.2nm，颗粒分布均匀，Zeta电位为+16.4mV，能够通过静电吸附作用与带负电的HO-1质粒结合；可以转染海马神经细胞，但其透过BBB的能力稍差，原因可能在于带正电荷的DOPE仅以嵌入的形式掺杂于纳米载体中，与载体主体的结合强度不够而易脱落。
为使纳米载体中带正电荷的部分更加稳定，本文选用甲基丙烯酰氧乙基三甲基氯化铵（DMC）和十四烷酸（MA）通过共价键共同接枝于壳聚糖（CS）上，制得季铵盐-十四烷酸-壳聚糖（QMC）。再以PEG-醛为媒介将Lf接枝到QMC上，制得Lf-PEG-QMC，通过自组装法制得纳米载体。对载体进行了鉴定、表征和性能评价，并将其初步应用于神经细胞转染和透过BBB入脑实验。结果表明：阳离子成份DMC以共价键接枝到了CS上，MA和Lf也接枝到了CS上；该载体呈晶型结构，热稳定性很好，平均粒径为244.7nm，且分布比较均匀，Zeta电位为+27.9mV，能够荷载基因；还可荷载难溶性药物紫杉醇（PTX），包封率可达80%以上，具有较好的缓释效果；能够转染海马神经细胞并可透过BBB入脑；通过毒性实验，发现除QMC对离体海马神经细胞稍有毒性外，PEG-QMC和Lf-PEG-QMC对海马神经细胞及小鼠的心、肝、脾、肺和肾等均无明显毒性，但在尾静脉注射载体时多数小鼠出现短暂的抽搐，约10%死亡。
为提高纳米载体的静脉注射安全性，本文换用生物相容性更好的八聚精氨酸（R8）作为阳离子成份与MA共接枝于CS，制得八聚精氨酸-十四烷酸-壳聚糖（RMC），以PEG-醛为媒介将Lf接枝到RMC上，制得Lf-PEG-RMC，通过自组装法制得纳米载体。对载体进行了鉴定、表征和性能评价，并将其初步应用于神经细胞转染和透过BBB入脑实验。结果表明：带正电荷的R8和MA共同接枝到了CS上，Lf接枝到了RMC上；该载体呈晶型结构，热稳定性很好，平均粒径为226.7nm，分布均匀，Zeta电位为+18.7mV且能够荷载基因；对PTX的包封率亦超过80%，可较好地控制药物缓慢释放；能够高效转染海马神经细胞并可透过BBB入脑；对离体海马神经细胞及小鼠心、肝、脾、肺和肾等均无明显毒性，尾静脉注射时小鼠未出现异常。
为进一步增强纳米载体的靶向递药能力，本文试用油酸修饰的Fe_3O_4为超顺磁性材料，对应用前景较好的QMC和RMC及两者的衍生物纳米载体磁性化修饰，制得了相应系列的磁性纳米载体（MNC）。对载体进行了表征，通过VSM方法对其磁性能进行了初步分析，并将其初步应用于神经细胞摄取实验。结果表明：Fe_3O_4成功包入了QMC和RMC系列的纳米载体中，MNC的晶型与包入Fe_3O_4前相应纳米载体的晶型一致，具有较好的热稳定性和超顺磁性，且能够顺利进入神经细胞。
以大鼠缺血性脑中风模型为基础，将荷载HO-1基因的Lf-PEG-QMC、Lf-PEG-RMC、磁性Lf-PEG-QMC和磁性Lf-PEG-RMC纳米载体初步应用于缺血性脑中风的治疗。结果表明：该4种荷载HO-1基因的纳米载体能够对缺血性脑中风诱导的海马神经元损伤起到明显的抑制作用，其中后两者的效果相对更好。
It is important for the basic research and clinical treatment of brain diseases thatdrugs transfect neurons and enter brain through the blood-brain-barrier (BBB). Thegoal of the project is to prepare nano carriers loading drugs which are able to transfectneurons and enter brain through the BBB.
Lf-PEG-PLGA/DOPE nano carriers were made from Poly (lactic acid-glycolicacid) copolymer (PLGA), polyethylene glycol (PEG), lactoferrin (Lf) anddioleoylphosphatidyl ethanolamine (DOPE) by water/oil/water (W/O/W) doubleemulsion method. The Lf-PEG-PLGA/DOPE nano carriers were identificated andexosyndromed by means of FTIR,~1H-NMR, XRD, TGA, UV-vis, DLLS and TEM.We studied the nano carriers’ ability of loading drugs, transfecting hippocampalneurons and carring them into brain through the BBB using the model gene drugsHeme oxygenase-1(HO-1) plasmid. The results showed that Lf was successfullylinked to PLGA through covalent bond, the prepared nano carriers had amorphousstructure and good thermal stability with an average particle size of142.2nm,uniform particle size distribution and Zeta potential of+16.4mV. The nano carrierscould bind plasmid with negatively charge through electrostatic adsorption andtransfect the hippocampal neurons, but they had temperate ability to enter brainthrough the BBB with the probalble reason that the binding between nano carriers andDOPE with positive charge was too slender because of the only imbedded form ofDOPE in the nano carriers.
To stabilize the positively charged groups in the nano carriers, QMC wereprepared by grafting Methacryloxyethyltrimethyl ammonium chloride (DMC) andmyristic acid (MA) to chitosan (CS) through covalent bond. Lf was grafted to QMCthrough PEG-aldehyde and then Lf-PEG-QMC nano carriers were prepared by meansof self-assembly. The nano carriers were identificated, exosyndromed and functionevaluated. Their abilities of transfecting neurons and entering brain through BBBwere studied. The results showed that DMC with positive charge was grafted to CS,MA and Lf were also grafted to CS. Lf-PEG-QMC nano carriers had the crystalstructure, good thermal stability with an average diameter of244.7nm, more evenlydistributed, and the Zeta potential of+27.9mV. The nano carriers could load gene andpackage insoluble paclitaxel with high encapsulation efficiency of more than80%andgood slow-releasing effect. They could efficiently transfect the hippocampal neurons and enter brain through the BBB without significant toxicity for the isolatedhippocampal neurons and heart, liver, spleen, lung and kidney of mice except forQMC. But brief convulsions were found in the majority of mice and approximately10%of them died after the tail vein injection with Lf-PEG-QMC nano carriers.
To improve the security of the intravenous injection of nano carriers,8poly-arginine (R8) with positive charge and MA were grafted to CS to prepare RMC.Lf was grafted to RMC through PEG-aldehyde and then Lf-PEG-RMC nano carrierswere prepared by means of self-assembly. The nano carriers were identificated,exosyndromed and function evaluated. Their abilities of transfecting neurons andentering brain through the BBB were studied. The results showed that R8and MAwas successfully grafted to CS, Lf was grafted to the RMC and Lf-PEG-RMC nanocarriers were prepared with the crystal structure, good thermal stability, averageparticle size of226.7nm, uniform distribution and Zeta potential of+18.7mV. Thenano carriers could load gene and package paclitaxel with high encapsulationefficiency of more than80%and good slow-releasing effect. They could efficientlytransfect the hippocampal neurons and enter brain through the BBB withoutsignificant toxicity for the isolated hippocampal neurons, heart, liver, spleen, lung andkidney and abnormity after the tail vein injection with the nano carriers in mice.
To enhance the potential applications of nano carriers, oleic acid modified Fe_3O_4magnetic materials were used to modify QMC, RMC together with their derivativesand prepared corresponding series of magnetic nano carriers (MNC). They wereexosyndromed and performed by VSM analysis for their magnetic properties. Theresults showed that Fe_3O_4were successfully packed into QMC, RMC together withtheir derivatives. MNC had good thermal stability and magnetic properties withcrystal form consistent with that of the corresponding nano carriers without Fe_3O_4,and can easily enter the neurons.
Lf-PEG-QMC, Lf-PEG-RMC, magnetic Lf-PEG-QMC and magneticLf-PEG-RMC nano carriers loading HO-1gene were initially applied to the braindiseases based on the ischemic stroke model of rats. The results showed that the4kinds of nano carriers loading HO-1especially the latter two kinds could significantlyinhibit the injury of hippocampal neurons induced by ischemic stroke.
以聚（乳酸-羟基乙酸）共聚物（PLGA）、聚乙二醇（PEG）、乳铁蛋白（Lf）和二油酰磷脂酰乙醇胺（DOPE）等为主要原料，采用水/油/水（W/O/W）复乳法制得了Lf-PEG-PLGA/DOPE纳米载体，借助FTIR、~1H-NMR、XRD、TGA、UV-vis、DLLS和TEM等分析手段对该载体进行了鉴定和表征。以血红素加氧酶-1（HO-1）质粒为模型基因药物，考察了载体对药物的荷载效果，并将其在神经细胞转染和透过BBB入脑方面进行了初步应用。结果表明：Lf通过PEG以共价键与PLGA成功接枝；Lf-PEG-PLGA/DOPE纳米载体呈无定型结构，热稳定性较好，平均粒径为142.2nm，颗粒分布均匀，Zeta电位为+16.4mV，能够通过静电吸附作用与带负电的HO-1质粒结合；可以转染海马神经细胞，但其透过BBB的能力稍差，原因可能在于带正电荷的DOPE仅以嵌入的形式掺杂于纳米载体中，与载体主体的结合强度不够而易脱落。
为使纳米载体中带正电荷的部分更加稳定，本文选用甲基丙烯酰氧乙基三甲基氯化铵（DMC）和十四烷酸（MA）通过共价键共同接枝于壳聚糖（CS）上，制得季铵盐-十四烷酸-壳聚糖（QMC）。再以PEG-醛为媒介将Lf接枝到QMC上，制得Lf-PEG-QMC，通过自组装法制得纳米载体。对载体进行了鉴定、表征和性能评价，并将其初步应用于神经细胞转染和透过BBB入脑实验。结果表明：阳离子成份DMC以共价键接枝到了CS上，MA和Lf也接枝到了CS上；该载体呈晶型结构，热稳定性很好，平均粒径为244.7nm，且分布比较均匀，Zeta电位为+27.9mV，能够荷载基因；还可荷载难溶性药物紫杉醇（PTX），包封率可达80%以上，具有较好的缓释效果；能够转染海马神经细胞并可透过BBB入脑；通过毒性实验，发现除QMC对离体海马神经细胞稍有毒性外，PEG-QMC和Lf-PEG-QMC对海马神经细胞及小鼠的心、肝、脾、肺和肾等均无明显毒性，但在尾静脉注射载体时多数小鼠出现短暂的抽搐，约10%死亡。
为提高纳米载体的静脉注射安全性，本文换用生物相容性更好的八聚精氨酸（R8）作为阳离子成份与MA共接枝于CS，制得八聚精氨酸-十四烷酸-壳聚糖（RMC），以PEG-醛为媒介将Lf接枝到RMC上，制得Lf-PEG-RMC，通过自组装法制得纳米载体。对载体进行了鉴定、表征和性能评价，并将其初步应用于神经细胞转染和透过BBB入脑实验。结果表明：带正电荷的R8和MA共同接枝到了CS上，Lf接枝到了RMC上；该载体呈晶型结构，热稳定性很好，平均粒径为226.7nm，分布均匀，Zeta电位为+18.7mV且能够荷载基因；对PTX的包封率亦超过80%，可较好地控制药物缓慢释放；能够高效转染海马神经细胞并可透过BBB入脑；对离体海马神经细胞及小鼠心、肝、脾、肺和肾等均无明显毒性，尾静脉注射时小鼠未出现异常。
为进一步增强纳米载体的靶向递药能力，本文试用油酸修饰的Fe_3O_4为超顺磁性材料，对应用前景较好的QMC和RMC及两者的衍生物纳米载体磁性化修饰，制得了相应系列的磁性纳米载体（MNC）。对载体进行了表征，通过VSM方法对其磁性能进行了初步分析，并将其初步应用于神经细胞摄取实验。结果表明：Fe_3O_4成功包入了QMC和RMC系列的纳米载体中，MNC的晶型与包入Fe_3O_4前相应纳米载体的晶型一致，具有较好的热稳定性和超顺磁性，且能够顺利进入神经细胞。
以大鼠缺血性脑中风模型为基础，将荷载HO-1基因的Lf-PEG-QMC、Lf-PEG-RMC、磁性Lf-PEG-QMC和磁性Lf-PEG-RMC纳米载体初步应用于缺血性脑中风的治疗。结果表明：该4种荷载HO-1基因的纳米载体能够对缺血性脑中风诱导的海马神经元损伤起到明显的抑制作用，其中后两者的效果相对更好。
It is important for the basic research and clinical treatment of brain diseases thatdrugs transfect neurons and enter brain through the blood-brain-barrier (BBB). Thegoal of the project is to prepare nano carriers loading drugs which are able to transfectneurons and enter brain through the BBB.
Lf-PEG-PLGA/DOPE nano carriers were made from Poly (lactic acid-glycolicacid) copolymer (PLGA), polyethylene glycol (PEG), lactoferrin (Lf) anddioleoylphosphatidyl ethanolamine (DOPE) by water/oil/water (W/O/W) doubleemulsion method. The Lf-PEG-PLGA/DOPE nano carriers were identificated andexosyndromed by means of FTIR,~1H-NMR, XRD, TGA, UV-vis, DLLS and TEM.We studied the nano carriers’ ability of loading drugs, transfecting hippocampalneurons and carring them into brain through the BBB using the model gene drugsHeme oxygenase-1(HO-1) plasmid. The results showed that Lf was successfullylinked to PLGA through covalent bond, the prepared nano carriers had amorphousstructure and good thermal stability with an average particle size of142.2nm,uniform particle size distribution and Zeta potential of+16.4mV. The nano carrierscould bind plasmid with negatively charge through electrostatic adsorption andtransfect the hippocampal neurons, but they had temperate ability to enter brainthrough the BBB with the probalble reason that the binding between nano carriers andDOPE with positive charge was too slender because of the only imbedded form ofDOPE in the nano carriers.
To stabilize the positively charged groups in the nano carriers, QMC wereprepared by grafting Methacryloxyethyltrimethyl ammonium chloride (DMC) andmyristic acid (MA) to chitosan (CS) through covalent bond. Lf was grafted to QMCthrough PEG-aldehyde and then Lf-PEG-QMC nano carriers were prepared by meansof self-assembly. The nano carriers were identificated, exosyndromed and functionevaluated. Their abilities of transfecting neurons and entering brain through BBBwere studied. The results showed that DMC with positive charge was grafted to CS,MA and Lf were also grafted to CS. Lf-PEG-QMC nano carriers had the crystalstructure, good thermal stability with an average diameter of244.7nm, more evenlydistributed, and the Zeta potential of+27.9mV. The nano carriers could load gene andpackage insoluble paclitaxel with high encapsulation efficiency of more than80%andgood slow-releasing effect. They could efficiently transfect the hippocampal neurons and enter brain through the BBB without significant toxicity for the isolatedhippocampal neurons and heart, liver, spleen, lung and kidney of mice except forQMC. But brief convulsions were found in the majority of mice and approximately10%of them died after the tail vein injection with Lf-PEG-QMC nano carriers.
To improve the security of the intravenous injection of nano carriers,8poly-arginine (R8) with positive charge and MA were grafted to CS to prepare RMC.Lf was grafted to RMC through PEG-aldehyde and then Lf-PEG-RMC nano carrierswere prepared by means of self-assembly. The nano carriers were identificated,exosyndromed and function evaluated. Their abilities of transfecting neurons andentering brain through the BBB were studied. The results showed that R8and MAwas successfully grafted to CS, Lf was grafted to the RMC and Lf-PEG-RMC nanocarriers were prepared with the crystal structure, good thermal stability, averageparticle size of226.7nm, uniform distribution and Zeta potential of+18.7mV. Thenano carriers could load gene and package paclitaxel with high encapsulationefficiency of more than80%and good slow-releasing effect. They could efficientlytransfect the hippocampal neurons and enter brain through the BBB withoutsignificant toxicity for the isolated hippocampal neurons, heart, liver, spleen, lung andkidney and abnormity after the tail vein injection with the nano carriers in mice.
To enhance the potential applications of nano carriers, oleic acid modified Fe_3O_4magnetic materials were used to modify QMC, RMC together with their derivativesand prepared corresponding series of magnetic nano carriers (MNC). They wereexosyndromed and performed by VSM analysis for their magnetic properties. Theresults showed that Fe_3O_4were successfully packed into QMC, RMC together withtheir derivatives. MNC had good thermal stability and magnetic properties withcrystal form consistent with that of the corresponding nano carriers without Fe_3O_4,and can easily enter the neurons.
Lf-PEG-QMC, Lf-PEG-RMC, magnetic Lf-PEG-QMC and magneticLf-PEG-RMC nano carriers loading HO-1gene were initially applied to the braindiseases based on the ischemic stroke model of rats. The results showed that the4kinds of nano carriers loading HO-1especially the latter two kinds could significantlyinhibit the injury of hippocampal neurons induced by ischemic stroke.
引文
[1]韩胜红. GH-IGF-I轴基因多态性及环境因素与缺血性脑卒中的分子流行病学研究[D].华中科技大学博士论文，2009.
[2]张红梅.延长静脉溶栓时间窗治疗后循环进展性卒中的研究[D].天津医科大学硕士论文，2010.
[3] Liu Y, Miyoshi H, Nakamura M. Nanomedicine for drug delivery and imaging: a promisingavenue for cancer therapy and diagnosis using targeted functional nano carriers[J]. Int JCancer,2007,120(12):2527-2537.
[4] Whitesides GM. Nanoscience, nanotechnology, and chemistry[J]. Small,2005;1(2):172-179.
[5] Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nano carriers:theory to practice[J]. Pharmacol Rev,2001,53(2):283-318.
[6] Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging[J]. Drug DiscovToday,2003,8(24):1112-1120.
[7] Wickline SA, Neubauer AM, Winter P, et al. Applications of nanotechnology toatherosclerosis, thrombosis, and vascular biology[J]. Arterioscler Thromb Vasc Biol,2006,26(3):435-441.
[8] Panyam J, Labhasetwar V. Biodegradable nano carriers for drug and gene delivery to cells andtissue[J]. Adv Drug Deliv Rev,2003,55(3):329-347.
[9] Jain RA. The manufacturing techniques of various drug loaded biodegradablepoly(lactide-co-glycolide)(PLGA) devices[J]. Biomaterials,2000,21(23):2475-2490.
[10] Wickline SA, Neubauer AM, Winter PM, et al. Molecular imaging and therapy ofatherosclerosis with targeted nano carriers[J]. J Magn Reson Imaging,2007,25(4):667-680.
[11] Studer M, Briel M, Leimenstoll B, et al. Effect of different antilipidemic agents and diets onmortality: a systematic review[J]. Arch Intern Med,2005,165(7):725-730.
[12] Wang CK, Wang WY, Meyer RF, et al. A rapid method for creating drug implants: translatinglaboratory-based methods into a scalable manufacturing process[J]. J Biomed Mater Res BAppl Biomater,2010,93(2):562-572.
[13] Jalil R, Nixon JR. Biodegradable poly(lactic acid) and poly(lactide-co-glycolide)microcapsules: problems associated with preparative techniques and release properties[J]. JMicroencapsul,1990,7(3):297-325.
[14] Cohen S, Alonso MJ, Langer R. Novel approaches to controlled-release antigen delivery[J].Int J Technol Assess Health Care,1994,10(1):121-130.
[15] Han B, Wang HT, Liu HY, et al. Preparation of pingyangmycin PLGA microspheres andrelated in vitro/in vivo studies[J]. Int J Pharm,2010,398(1-2):130-136.
[16] Sun F, Sui C, Teng L, et al. Studies on the preparation, characterization and pharmacologicalevaluation of tolterodine PLGA microspheres[J]. Int J Pharm,2010,397(1-2):44-49.
[17] Tian J, Sun X, Chen X, et al. The formulation and immunisation of oralpoly(DL-lactide-co-glycolide) microcapsules containing a plasmid vaccine againstlymphocystis disease virus in Japanese flounder (Paralichthys olivaceus)[J]. IntImmunopharmacol,2008,8(6):900-908.
[18] Mohamed F, van der Walle CF. PLGA microcapsules with novel dimpled surfaces forpulmonary delivery of DNA[J]. Int J Pharm,2006,311(1-2):97-107.
[19] Son S, Lee WR, Joung YK, et al. Optimized stability retention of a monoclonal antibody inthe PLGA nano carriers[J]. Int J Pharm,2009,368(1-2):178-185.
[20] Javadzadeh Y, Ahadi F, Davaran S, et al. Preparation and physicochemical characterization ofnaproxen-PLGA nano carriers[J]. Colloids Surf B Biointerfaces,2010,81(2):498-502.
[21] Wang CK, Wang WY, Meyer RF, et al. A rapid method for creating drug implants: translatinglaboratory-based methods into a scalable manufacturing process[J]. J Biomed Mater Res BAppl Biomater,2010,93(2):562-572.
[22] Siegel SJ, Kahn JB, Metzger K, et al. Effect of drug type on the degradation rate of PLGAmatrices[J]. Eur J Pharm Biopharm,2006,64(3):287-293.
[23] Wischke C, Zhang Y, Mittal S, et al. Development of PLGA-based injectable deliverysystems for hydrophobic fenretinide[J]. Pharm Res,2010,27(10):2063-2074.
[24] Liu Q, Zhang H, Zhou G, et al. In vitro and in vivo study of thymosin alpha1biodegradable insitu forming poly(lactide-co-glycolide) implants[J]. Int J Pharm,2010,397(1-2):122-129.
[25] Loo SC, Tan ZY, Chow YJ, et al. Drug release from irradiated PLGA and PLLA multi-layeredfilms[J]. J Pharm Sci,2010,99(7):3060-3071.
[26] Shen H, Hu X, Yang F, et al. The bioactivity of rhBMP-2immobilizedpoly(lactide-co-glycolide) scaffolds[J]. Biomaterials,2009,30(18):3150-3157.
[27] Wang GJ, Lin YC, Hsu SH. The fabrication of PLGA microvessel scaffolds withnano-patterned inner walls[J]. Biomed Microdevices,2010,12(5):841-848.
[28] Mooney DJ, Sano K, Kaufmann PM, et al. Long-term engraftment of hepatocytestransplanted on biodegradable polymer sponges[J]. J Biomed Mater Res,1997,37(3):413-420.
[29] Eiselt P, Kim BS, Chacko B, et al. Development of technologies aiding large-tissueengineering[J]. Biotechnol Prog,1998,14(1):134-140.
[30] Mundargi RC, Babu VR, Rangaswamy V, et al. Nano/micro technologies for deliveringmacromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives[J]. JControl Release,2008,125(3):193-209.
[31] Wischke C, Schwendeman SP. Principles of encapsulating hydrophobic drugs in PLA/PLGAmicroparticles[J]. Int J Pharm,2008,364(2):298-327.
[32] Pai Kasturi S, Qin H, Thomson KS, et al. Prophylactic anti-tumor effects in a B celllymphoma model with DNA vaccines delivered on polyethylenimine (PEI) functionalizedPLGA microparticles[J]. J Control Release,2006,113(3):261-270.
[33] Kocbek P, Obermajer N, Cegnar M, et al. Targeting cancer cells using PLGA nano carrierssurface modified with monoclonal antibody[J]. J Control Release,2007,120(1-2):18-26.
[34] Benny O, Duvshani-Eshet M, Cargioli T, et al. Continuous delivery of endogenous inhibitorsfrom poly(lactic-co-glycolic acid) polymeric microspheres inhibits glioma tumor growth[J].Clin Cancer Res,2005,11(2Pt1):768-776.
[35] Mo Y, Lim LY. Paclitaxel-loaded PLGA nano carriers: potentiation of anticancer activity bysurface conjugation with wheat germ agglutinin[J]. J Control Release,2005,108(2-3):244-262.
[36] Fonseca C, Simoes S, Gaspar R. Paclitaxel-loaded PLGA nano carriers: preparation,physicochemical characterization and in vitro anti-tumoral activity[J]. J Control Release,2002,83(2):273-286.
[37] van Vlerken LE, Duan Z, Little SR, et al. Biodistribution and pharmacokinetic analysis ofPaclitaxel and ceramide administered in multifunctional polymer-blend nano carriers in drugresistant breast cancer model[J]. Mol Pharm,2008,5(4):516-526.
[38] Zeisser-Labouebe M, Lange N, Gurny R, et al. Hypericin-loaded nano carriers for thephotodynamic treatment of ovarian cancer[J]. Int J Pharm,2006,326(1-2):174-181.
[39] Gryparis EC, Hatziapostolou M, Papadimitriou E, et al. Anticancer activity ofcisplatin-loaded PLGA-mPEG nano carriers on LNCaP prostate cancer cells[J]. Eur J PharmBiopharm,2007,67(1):1-8.
[40] Yemisci M, Bozdag S, Cetin M, et al. Treatment of malignant gliomas withmitoxantrone-loaded poly (lactide-co-glycolide) microspheres[J]. Neurosurgery,2006,59(6):1296-1302; discussion1302-1293.
[41] Bharali DJ, Mousa SA, Thanavala Y. Micro-and nano carrier-based vaccines for hepatitisB[J]. Adv Exp Med Biol,2007,601:415-421.
[42] Zhao Z, Leong KW. Controlled delivery of antigens and adjuvants in vaccine development[J].J Pharm Sci,1996,85(12):1261-1270.
[43] Nayak B, Panda AK, Ray P, et al. Formulation, characterization and evaluation of rotavirusencapsulated PLA and PLGA particles for oral vaccination[J]. J Microencapsul,2009,26(2):154-165.
[44] Wang JJ, Zeng ZW, Xiao RZ, et al. Recent advances of chitosan nano carriers as drugcarriers[J]. Int J Nanomedicine,2011,6:765-774.
[45] Jin MX, Hu QH. Characterization and application in bioadhesive drug delivery system ofchitosan[J]. Centr South Pharm,2008,6(003):324–327.
[46] Dudhani AR, Kosaraju SL. Bioadhesive chitosan nano carriers:preparation andcharacterization[J]. Carbohydr Polym,2010,81(2):243–251.
[47] Hagens WI, Oomen AG, de Jong WH, et al. What do we (need to) know about the kineticproperties of nano carriers in the body[J]? Regul Toxicol Pharmacol,2007,49(3):217-229.
[48] Gaumet M, Vargas A, Gurny R, et al. Nano carriers for drug delivery: the need for precisionin reporting particle size parameters[J]. Eur J Pharm Biopharm,2008,69(1):1-9.
[49] Qian F, Cui F, Ding J, et al. Chitosan graft copolymer nano carriers for oral protein drugdelivery: preparation and characterization[J]. Biomacromolecules,2006,7(10):2722-2727.
[50] Brigger I, Dubernet C, Couvreur P. Nano carriers in cancer therapy and diagnosis[J]. AdvDrug Deliv Rev,2002,54(5):631-651.
[51] Brannon-Peppas L, Blanchette JO. Nano carrier and targeted systems for cancer therapy[J].Adv Drug Deliv Rev,2004,56(11):1649-1659.
[52] Yuan Q, Shah J, Hein S, et al. Controlled and extended drug release behavior ofchitosan-based nano carrier carrier[J]. Acta Biomater,2010,6(3):1140-1148.
[53] Park JH, Saravanakumar G, Kim K, Kwon IC. Targeted delivery of low molecular drugs usingchitosan and its derivatives[J]. Adv Drug Deliv Rev,2010,62(1):28–41.
[54] Park K, Kim JH, Nam YS, et al. Effect of polymer molecular weight on the tumor targetingcharacteristics of self-assembled glycol chitosan nano carriers[J]. J Control Release,2007,122(3):305-314.
[55] Xu XY, Zhou JP, Li L, et al. Preparation of doxorubicin-loaded chitosan polymeric micelleand study on its tissue biodistribution in mice[J]. Yao Xue Xue Bao,2008,43(7):743-748.
[56] Kiang T, Bright C, Cheung CY, et al. Formulation of chitosan-DNA nano carriers withpoly(propyl acrylic acid) enhances gene expression[J]. J Biomater Sci Polym Ed,2004,15(11):1405-1421.
[57] Na K, Bae YH. Self-assembled hydrogel nano carriers responsive to tumor extracellular pHfrom pullulan derivative/sulfonamide conjugate: characterization, aggregation, andadriamycin release in vitro[J]. Pharm Res,2002,19(5):681-688.
[58] Rejinold NS, Sreerekha PR, Chennazhi KP, et al. Biocompatible, biodegradable andthermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drugdelivery[J]. Int J Biol Macromol,2011,49(2):161-172.
[59] Chung JE, Yokoyama M, Aoyagi T, et al. Effect of molecular architecture of hydrophobicallymodified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shellmicellar drug carriers[J]. J Control Release,1998,53(1-3):119-130.
[60] Chung JE, Yokoyama M, Yamato M, et al. Thermo-responsive drug delivery from polymericmicelles constructed using block copolymers of poly(N-isopropylacrylamide) andpoly(butylmethacrylate)[J]. J Control Release,1999,62(1-2):115-127.
[61] Chauvierre C, Labarre D, Couvreur P, et al. Novel polysaccharide-decorated poly(isobutylcyanoacrylate) nano carriers[J]. Pharm Res,2003,20(11):1786-1793.
[62] Bravo-Osuna I, Vauthier C, Farabollini A, et al. Mucoadhesion mechanism of chitosan andthiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nano carriers[J]. Biomaterials,2007,28(13):2233-2243.
[63] Chuang WY, Young TH, Yao CH, et al. Properties of the poly(vinyl alcohol)/chitosan blendand its effect on the culture of fibroblast in vitro[J]. Biomaterials,1999,20(16):1479-1487.
[64] Huang HY, Shieh YT, Shih CM, Twu YK. Magnetic chitosan/iron (II, III) oxide nanocarriers prepared by spray-drying[J]. Carbohydr Polym,2010,81(4):906–910.
[65] Singh R, Lillard JW, Jr. Nano carrier-based targeted drug delivery[J]. Exp Mol Pathol,2009,86(3):215-223.
[66]姚倩.双配体修饰的壳聚糖纳米粒肝癌细胞主动靶向给药系统的研究[D].四川大学博士论文，2006.
[67] Kim JH, Kim YS, Park K, et al. Antitumor efficacy of cisplatin-loaded glycol chitosan nanocarriers in tumor-bearing mice[J]. J Control Release,2008,127(1):41-49.
[68] Min KH, Park K, Kim YS, et al. Hydrophobically modified glycol chitosan nanocarriers-encapsulated camptothecin enhance the drug stability and tumor targeting in cancertherapy[J]. J Control Release,2008,127(3):208-218.
[69] Douglas KL, Piccirillo CA, Tabrizian M. Cell line-dependent internalization pathways andintracellular trafficking determine transfection efficiency of nano carrier vectors[J]. Eur JPharm Biopharm,2008,68(3):676-687.
[70] Douglas KL, Piccirillo CA, Tabrizian M. Effects of alginate inclusion on the vector propertiesof chitosan-based nano carriers[J]. J Control Release,2006,115(3):354-361.
[71] Duceppe N, Tabrizian M. Factors influencing the transfection efficiency of ultra lowmolecular weight chitosan/hyaluronic acid nano carriers[J]. Biomaterials,2009,30(13):2625-2631.
[72]陈记稷.阳离子修饰的PEG化聚乳酸纳米基因载体的实验研究[D].中南大学硕士论文，2007.
[73]黄帆.壳聚糖/DNA传递系统的制备及其性能研究[D].华南理工大学硕士论文，2010.
[74]刘璠娜.新型季铵盐壳聚糖纳米载药体系的研究[D].暨南大学博士论文，2008.
[75] Huang M, Khor E, Lim LY. Uptake and cytotoxicity of chitosan molecules and nano carriers:effects of molecular weight and degree of deacetylation[J]. Pharm Res,2004,21(2):344-353.
[76] Kiang T, Wen J, Lim HW, et al. The effect of the degree of chitosan deacetylation on theefficiency of gene transfection[J]. Biomaterials,2004,25(22):5293-5301.
[77] Liu X, Howard KA, Dong M, et al. The influence of polymeric properties on chitosan/siRNAnano carrier formulation and gene silencing[J]. Biomaterials,2007,28(6):1280-1288.
[78] Lavertu M, Methot S, Tran-Khanh N, et al. High efficiency gene transfer using chitosan/DNAnano carriers with specific combinations of molecular weight and degree of deacetylation[J].Biomaterials,2006,27(27):4815-4824.
[79] Koping-Hoggard M, Varum KM, Issa M, et al. Improved chitosan-mediated gene deliverybased on easily dissociated chitosan polyplexes of highly defined chitosan oligomers[J].Gene Ther,2004,11(19):1441-1452.
[80] Sato T, Ishii T, Okahata Y. In vitro gene delivery mediated by chitosan. effect of pH, serum,and molecular mass of chitosan on the transfection efficiency[J]. Biomaterials,2001,22(15):2075-2080.
[81] Huang YC, Vieira A, Huang KL, et al. Pulmonary inflammation caused by chitosanmicroparticles[J]. J Biomed Mater Res A,2005,75(2):283-287.
[82] Xu X, Capito RM, Spector M. Plasmid size influences chitosan nano carrier mediated genetransfer to chondrocytes[J]. J Biomed Mater Res A,2008,84(4):1038-1048.
[83] Yang XR, Zong L, Yuan XY. Chitosan nano carriers as gene vector: effect of particle size ontransfection efficiency[J]. Yao Xue Xue Bao,2007,42(7):774-779.
[84] Huang M, Fong CW, Khor E, et al. Transfection efficiency of chitosan vectors: effect ofpolymer molecular weight and degree of deacetylation[J]. J Control Release,2005,106(3):391-406.
[85] Zhao X, Yu SB, Wu FL, et al. Transfection of primary chondrocytes using chitosan-pEGFPnano carriers[J]. J Control Release,2006,112(2):223-228.
[86]张海玲，王芹，宋丽萍，等.壳聚糖基因纳米粒子的细胞摄入和体外毒性研究[J].生物医学工程学杂志，2007，24(6)：1295-1300.
[87] Erbacher P, Zou S, Bettinger T, et al. Chitosan-based vector/DNA complexes for genedelivery: biophysical characteristics and transfection ability[J]. Pharm Res,1998,15(9):1332-1339.
[88] Ishii T, Okahata Y, Sato T. Mechanism of cell transfection with plasmid/chitosancomplexes[J]. Biochim Biophys Acta,2001,1514(1):51-64.
[89] Corsi K, Chellat F, Yahia L, et al. Mesenchymal stem cells, MG63and HEK293transfectionusing chitosan-DNA nano carriers. Biomaterials,2003,24(7):1255-1264.
[90] Pouton CW, Lucas P, Thomas BJ, et al. Polycation-DNA complexes for gene delivery: acomparison of the biopharmaceutical properties of cationic polypeptides and cationiclipids[J]. J Control Release,1998,53(1-3):289-299.
[91] Fernandez-Urrusuno R, Calvo P, Remunan-Lopez C, et al. Enhancement of nasal absorptionof insulin using chitosan nano carriers[J]. Pharm Res,1999,16(10):1576-1581.
[92] Pan Y, Li YJ, Zhao HY, et al. Bioadhesive polysaccharide in protein delivery system: chitosannano carriers improve the intestinal absorption of insulin in vivo[J]. Int J Pharm,2002,249(1-2):139-147.
[93] Ma Z, Yeoh HH, Lim LY. Formulation pH modulates the interaction of insulin with chitosannano carriers[J]. J Pharm Sci,2002,91(6):1396-1404.
[94] Cui F, Qian F, Zhao Z, et al. Preparation, characterization, and oral delivery of insulin loadedcarboxylated chitosan grafted poly(methyl methacrylate) nano carriers[J].Biomacromolecules,2009,10(5):1253-1258.
[95] Wang X, Zheng C, Wu Z, et al. Chitosan-NAC nano carriers as a vehicle for nasal absorptionenhancement of insulin[J]. J Biomed Mater Res B Appl Biomater,2009,88(1):150-161.
[96] Jo HG, Min KH, Nam TH, et al. Prolonged antidiabetic effect of zinc-crystallized insulinloaded glycol chitosan nano carriers in type1diabetic rats[J]. Arch Pharm Res,2008,31(7):918-923.
[97] Yin L, Ding J, He C, et al. Drug permeability and mucoadhesion properties of thiolatedtrimethyl chitosan nano carriers in oral insulin delivery[J]. Biomaterials,2009,30(29):5691-5700.
[98] Zhang X, Zhang H, Wu Z, et al. Nasal absorption enhancement of insulin using PEG-graftedchitosan nano carriers[J]. Eur J Pharm Biopharm,2008,68(3):526-534.
[99] Parveen S, Sahoo SK. Polymeric nano carriers for cancer therapy[J]. J Drug Target,2008,16(2):108-123.
[100] Qi L, Xu Z, Chen M. In vitro and in vivo suppression of hepatocellular carcinoma growth bychitosan nano carriers[J]. Eur J Cancer,2007,43(1):184-193.
[101] Agnihotri SA, Aminabhavi TM. Chitosan nano carriers for prolonged delivery of timololmaleate[J]. Drug Dev Ind Pharm,2007,33(11):1254-1262.
[102] Tiyaboonchai W, Limpeanchob N. Formulation and characterization of amphotericinB-chitosan-dextran sulfate nano carriers[J]. Int J Pharm,2007,329(1-2):142-149.
[103] Motwani SK, Chopra S, Talegaonkar S, et al. Chitosan-sodium alginate nano carriers assubmicroscopic reservoirs for ocular delivery: formulation, optimisation and in vitrocharacterisation[J]. Eur J Pharm Biopharm,2008,68(3):513-525.
[104] Jain D, Banerjee R. Comparison of ciprofloxacin hydrochloride-loaded protein, lipid, andchitosan nano carriers for drug delivery[J]. J Biomed Mater Res B Appl Biomater,2008,86(1):105-112.
[105]黄容琴.脑靶向树枝状高分子纳米基因递释系统的研究[D].复旦大学博士论文，2008.
[106]邵堃，黄容琴，蒋晨，等.脑靶向药物纳米递释系统[J].东南大学学报（医学版），2011，30(1)：169-184.
[107]姚鹏，黄杰，康春生，等.跨血脑屏障复合功能纳米载体系统的构建[J].中国医学科学院学报，2011，30(1)：481-485.
[108] Mistry A, Stolnik S, Illum L. Nano carriers for direct nose-to-brain delivery of drugs[J]. Int JPharm,2009,379(1):146-157.
[109] Wang X, Chi N, Tang X. Preparation of estradiol chitosan nano carriers for improving nasalabsorption and brain targeting[J]. Eur J Pharm Biopharm,2008,70(3):735-740.
[110] Kumar M, Pathak K, Misra A. Formulation and characterization of nanoemulsion-baseddrug delivery system of risperidone[J]. Drug Dev Ind Pharm,2009,35(4):387-395.
[111] Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins[J]. CritRev Ther Drug Carrier Syst,1992,9(3-4):249-304.
[112]杨柳.生物可吸收聚乳酸-聚乙二醇嵌段共聚物自组装纳米胶束药物控释体系研究[D].复旦大学博士论文，2010.
[113] Greenwald RB, Choe YH, McGuire J, et al. Effective drug delivery by PEGylated drugconjugates[J]. Adv Drug Deliv Rev,2003,55(2):217-250.
[114] Veronese FM, Pasut G. PEGylation, successful approach to drug delivery[J]. Drug DiscovToday,2005,10(21):1451-1458.
[115] Luo Y, Prestwich GD. Cancer-targeted polymeric drugs[J]. Curr Cancer Drug Targets,2002,2(3):209-226.
[116] Abuchowski A, McCoy JR, Palczuk NC, et al. Effect of covalent attachment of polyethyleneglycol on immunogenicity and circulating life of bovine liver catalase[J]. J Biol Chem,1977,252(11):3582-3586.
[117] Abuchowski A, van Es T, Palczuk NC, et al. Alteration of immunological properties ofbovine serum albumin by covalent attachment of polyethylene glycol[J]. J Biol Chem,1977,252(11):3578-3581.
[118] Jorgensen KE, Moller JV. Use of flexible polymers as probes of glomerular pore size[J]. AmJ Physiol,1979,236(2):F103-111.
[119]黄容琴，柯伟伦，蒋晨，等.脑靶向非病毒基因递释系统的研究进展[J].国际药学研究杂志，2010，37(1)：36-39.
[120] Xie H, Zhu Y, Jiang W, et al. Lactoferrin-conjugated superparamagnetic iron oxide nanocarriers as a specific MRI contrast agent for detection of brain glioma in vivo[J]. Biomaterials,2011,32(2):495-502.
[121] Hu K, Li J, Shen Y, et al. Lactoferrin-conjugated PEG-PLA nano carriers with improvedbrain delivery: in vitro and in vivo evaluations[J]. J Control Release,2009,134(1):55-61.
[122] Huang R, Ke W, Liu Y, et al. The use of lactoferrin as a ligand for targeting thepolyamidoamine-based gene delivery system to the brain[J]. Biomaterials,2008,29(2):238-246.
[123] Yonemori K, Tsuta K, Ono M, et al. Disruption of the blood brain barrier by brainmetastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breastcancer[J]. Cancer,2010,116(2):302-308.
[124] Astete CE, Sabliov CM. Synthesis and characterization of PLGA nano carriers[J]. JBiomater Sci Polym Ed,2006,17(3):247-289.
[125] Eley JG, Pujari VD, McLane J. Poly (lactide-co-glycolide) nano carriers containingcoumarin-6for suppository delivery: in vitro release profile and in vivo tissue distribution[J].Drug Deliv,2004,11(4):255-261.
[126] Konan YN, Gurny R, Allemann E. Preparation and characterization of sterile andfreeze-dried sub-200nm nano carriers[J]. Int J Pharm,2002,233(1-2):239-252.
[127] Quintanar-Guerrero D, Allemann E, Fessi H, et al. Preparation techniques and mechanismsof formation of biodegradable nano carriers from preformed polymers[J]. Drug Dev IndPharm,1998,24(12):1113-1128.
[128] Ahlin P, Kristl J, Kristl A, et al. Investigation of polymeric nano carriers as carriers ofenalaprilat for oral administration[J]. Int J Pharm,2002,239(1-2):113-120.
[129] Pietzonka P, Walter E, Duda-Johner S, et al. Compromised integrity of excised porcineintestinal epithelium obtained from the abattoir affects the outcome of in vitro particle uptakestudies[J]. Eur J Pharm Sci,2002,15(1):39-47.
[130] Kwon HY, Lee JY, Choi SW, et al. Preparation of PLGA nano carriers containing estrogenby emulsification-diffusion method[J]. Colloids Surf A,2001,182(1/3):123-130.
[131] Lee S, Jeong J, Shin S, et al. Magnetic enhancement of iron oxide nano carriersencapsulated with poly(d,l-latide-co-glycolide)[J]. Colloids Surf A,2005,255(1/3):19-25.
[132] Choi SW, Kwon HY, Kim WS, et al. Thermodynamic parameters onpoly(d,l-lactide-co-glycolide) particle size in emulsification-diffusion process[J]. ColloidsSurf A,2002,201(1/3):283-289.
[133] Jia Z, shen D, Xu W. Synthesis and antibacterial activities of quaternary ammonium salt ofchitosan[J]. Carbohydr Res,2001,333(1):1-6.
[134] Uchegbu IF, Sadiq L, Arastoo M, et al. Quaternary ammonium palmitoyl glycol chitosan--anew polysoap for drug delivery[J]. Int J Pharm,2001,224(1-2):185-199.
[135] Holappa J, Nevalainen T, Soininen P, et al. Synthesis of novel quaternary chitosanderivatives via N-Chloroacyl-6-O-triphenylmethylchitosans[J]. Biomacromolecules,2006,7(2):407-410.
[136] de Britto D, de Assis OB. Synthesis and mechanical properties of quaternary salts ofchitosan-based films for food application[J]. Int J Biol Macromol,2007,41(2):198-203.
[137] Illum L. Chitosan and its use as a pharmaceutical excipient[J]. Pharm Res,1998,15(9):1326-1331.
[138] Felt O, Buri P, Gurny R. Chitosan: a unique polysaccharide for drug delivery[J]. Drug DevInd Pharm,1998,24(11):979-993.
[139] Sankar C, Rani M, Srivastava AK, et al. Chitosan based pentazocine microspheres forintranasal systemic delivery: development and biopharmaceutical evaluation[J]. Pharmazie,2001,56(3):223-226.
[140] Boriwanwattanarak P, Ingkaninan K, Khorana N, et al. Development of curcuminoidshydrogel patch using chitosan from various sources as controlled-release matrix[J]. Int JCosmet Sci,2008,30(3):205-218.
[141]魏谭军，董德刚，裘梁，等.离子交联法制备壳聚糖纳米载体[J].安徽农业科学，2012，40(5)：2885-2886,2889.
[142]邢志华，方桂珍.离子交联法制备叶酸-壳聚糖微球工艺研究[J].黑龙江医药，2011，24(6)：915-917.
[143]蒋新宇，周春山，张俊山，等.应用三聚磷酸钠为交联剂制备载药物纳米粒的研究[J].中国现代医学杂志，2003，13(22)：69-71.
[144] Amidi M, Mastrobattista E, Jiskoot W, et al. Chitosan-based delivery systems for proteintherapeutics and antigens[J]. Adv Drug Deliv Rev,2010,62(1):59-82.
[145] Avadi MR, Sadeghi AM, Mohammadpour N, et al. Preparation and characterization ofinsulin nano carriers using chitosan and Arabic gum with ionic gelation method[J].Nanomedicine,2010,6(1):58-63.
[146] Mi FL. Synthesis and characterization of a novel chitosan-gelatin bioconjugate withfluorescence emission[J]. Biomacromolecules,2005,6(2):975-987.
[147] Sun JM, Xu P, Han XT, et al. Determination of trace silver by flame atomic absorptionspectrometry using chitosan enriching method[J]. Guang Pu Xue Yu Guang Pu Fen Xi,2005,25(2):290-292.
[148]张涛，黄哲，林章凛.固定化β-葡萄糖苷酶双相体系中水解大豆异黄酮[J].化工学报，2008，59(2)：387-392.
[149] Prabaharan M, Mano JF. Chitosan-based particles as controlled drug delivery systems[J].Drug Deliv,2005,12(1):41-57.
[150] Ohya Y, Takei T, Kobayashi H, et al. Release behaviour of5-fluorouracil from chitosan-gelmicrospheres immobilizing5-fluorouracil derivative coated with polysaccharides and theircell specific recognition[J]. J Microencapsul,1993,10(1):1-9.
[151] Goldberg M, Langer R, Jia X. Nanostructured materials for applications in drug delivery andtissue engineering[J]. J Biomater Sci Polym Ed,2007,18(3):241-268.
[152] Bodnar M, Hartmann JF, Borbely J. Preparation and characterization of chitosan-based nanocarriers[J]. Biomacromolecules,2005,6(5):2521-2527.
[153] He L, Yao L, Liu F, et al. Magnetic Fe3O4-chitosan nano carrier: synthesis, characterizationand application as catalyst carrier[J]. J Nanosci Nanotechnol,2010,10(10):6348-6355.
[154] Tian XX, Groves MJ. Formulation and biological activity of antineoplastic proteoglycansderived from Mycobacterium vaccae in chitosan nano carriers[J]. J Pharm Pharmacol,1999,51(2):151-157.
[155] El-Shabouri MH. Positively charged nano carriers for improving the oral bioavailability ofcyclosporin-A[J]. Int J Pharm,2002,249(1-2):101-108.
[156] Chauvierre C, Labarre D, Couvreur P, et al. Radical emulsion polymerization ofalkylcyanoacrylates initiated by the redox system dextran-cerium (IV) under acidicaqueous conditions[J]. Macromolecules,2003,36(16):6018–6027.
[157] Chauvierre C, Labarre D, Couvreur P, et al. Plug-in spectrometry with optical fbers as anovel analytical tool for nano carriers technology: application to the investigation of theemulsion polymerization of the alkylcyanoacrylate[J]. J Nanopart Res,2003,5(3):365–371.
[158] Chauvierre C, Labarre D, Couvreur P, et al. Novel polysaccharide-decorated poly (isobutylcyanoacrylate) nano carriers[J]. Pharm Res,2003,20(11):1786–1793.
[159] Bravo-Osuna I, Vauthier C, Farabollini A, et al. Mucoadhesion mechanism of chitosan andthiolated chitosan-poly (isobutyl cyanoacrylate) core-shell nano carriers[J]. Biomaterials,2007,28(13):2233–2243.
[160] de Moura MR, Aouada FA, Mattoso LHC. Preparation of chitosan nano carriers usingmethacrylic acid[J]. J Colloid Interface Sci,2008,321(2):477–483.
[161] Cheng MH, Huang YX, Zhou HJ, et al. Rapid preparation and characterization ofchitosan nano carriers for oligonucleotide[J]. Curr Appl Phys,2010,10(3):797–800.
[162] Kim D, Jeong Y, Choi C, et al. Retinol-encapsulated low molecular water soluble chitosannano carriers[J]. Int J Pharm,2006,319(1–2):130–138.
[163] Grenha A, Seijo B, Serra C, et al. Chitosan nano carrier loaded mannitol microspheres:structure and surface characterization[J]. Biomacromolecules,2007,8(7):2072–2079.
[164]陆建男，钱红艳，周建平，等.牛血清蛋白壳聚糖自组装纳米胶束的制备及理化性质研究[J].中国药科大学学报，2008，39(6)：500-504.
[165]霍美蓉，周建平，张勇，等. N-辛基-O,N-羧甲基壳聚糖自组装纳米粒的制备、理化性质及安全性评价[J].中国药科大学学报，2007，38(6)：512-515.
[166]杨心督，陈汉，张惠珠，等.聚乙二醇单甲醚接枝壳聚糖自组装纳米球的制备[J].中国新药杂志，2007，16(21)：1780-1783,1787.
[167] Huo MR, Zhou JP, Zhang Y. Synthesis and characterization of novel amphiphilic chitosanderivatives and its solubilizing abilities for water insoluble drugs[J]. Chem J Chinese U,2007,28(10):1995–1999.
[168] Natsume H, Iwata S, Ohtake K, et al. Screening of cationic compounds as an absorptionenhancer for nasal drug delivery[J]. Int J Pharm,1999,185(1):1-12.
[169] Mitchell DJ, Kim DT, Steinman L, et al. Polyarginine enters cells more efficiently than otherpolycationic homopolymers[J]. J Pept Res,2000,56(5):318-325.
[170]程男.温度敏感聚异丙基丙烯酰胺/聚精氨酸缀合物转基因载体[D].天津大学硕士论文，2006.
[171] Chang M, Chou JC, Lee HJ. Cellular internalization of fluorescent proteins via arginine-richintracellular delivery peptide in plant cells[J]. Plant Cell Physiol,2005,46(3):482-488.
[172] Z aki NM, Awad GA, Mortada ND, et al. Rapid-onset intranasal delivery of metoclopramidehydrochloride. Part I. Influence of formulation variables on drug absorption in anesthetizedrats[J]. Int J Pharm,2006,327(1-2):89-96.
[173] Miyamoto M, Natsume H, Iwata S, et al. Improved nasal absorption of drugs usingpoly-L-arginine: effects of concentration and molecular weight of poly-L-arginine on thenasal absorption of fluorescein isothiocyanate-dextran in rats[J]. Eur J Pharm Biopharm,2001,52(1):21-30.
[174] Siprashvili Z, Scholl FA, Oliver SF, et al. Gene transfer via reversible plasmid condensationwith cysteine-flanked, internally spaced arginine-rich peptides[J]. Hum Gene Ther,2003,14(13):1225-1233.
[175] Futaki S, Ohashi W, Suzuki T, et al. Stearylated arginine-rich peptides: a new class oftransfection systems[J]. Bioconjug Chem,2001,12(6):1005-1011.
[176] Choi JS, Nam K, Park JY, et al. Enhanced transfection efficiency of PAMAM dendrimer bysurface modification with L-arginine[J]. J Control Release,2004,99(3):445-456.
[177]尹愈佳，王小双，唐洁，等.八聚精氨酸修饰的载紫杉醇脂质体的构建及体外评价[C].第十三次全国心血管病学术会议论文集.
[178] Sun C, Lee JS, Zhang M. Magnetic nano carriers in MR imaging and drug delivery[J]. AdvDrug Deliv Rev,2008,60(11):1252-1265.
[179] Latorre M, Rinaldi C. Applications of magnetic nano carriers in medicine: magnetic fluidhyperthermia[J]. P R Health Sci J,2009,28(3):227-238.
[180] Chomoucka J, Drbohlavova J, Huska D, et al. Magnetic nano carriers and targeted drugdelivering[J]. Pharmacol Res,2010,62(2):144-149.
[181] Itoh H, Sugimoto T. Systematic control of size, shape, structure, and magnetic properties ofuniform magnetite and maghemite particles[J]. J Colloid Interface Sci,2003,265(2):283-295.
[182] Tucek J, Zboril R, Petridis D. Maghemite nano carriers by view of Mossbauerspectroscopy[J]. J Nanosci Nanotechnol,2006,6(4):926-947.
[183] Reshmi G, Mohan Kumar P, Malathi M. Preparation, characterization and dielectric studieson carbonyl iron/cellulose acetate hydrogen phthalate core/shell nano carriers for drugdelivery applications[J]. Int J Pharm,2009,365(1-2):131-135.
[184] Arias JL, Lopez-Viota M, Lopez-Viota J, et al. Development of iron/ethylcellulose(core/shell) nano carriers loaded with diclofenac sodium for arthritis treatment[J]. Int J Pharm,2009,382(1-2):270-276.
[185] Pouponneau P, Leroux JC, Martel S. Magnetic nano carriers encapsulated into biodegradablemicroparticles steered with an upgraded magnetic resonance imaging system for tumorchemoembolization[J]. Biomaterials,2009,30(31):6327-6332.
[186] Hu FX, Neoh KG, Kang ET. Synthesis and in vitro anti-cancer evaluation oftamoxifen-loaded magnetite/PLLA composite nano carriers[J]. Biomaterials,2006,27(33):5725-5733.
[187] Parvin S, Matsui J, Sato E, et al. Side-chain effect on Langmuir and Langmuir-Blodgett filmproperties of poly(N-alkylmethacrylamide)-coated magnetic nano carrier[J]. J ColloidInterface Sci,2007,313(1):128-134.
[188] Shubayev VI, Pisanic TR,2nd, Jin S. Magnetic nano carriers for theragnostics[J]. Adv DrugDeliv Rev,2009,61(6):467-477.
[189] Faraji AH, Wipf P. Nano carriers in cellular drug delivery[J]. Bioorg Med Chem,2009,17(8):2950-2962.
[190] Singh R, Lillard JW, Jr. Nano carrier-based targeted drug delivery[J]. Exp Mol Pathol,2009,86(3):215-223.
[191] Arias JL, Lopez-Viota M, Ruiz MA, et al. Development of carbonyl iron/ethylcellulosecore/shell nano carriers for biomedical applications[J]. Int J Pharm,2007,339(1-2):237-245.
[192] Chertok B, Moffat BA, David AE, et al. Iron oxide nano carriers as a drug delivery vehiclefor MRI monitored magnetic targeting of brain tumors[J]. Biomaterials,2008,29(4):487-496.
[193] Kumar A, Jena PK, Behera S, et al. Multifunctional magnetic nano carriers for targeteddelivery[J]. Nanomedicine,2010,6(1):64-69.
[194] Bi F, Zhang J, Su Y, et al. Chemical conjugation of urokinase to magnetic nano carriers fortargeted thrombolysis[J]. Biomaterials,2009,30(28):5125-5130.
[195] Purushotham S, Ramanujan RV. Thermoresponsive magnetic composite nanomaterials formultimodal cancer therapy[J]. Acta Biomater,2010,6(2):502-510.
[196] Yuan Q, Venkatasubramanian R, Hein S, et al. A stimulus-responsive magnetic nano carrierdrug carrier: magnetite encapsulated by chitosan-grafted-copolymer[J]. Acta Biomater,2008,4(4):1024-1037.
[197] Skaat H, Margel S. Synthesis of fluorescent-maghemite nano carriers as multimodalimaging agents for amyloid-beta fibrils detection and removal by a magnetic field[J].Biochem Biophys Res Commun,2009,386(4):645-649.
[198] Huang WC, Hu SH, Liu KH, et al. A flexible drug delivery chip for themagnetically-controlled release of anti-epileptic drugs[J]. J Control Release,2009,139(3):221-228.
[199] Wang X, Wang L, He X, et al. A molecularly imprinted polymer-coated nanocomposite ofmagnetic nano carriers for estrone recognition[J]. Talanta,2009,78(2):327-332.
[200]任志强，巩驰昊，吴有金，等.油酸改性的二甲苯基Fe3O4磁流体的制备及表征[J].材料研究与应用，2008，2(1)：18-21.
[201]马啸华，刘瑛，任军哲，等.新型磁性纳米级油酸改性铁氧磁流体磁性粒子的制备及表征[J].化工时刊，2006，20(1)：6-8.
[202] Ozturk N, Gunay ME, Akgol S, et al. Silane-modified magnetic beads: application toimmunoglobulin G separation[J]. Biotechnol Prog,2007,23(5):1149-1156.
[203] Chertok B, David AE, Moffat BA, et al. Substantiating in vivo magnetic brain tumortargeting of cationic iron oxide nanocarriers via adsorptive surface masking[J]. Biomaterials,2009,30(35):6780-6787.
[204] Lin JJ, Chen JS, Huang SJ, et al. Folic acid-Pluronic F127magnetic nano carrier clusters forcombined targeting, diagnosis, and therapy applications[J]. Biomaterials,2009,30(28):5114-5124.
[205] Lim YT, Cho MY, Lee JM, et al. Simultaneous intracellular delivery of targeting antibodiesand functional nano carriers with engineered protein G system[J]. Biomaterials,2009,30(6):1197-1204.
[206]周宓，王志强.跨血脑屏障药物转运的研究进展[J].生命科学研究，2009，13（4）：370-376.
[207]张微.脂质纳米粒的制备及基因转染研究[D].浙江大学硕士论文，2010.
[2]张红梅.延长静脉溶栓时间窗治疗后循环进展性卒中的研究[D].天津医科大学硕士论文，2010.
[3] Liu Y, Miyoshi H, Nakamura M. Nanomedicine for drug delivery and imaging: a promisingavenue for cancer therapy and diagnosis using targeted functional nano carriers[J]. Int JCancer,2007,120(12):2527-2537.
[4] Whitesides GM. Nanoscience, nanotechnology, and chemistry[J]. Small,2005;1(2):172-179.
[5] Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nano carriers:theory to practice[J]. Pharmacol Rev,2001,53(2):283-318.
[6] Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging[J]. Drug DiscovToday,2003,8(24):1112-1120.
[7] Wickline SA, Neubauer AM, Winter P, et al. Applications of nanotechnology toatherosclerosis, thrombosis, and vascular biology[J]. Arterioscler Thromb Vasc Biol,2006,26(3):435-441.
[8] Panyam J, Labhasetwar V. Biodegradable nano carriers for drug and gene delivery to cells andtissue[J]. Adv Drug Deliv Rev,2003,55(3):329-347.
[9] Jain RA. The manufacturing techniques of various drug loaded biodegradablepoly(lactide-co-glycolide)(PLGA) devices[J]. Biomaterials,2000,21(23):2475-2490.
[10] Wickline SA, Neubauer AM, Winter PM, et al. Molecular imaging and therapy ofatherosclerosis with targeted nano carriers[J]. J Magn Reson Imaging,2007,25(4):667-680.
[11] Studer M, Briel M, Leimenstoll B, et al. Effect of different antilipidemic agents and diets onmortality: a systematic review[J]. Arch Intern Med,2005,165(7):725-730.
[12] Wang CK, Wang WY, Meyer RF, et al. A rapid method for creating drug implants: translatinglaboratory-based methods into a scalable manufacturing process[J]. J Biomed Mater Res BAppl Biomater,2010,93(2):562-572.
[13] Jalil R, Nixon JR. Biodegradable poly(lactic acid) and poly(lactide-co-glycolide)microcapsules: problems associated with preparative techniques and release properties[J]. JMicroencapsul,1990,7(3):297-325.
[14] Cohen S, Alonso MJ, Langer R. Novel approaches to controlled-release antigen delivery[J].Int J Technol Assess Health Care,1994,10(1):121-130.
[15] Han B, Wang HT, Liu HY, et al. Preparation of pingyangmycin PLGA microspheres andrelated in vitro/in vivo studies[J]. Int J Pharm,2010,398(1-2):130-136.
[16] Sun F, Sui C, Teng L, et al. Studies on the preparation, characterization and pharmacologicalevaluation of tolterodine PLGA microspheres[J]. Int J Pharm,2010,397(1-2):44-49.
[17] Tian J, Sun X, Chen X, et al. The formulation and immunisation of oralpoly(DL-lactide-co-glycolide) microcapsules containing a plasmid vaccine againstlymphocystis disease virus in Japanese flounder (Paralichthys olivaceus)[J]. IntImmunopharmacol,2008,8(6):900-908.
[18] Mohamed F, van der Walle CF. PLGA microcapsules with novel dimpled surfaces forpulmonary delivery of DNA[J]. Int J Pharm,2006,311(1-2):97-107.
[19] Son S, Lee WR, Joung YK, et al. Optimized stability retention of a monoclonal antibody inthe PLGA nano carriers[J]. Int J Pharm,2009,368(1-2):178-185.
[20] Javadzadeh Y, Ahadi F, Davaran S, et al. Preparation and physicochemical characterization ofnaproxen-PLGA nano carriers[J]. Colloids Surf B Biointerfaces,2010,81(2):498-502.
[21] Wang CK, Wang WY, Meyer RF, et al. A rapid method for creating drug implants: translatinglaboratory-based methods into a scalable manufacturing process[J]. J Biomed Mater Res BAppl Biomater,2010,93(2):562-572.
[22] Siegel SJ, Kahn JB, Metzger K, et al. Effect of drug type on the degradation rate of PLGAmatrices[J]. Eur J Pharm Biopharm,2006,64(3):287-293.
[23] Wischke C, Zhang Y, Mittal S, et al. Development of PLGA-based injectable deliverysystems for hydrophobic fenretinide[J]. Pharm Res,2010,27(10):2063-2074.
[24] Liu Q, Zhang H, Zhou G, et al. In vitro and in vivo study of thymosin alpha1biodegradable insitu forming poly(lactide-co-glycolide) implants[J]. Int J Pharm,2010,397(1-2):122-129.
[25] Loo SC, Tan ZY, Chow YJ, et al. Drug release from irradiated PLGA and PLLA multi-layeredfilms[J]. J Pharm Sci,2010,99(7):3060-3071.
[26] Shen H, Hu X, Yang F, et al. The bioactivity of rhBMP-2immobilizedpoly(lactide-co-glycolide) scaffolds[J]. Biomaterials,2009,30(18):3150-3157.
[27] Wang GJ, Lin YC, Hsu SH. The fabrication of PLGA microvessel scaffolds withnano-patterned inner walls[J]. Biomed Microdevices,2010,12(5):841-848.
[28] Mooney DJ, Sano K, Kaufmann PM, et al. Long-term engraftment of hepatocytestransplanted on biodegradable polymer sponges[J]. J Biomed Mater Res,1997,37(3):413-420.
[29] Eiselt P, Kim BS, Chacko B, et al. Development of technologies aiding large-tissueengineering[J]. Biotechnol Prog,1998,14(1):134-140.
[30] Mundargi RC, Babu VR, Rangaswamy V, et al. Nano/micro technologies for deliveringmacromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives[J]. JControl Release,2008,125(3):193-209.
[31] Wischke C, Schwendeman SP. Principles of encapsulating hydrophobic drugs in PLA/PLGAmicroparticles[J]. Int J Pharm,2008,364(2):298-327.
[32] Pai Kasturi S, Qin H, Thomson KS, et al. Prophylactic anti-tumor effects in a B celllymphoma model with DNA vaccines delivered on polyethylenimine (PEI) functionalizedPLGA microparticles[J]. J Control Release,2006,113(3):261-270.
[33] Kocbek P, Obermajer N, Cegnar M, et al. Targeting cancer cells using PLGA nano carrierssurface modified with monoclonal antibody[J]. J Control Release,2007,120(1-2):18-26.
[34] Benny O, Duvshani-Eshet M, Cargioli T, et al. Continuous delivery of endogenous inhibitorsfrom poly(lactic-co-glycolic acid) polymeric microspheres inhibits glioma tumor growth[J].Clin Cancer Res,2005,11(2Pt1):768-776.
[35] Mo Y, Lim LY. Paclitaxel-loaded PLGA nano carriers: potentiation of anticancer activity bysurface conjugation with wheat germ agglutinin[J]. J Control Release,2005,108(2-3):244-262.
[36] Fonseca C, Simoes S, Gaspar R. Paclitaxel-loaded PLGA nano carriers: preparation,physicochemical characterization and in vitro anti-tumoral activity[J]. J Control Release,2002,83(2):273-286.
[37] van Vlerken LE, Duan Z, Little SR, et al. Biodistribution and pharmacokinetic analysis ofPaclitaxel and ceramide administered in multifunctional polymer-blend nano carriers in drugresistant breast cancer model[J]. Mol Pharm,2008,5(4):516-526.
[38] Zeisser-Labouebe M, Lange N, Gurny R, et al. Hypericin-loaded nano carriers for thephotodynamic treatment of ovarian cancer[J]. Int J Pharm,2006,326(1-2):174-181.
[39] Gryparis EC, Hatziapostolou M, Papadimitriou E, et al. Anticancer activity ofcisplatin-loaded PLGA-mPEG nano carriers on LNCaP prostate cancer cells[J]. Eur J PharmBiopharm,2007,67(1):1-8.
[40] Yemisci M, Bozdag S, Cetin M, et al. Treatment of malignant gliomas withmitoxantrone-loaded poly (lactide-co-glycolide) microspheres[J]. Neurosurgery,2006,59(6):1296-1302; discussion1302-1293.
[41] Bharali DJ, Mousa SA, Thanavala Y. Micro-and nano carrier-based vaccines for hepatitisB[J]. Adv Exp Med Biol,2007,601:415-421.
[42] Zhao Z, Leong KW. Controlled delivery of antigens and adjuvants in vaccine development[J].J Pharm Sci,1996,85(12):1261-1270.
[43] Nayak B, Panda AK, Ray P, et al. Formulation, characterization and evaluation of rotavirusencapsulated PLA and PLGA particles for oral vaccination[J]. J Microencapsul,2009,26(2):154-165.
[44] Wang JJ, Zeng ZW, Xiao RZ, et al. Recent advances of chitosan nano carriers as drugcarriers[J]. Int J Nanomedicine,2011,6:765-774.
[45] Jin MX, Hu QH. Characterization and application in bioadhesive drug delivery system ofchitosan[J]. Centr South Pharm,2008,6(003):324–327.
[46] Dudhani AR, Kosaraju SL. Bioadhesive chitosan nano carriers:preparation andcharacterization[J]. Carbohydr Polym,2010,81(2):243–251.
[47] Hagens WI, Oomen AG, de Jong WH, et al. What do we (need to) know about the kineticproperties of nano carriers in the body[J]? Regul Toxicol Pharmacol,2007,49(3):217-229.
[48] Gaumet M, Vargas A, Gurny R, et al. Nano carriers for drug delivery: the need for precisionin reporting particle size parameters[J]. Eur J Pharm Biopharm,2008,69(1):1-9.
[49] Qian F, Cui F, Ding J, et al. Chitosan graft copolymer nano carriers for oral protein drugdelivery: preparation and characterization[J]. Biomacromolecules,2006,7(10):2722-2727.
[50] Brigger I, Dubernet C, Couvreur P. Nano carriers in cancer therapy and diagnosis[J]. AdvDrug Deliv Rev,2002,54(5):631-651.
[51] Brannon-Peppas L, Blanchette JO. Nano carrier and targeted systems for cancer therapy[J].Adv Drug Deliv Rev,2004,56(11):1649-1659.
[52] Yuan Q, Shah J, Hein S, et al. Controlled and extended drug release behavior ofchitosan-based nano carrier carrier[J]. Acta Biomater,2010,6(3):1140-1148.
[53] Park JH, Saravanakumar G, Kim K, Kwon IC. Targeted delivery of low molecular drugs usingchitosan and its derivatives[J]. Adv Drug Deliv Rev,2010,62(1):28–41.
[54] Park K, Kim JH, Nam YS, et al. Effect of polymer molecular weight on the tumor targetingcharacteristics of self-assembled glycol chitosan nano carriers[J]. J Control Release,2007,122(3):305-314.
[55] Xu XY, Zhou JP, Li L, et al. Preparation of doxorubicin-loaded chitosan polymeric micelleand study on its tissue biodistribution in mice[J]. Yao Xue Xue Bao,2008,43(7):743-748.
[56] Kiang T, Bright C, Cheung CY, et al. Formulation of chitosan-DNA nano carriers withpoly(propyl acrylic acid) enhances gene expression[J]. J Biomater Sci Polym Ed,2004,15(11):1405-1421.
[57] Na K, Bae YH. Self-assembled hydrogel nano carriers responsive to tumor extracellular pHfrom pullulan derivative/sulfonamide conjugate: characterization, aggregation, andadriamycin release in vitro[J]. Pharm Res,2002,19(5):681-688.
[58] Rejinold NS, Sreerekha PR, Chennazhi KP, et al. Biocompatible, biodegradable andthermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drugdelivery[J]. Int J Biol Macromol,2011,49(2):161-172.
[59] Chung JE, Yokoyama M, Aoyagi T, et al. Effect of molecular architecture of hydrophobicallymodified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shellmicellar drug carriers[J]. J Control Release,1998,53(1-3):119-130.
[60] Chung JE, Yokoyama M, Yamato M, et al. Thermo-responsive drug delivery from polymericmicelles constructed using block copolymers of poly(N-isopropylacrylamide) andpoly(butylmethacrylate)[J]. J Control Release,1999,62(1-2):115-127.
[61] Chauvierre C, Labarre D, Couvreur P, et al. Novel polysaccharide-decorated poly(isobutylcyanoacrylate) nano carriers[J]. Pharm Res,2003,20(11):1786-1793.
[62] Bravo-Osuna I, Vauthier C, Farabollini A, et al. Mucoadhesion mechanism of chitosan andthiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nano carriers[J]. Biomaterials,2007,28(13):2233-2243.
[63] Chuang WY, Young TH, Yao CH, et al. Properties of the poly(vinyl alcohol)/chitosan blendand its effect on the culture of fibroblast in vitro[J]. Biomaterials,1999,20(16):1479-1487.
[64] Huang HY, Shieh YT, Shih CM, Twu YK. Magnetic chitosan/iron (II, III) oxide nanocarriers prepared by spray-drying[J]. Carbohydr Polym,2010,81(4):906–910.
[65] Singh R, Lillard JW, Jr. Nano carrier-based targeted drug delivery[J]. Exp Mol Pathol,2009,86(3):215-223.
[66]姚倩.双配体修饰的壳聚糖纳米粒肝癌细胞主动靶向给药系统的研究[D].四川大学博士论文，2006.
[67] Kim JH, Kim YS, Park K, et al. Antitumor efficacy of cisplatin-loaded glycol chitosan nanocarriers in tumor-bearing mice[J]. J Control Release,2008,127(1):41-49.
[68] Min KH, Park K, Kim YS, et al. Hydrophobically modified glycol chitosan nanocarriers-encapsulated camptothecin enhance the drug stability and tumor targeting in cancertherapy[J]. J Control Release,2008,127(3):208-218.
[69] Douglas KL, Piccirillo CA, Tabrizian M. Cell line-dependent internalization pathways andintracellular trafficking determine transfection efficiency of nano carrier vectors[J]. Eur JPharm Biopharm,2008,68(3):676-687.
[70] Douglas KL, Piccirillo CA, Tabrizian M. Effects of alginate inclusion on the vector propertiesof chitosan-based nano carriers[J]. J Control Release,2006,115(3):354-361.
[71] Duceppe N, Tabrizian M. Factors influencing the transfection efficiency of ultra lowmolecular weight chitosan/hyaluronic acid nano carriers[J]. Biomaterials,2009,30(13):2625-2631.
[72]陈记稷.阳离子修饰的PEG化聚乳酸纳米基因载体的实验研究[D].中南大学硕士论文，2007.
[73]黄帆.壳聚糖/DNA传递系统的制备及其性能研究[D].华南理工大学硕士论文，2010.
[74]刘璠娜.新型季铵盐壳聚糖纳米载药体系的研究[D].暨南大学博士论文，2008.
[75] Huang M, Khor E, Lim LY. Uptake and cytotoxicity of chitosan molecules and nano carriers:effects of molecular weight and degree of deacetylation[J]. Pharm Res,2004,21(2):344-353.
[76] Kiang T, Wen J, Lim HW, et al. The effect of the degree of chitosan deacetylation on theefficiency of gene transfection[J]. Biomaterials,2004,25(22):5293-5301.
[77] Liu X, Howard KA, Dong M, et al. The influence of polymeric properties on chitosan/siRNAnano carrier formulation and gene silencing[J]. Biomaterials,2007,28(6):1280-1288.
[78] Lavertu M, Methot S, Tran-Khanh N, et al. High efficiency gene transfer using chitosan/DNAnano carriers with specific combinations of molecular weight and degree of deacetylation[J].Biomaterials,2006,27(27):4815-4824.
[79] Koping-Hoggard M, Varum KM, Issa M, et al. Improved chitosan-mediated gene deliverybased on easily dissociated chitosan polyplexes of highly defined chitosan oligomers[J].Gene Ther,2004,11(19):1441-1452.
[80] Sato T, Ishii T, Okahata Y. In vitro gene delivery mediated by chitosan. effect of pH, serum,and molecular mass of chitosan on the transfection efficiency[J]. Biomaterials,2001,22(15):2075-2080.
[81] Huang YC, Vieira A, Huang KL, et al. Pulmonary inflammation caused by chitosanmicroparticles[J]. J Biomed Mater Res A,2005,75(2):283-287.
[82] Xu X, Capito RM, Spector M. Plasmid size influences chitosan nano carrier mediated genetransfer to chondrocytes[J]. J Biomed Mater Res A,2008,84(4):1038-1048.
[83] Yang XR, Zong L, Yuan XY. Chitosan nano carriers as gene vector: effect of particle size ontransfection efficiency[J]. Yao Xue Xue Bao,2007,42(7):774-779.
[84] Huang M, Fong CW, Khor E, et al. Transfection efficiency of chitosan vectors: effect ofpolymer molecular weight and degree of deacetylation[J]. J Control Release,2005,106(3):391-406.
[85] Zhao X, Yu SB, Wu FL, et al. Transfection of primary chondrocytes using chitosan-pEGFPnano carriers[J]. J Control Release,2006,112(2):223-228.
[86]张海玲，王芹，宋丽萍，等.壳聚糖基因纳米粒子的细胞摄入和体外毒性研究[J].生物医学工程学杂志，2007，24(6)：1295-1300.
[87] Erbacher P, Zou S, Bettinger T, et al. Chitosan-based vector/DNA complexes for genedelivery: biophysical characteristics and transfection ability[J]. Pharm Res,1998,15(9):1332-1339.
[88] Ishii T, Okahata Y, Sato T. Mechanism of cell transfection with plasmid/chitosancomplexes[J]. Biochim Biophys Acta,2001,1514(1):51-64.
[89] Corsi K, Chellat F, Yahia L, et al. Mesenchymal stem cells, MG63and HEK293transfectionusing chitosan-DNA nano carriers. Biomaterials,2003,24(7):1255-1264.
[90] Pouton CW, Lucas P, Thomas BJ, et al. Polycation-DNA complexes for gene delivery: acomparison of the biopharmaceutical properties of cationic polypeptides and cationiclipids[J]. J Control Release,1998,53(1-3):289-299.
[91] Fernandez-Urrusuno R, Calvo P, Remunan-Lopez C, et al. Enhancement of nasal absorptionof insulin using chitosan nano carriers[J]. Pharm Res,1999,16(10):1576-1581.
[92] Pan Y, Li YJ, Zhao HY, et al. Bioadhesive polysaccharide in protein delivery system: chitosannano carriers improve the intestinal absorption of insulin in vivo[J]. Int J Pharm,2002,249(1-2):139-147.
[93] Ma Z, Yeoh HH, Lim LY. Formulation pH modulates the interaction of insulin with chitosannano carriers[J]. J Pharm Sci,2002,91(6):1396-1404.
[94] Cui F, Qian F, Zhao Z, et al. Preparation, characterization, and oral delivery of insulin loadedcarboxylated chitosan grafted poly(methyl methacrylate) nano carriers[J].Biomacromolecules,2009,10(5):1253-1258.
[95] Wang X, Zheng C, Wu Z, et al. Chitosan-NAC nano carriers as a vehicle for nasal absorptionenhancement of insulin[J]. J Biomed Mater Res B Appl Biomater,2009,88(1):150-161.
[96] Jo HG, Min KH, Nam TH, et al. Prolonged antidiabetic effect of zinc-crystallized insulinloaded glycol chitosan nano carriers in type1diabetic rats[J]. Arch Pharm Res,2008,31(7):918-923.
[97] Yin L, Ding J, He C, et al. Drug permeability and mucoadhesion properties of thiolatedtrimethyl chitosan nano carriers in oral insulin delivery[J]. Biomaterials,2009,30(29):5691-5700.
[98] Zhang X, Zhang H, Wu Z, et al. Nasal absorption enhancement of insulin using PEG-graftedchitosan nano carriers[J]. Eur J Pharm Biopharm,2008,68(3):526-534.
[99] Parveen S, Sahoo SK. Polymeric nano carriers for cancer therapy[J]. J Drug Target,2008,16(2):108-123.
[100] Qi L, Xu Z, Chen M. In vitro and in vivo suppression of hepatocellular carcinoma growth bychitosan nano carriers[J]. Eur J Cancer,2007,43(1):184-193.
[101] Agnihotri SA, Aminabhavi TM. Chitosan nano carriers for prolonged delivery of timololmaleate[J]. Drug Dev Ind Pharm,2007,33(11):1254-1262.
[102] Tiyaboonchai W, Limpeanchob N. Formulation and characterization of amphotericinB-chitosan-dextran sulfate nano carriers[J]. Int J Pharm,2007,329(1-2):142-149.
[103] Motwani SK, Chopra S, Talegaonkar S, et al. Chitosan-sodium alginate nano carriers assubmicroscopic reservoirs for ocular delivery: formulation, optimisation and in vitrocharacterisation[J]. Eur J Pharm Biopharm,2008,68(3):513-525.
[104] Jain D, Banerjee R. Comparison of ciprofloxacin hydrochloride-loaded protein, lipid, andchitosan nano carriers for drug delivery[J]. J Biomed Mater Res B Appl Biomater,2008,86(1):105-112.
[105]黄容琴.脑靶向树枝状高分子纳米基因递释系统的研究[D].复旦大学博士论文，2008.
[106]邵堃，黄容琴，蒋晨，等.脑靶向药物纳米递释系统[J].东南大学学报（医学版），2011，30(1)：169-184.
[107]姚鹏，黄杰，康春生，等.跨血脑屏障复合功能纳米载体系统的构建[J].中国医学科学院学报，2011，30(1)：481-485.
[108] Mistry A, Stolnik S, Illum L. Nano carriers for direct nose-to-brain delivery of drugs[J]. Int JPharm,2009,379(1):146-157.
[109] Wang X, Chi N, Tang X. Preparation of estradiol chitosan nano carriers for improving nasalabsorption and brain targeting[J]. Eur J Pharm Biopharm,2008,70(3):735-740.
[110] Kumar M, Pathak K, Misra A. Formulation and characterization of nanoemulsion-baseddrug delivery system of risperidone[J]. Drug Dev Ind Pharm,2009,35(4):387-395.
[111] Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins[J]. CritRev Ther Drug Carrier Syst,1992,9(3-4):249-304.
[112]杨柳.生物可吸收聚乳酸-聚乙二醇嵌段共聚物自组装纳米胶束药物控释体系研究[D].复旦大学博士论文，2010.
[113] Greenwald RB, Choe YH, McGuire J, et al. Effective drug delivery by PEGylated drugconjugates[J]. Adv Drug Deliv Rev,2003,55(2):217-250.
[114] Veronese FM, Pasut G. PEGylation, successful approach to drug delivery[J]. Drug DiscovToday,2005,10(21):1451-1458.
[115] Luo Y, Prestwich GD. Cancer-targeted polymeric drugs[J]. Curr Cancer Drug Targets,2002,2(3):209-226.
[116] Abuchowski A, McCoy JR, Palczuk NC, et al. Effect of covalent attachment of polyethyleneglycol on immunogenicity and circulating life of bovine liver catalase[J]. J Biol Chem,1977,252(11):3582-3586.
[117] Abuchowski A, van Es T, Palczuk NC, et al. Alteration of immunological properties ofbovine serum albumin by covalent attachment of polyethylene glycol[J]. J Biol Chem,1977,252(11):3578-3581.
[118] Jorgensen KE, Moller JV. Use of flexible polymers as probes of glomerular pore size[J]. AmJ Physiol,1979,236(2):F103-111.
[119]黄容琴，柯伟伦，蒋晨，等.脑靶向非病毒基因递释系统的研究进展[J].国际药学研究杂志，2010，37(1)：36-39.
[120] Xie H, Zhu Y, Jiang W, et al. Lactoferrin-conjugated superparamagnetic iron oxide nanocarriers as a specific MRI contrast agent for detection of brain glioma in vivo[J]. Biomaterials,2011,32(2):495-502.
[121] Hu K, Li J, Shen Y, et al. Lactoferrin-conjugated PEG-PLA nano carriers with improvedbrain delivery: in vitro and in vivo evaluations[J]. J Control Release,2009,134(1):55-61.
[122] Huang R, Ke W, Liu Y, et al. The use of lactoferrin as a ligand for targeting thepolyamidoamine-based gene delivery system to the brain[J]. Biomaterials,2008,29(2):238-246.
[123] Yonemori K, Tsuta K, Ono M, et al. Disruption of the blood brain barrier by brainmetastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breastcancer[J]. Cancer,2010,116(2):302-308.
[124] Astete CE, Sabliov CM. Synthesis and characterization of PLGA nano carriers[J]. JBiomater Sci Polym Ed,2006,17(3):247-289.
[125] Eley JG, Pujari VD, McLane J. Poly (lactide-co-glycolide) nano carriers containingcoumarin-6for suppository delivery: in vitro release profile and in vivo tissue distribution[J].Drug Deliv,2004,11(4):255-261.
[126] Konan YN, Gurny R, Allemann E. Preparation and characterization of sterile andfreeze-dried sub-200nm nano carriers[J]. Int J Pharm,2002,233(1-2):239-252.
[127] Quintanar-Guerrero D, Allemann E, Fessi H, et al. Preparation techniques and mechanismsof formation of biodegradable nano carriers from preformed polymers[J]. Drug Dev IndPharm,1998,24(12):1113-1128.
[128] Ahlin P, Kristl J, Kristl A, et al. Investigation of polymeric nano carriers as carriers ofenalaprilat for oral administration[J]. Int J Pharm,2002,239(1-2):113-120.
[129] Pietzonka P, Walter E, Duda-Johner S, et al. Compromised integrity of excised porcineintestinal epithelium obtained from the abattoir affects the outcome of in vitro particle uptakestudies[J]. Eur J Pharm Sci,2002,15(1):39-47.
[130] Kwon HY, Lee JY, Choi SW, et al. Preparation of PLGA nano carriers containing estrogenby emulsification-diffusion method[J]. Colloids Surf A,2001,182(1/3):123-130.
[131] Lee S, Jeong J, Shin S, et al. Magnetic enhancement of iron oxide nano carriersencapsulated with poly(d,l-latide-co-glycolide)[J]. Colloids Surf A,2005,255(1/3):19-25.
[132] Choi SW, Kwon HY, Kim WS, et al. Thermodynamic parameters onpoly(d,l-lactide-co-glycolide) particle size in emulsification-diffusion process[J]. ColloidsSurf A,2002,201(1/3):283-289.
[133] Jia Z, shen D, Xu W. Synthesis and antibacterial activities of quaternary ammonium salt ofchitosan[J]. Carbohydr Res,2001,333(1):1-6.
[134] Uchegbu IF, Sadiq L, Arastoo M, et al. Quaternary ammonium palmitoyl glycol chitosan--anew polysoap for drug delivery[J]. Int J Pharm,2001,224(1-2):185-199.
[135] Holappa J, Nevalainen T, Soininen P, et al. Synthesis of novel quaternary chitosanderivatives via N-Chloroacyl-6-O-triphenylmethylchitosans[J]. Biomacromolecules,2006,7(2):407-410.
[136] de Britto D, de Assis OB. Synthesis and mechanical properties of quaternary salts ofchitosan-based films for food application[J]. Int J Biol Macromol,2007,41(2):198-203.
[137] Illum L. Chitosan and its use as a pharmaceutical excipient[J]. Pharm Res,1998,15(9):1326-1331.
[138] Felt O, Buri P, Gurny R. Chitosan: a unique polysaccharide for drug delivery[J]. Drug DevInd Pharm,1998,24(11):979-993.
[139] Sankar C, Rani M, Srivastava AK, et al. Chitosan based pentazocine microspheres forintranasal systemic delivery: development and biopharmaceutical evaluation[J]. Pharmazie,2001,56(3):223-226.
[140] Boriwanwattanarak P, Ingkaninan K, Khorana N, et al. Development of curcuminoidshydrogel patch using chitosan from various sources as controlled-release matrix[J]. Int JCosmet Sci,2008,30(3):205-218.
[141]魏谭军，董德刚，裘梁，等.离子交联法制备壳聚糖纳米载体[J].安徽农业科学，2012，40(5)：2885-2886,2889.
[142]邢志华，方桂珍.离子交联法制备叶酸-壳聚糖微球工艺研究[J].黑龙江医药，2011，24(6)：915-917.
[143]蒋新宇，周春山，张俊山，等.应用三聚磷酸钠为交联剂制备载药物纳米粒的研究[J].中国现代医学杂志，2003，13(22)：69-71.
[144] Amidi M, Mastrobattista E, Jiskoot W, et al. Chitosan-based delivery systems for proteintherapeutics and antigens[J]. Adv Drug Deliv Rev,2010,62(1):59-82.
[145] Avadi MR, Sadeghi AM, Mohammadpour N, et al. Preparation and characterization ofinsulin nano carriers using chitosan and Arabic gum with ionic gelation method[J].Nanomedicine,2010,6(1):58-63.
[146] Mi FL. Synthesis and characterization of a novel chitosan-gelatin bioconjugate withfluorescence emission[J]. Biomacromolecules,2005,6(2):975-987.
[147] Sun JM, Xu P, Han XT, et al. Determination of trace silver by flame atomic absorptionspectrometry using chitosan enriching method[J]. Guang Pu Xue Yu Guang Pu Fen Xi,2005,25(2):290-292.
[148]张涛，黄哲，林章凛.固定化β-葡萄糖苷酶双相体系中水解大豆异黄酮[J].化工学报，2008，59(2)：387-392.
[149] Prabaharan M, Mano JF. Chitosan-based particles as controlled drug delivery systems[J].Drug Deliv,2005,12(1):41-57.
[150] Ohya Y, Takei T, Kobayashi H, et al. Release behaviour of5-fluorouracil from chitosan-gelmicrospheres immobilizing5-fluorouracil derivative coated with polysaccharides and theircell specific recognition[J]. J Microencapsul,1993,10(1):1-9.
[151] Goldberg M, Langer R, Jia X. Nanostructured materials for applications in drug delivery andtissue engineering[J]. J Biomater Sci Polym Ed,2007,18(3):241-268.
[152] Bodnar M, Hartmann JF, Borbely J. Preparation and characterization of chitosan-based nanocarriers[J]. Biomacromolecules,2005,6(5):2521-2527.
[153] He L, Yao L, Liu F, et al. Magnetic Fe3O4-chitosan nano carrier: synthesis, characterizationand application as catalyst carrier[J]. J Nanosci Nanotechnol,2010,10(10):6348-6355.
[154] Tian XX, Groves MJ. Formulation and biological activity of antineoplastic proteoglycansderived from Mycobacterium vaccae in chitosan nano carriers[J]. J Pharm Pharmacol,1999,51(2):151-157.
[155] El-Shabouri MH. Positively charged nano carriers for improving the oral bioavailability ofcyclosporin-A[J]. Int J Pharm,2002,249(1-2):101-108.
[156] Chauvierre C, Labarre D, Couvreur P, et al. Radical emulsion polymerization ofalkylcyanoacrylates initiated by the redox system dextran-cerium (IV) under acidicaqueous conditions[J]. Macromolecules,2003,36(16):6018–6027.
[157] Chauvierre C, Labarre D, Couvreur P, et al. Plug-in spectrometry with optical fbers as anovel analytical tool for nano carriers technology: application to the investigation of theemulsion polymerization of the alkylcyanoacrylate[J]. J Nanopart Res,2003,5(3):365–371.
[158] Chauvierre C, Labarre D, Couvreur P, et al. Novel polysaccharide-decorated poly (isobutylcyanoacrylate) nano carriers[J]. Pharm Res,2003,20(11):1786–1793.
[159] Bravo-Osuna I, Vauthier C, Farabollini A, et al. Mucoadhesion mechanism of chitosan andthiolated chitosan-poly (isobutyl cyanoacrylate) core-shell nano carriers[J]. Biomaterials,2007,28(13):2233–2243.
[160] de Moura MR, Aouada FA, Mattoso LHC. Preparation of chitosan nano carriers usingmethacrylic acid[J]. J Colloid Interface Sci,2008,321(2):477–483.
[161] Cheng MH, Huang YX, Zhou HJ, et al. Rapid preparation and characterization ofchitosan nano carriers for oligonucleotide[J]. Curr Appl Phys,2010,10(3):797–800.
[162] Kim D, Jeong Y, Choi C, et al. Retinol-encapsulated low molecular water soluble chitosannano carriers[J]. Int J Pharm,2006,319(1–2):130–138.
[163] Grenha A, Seijo B, Serra C, et al. Chitosan nano carrier loaded mannitol microspheres:structure and surface characterization[J]. Biomacromolecules,2007,8(7):2072–2079.
[164]陆建男，钱红艳，周建平，等.牛血清蛋白壳聚糖自组装纳米胶束的制备及理化性质研究[J].中国药科大学学报，2008，39(6)：500-504.
[165]霍美蓉，周建平，张勇，等. N-辛基-O,N-羧甲基壳聚糖自组装纳米粒的制备、理化性质及安全性评价[J].中国药科大学学报，2007，38(6)：512-515.
[166]杨心督，陈汉，张惠珠，等.聚乙二醇单甲醚接枝壳聚糖自组装纳米球的制备[J].中国新药杂志，2007，16(21)：1780-1783,1787.
[167] Huo MR, Zhou JP, Zhang Y. Synthesis and characterization of novel amphiphilic chitosanderivatives and its solubilizing abilities for water insoluble drugs[J]. Chem J Chinese U,2007,28(10):1995–1999.
[168] Natsume H, Iwata S, Ohtake K, et al. Screening of cationic compounds as an absorptionenhancer for nasal drug delivery[J]. Int J Pharm,1999,185(1):1-12.
[169] Mitchell DJ, Kim DT, Steinman L, et al. Polyarginine enters cells more efficiently than otherpolycationic homopolymers[J]. J Pept Res,2000,56(5):318-325.
[170]程男.温度敏感聚异丙基丙烯酰胺/聚精氨酸缀合物转基因载体[D].天津大学硕士论文，2006.
[171] Chang M, Chou JC, Lee HJ. Cellular internalization of fluorescent proteins via arginine-richintracellular delivery peptide in plant cells[J]. Plant Cell Physiol,2005,46(3):482-488.
[172] Z aki NM, Awad GA, Mortada ND, et al. Rapid-onset intranasal delivery of metoclopramidehydrochloride. Part I. Influence of formulation variables on drug absorption in anesthetizedrats[J]. Int J Pharm,2006,327(1-2):89-96.
[173] Miyamoto M, Natsume H, Iwata S, et al. Improved nasal absorption of drugs usingpoly-L-arginine: effects of concentration and molecular weight of poly-L-arginine on thenasal absorption of fluorescein isothiocyanate-dextran in rats[J]. Eur J Pharm Biopharm,2001,52(1):21-30.
[174] Siprashvili Z, Scholl FA, Oliver SF, et al. Gene transfer via reversible plasmid condensationwith cysteine-flanked, internally spaced arginine-rich peptides[J]. Hum Gene Ther,2003,14(13):1225-1233.
[175] Futaki S, Ohashi W, Suzuki T, et al. Stearylated arginine-rich peptides: a new class oftransfection systems[J]. Bioconjug Chem,2001,12(6):1005-1011.
[176] Choi JS, Nam K, Park JY, et al. Enhanced transfection efficiency of PAMAM dendrimer bysurface modification with L-arginine[J]. J Control Release,2004,99(3):445-456.
[177]尹愈佳，王小双，唐洁，等.八聚精氨酸修饰的载紫杉醇脂质体的构建及体外评价[C].第十三次全国心血管病学术会议论文集.
[178] Sun C, Lee JS, Zhang M. Magnetic nano carriers in MR imaging and drug delivery[J]. AdvDrug Deliv Rev,2008,60(11):1252-1265.
[179] Latorre M, Rinaldi C. Applications of magnetic nano carriers in medicine: magnetic fluidhyperthermia[J]. P R Health Sci J,2009,28(3):227-238.
[180] Chomoucka J, Drbohlavova J, Huska D, et al. Magnetic nano carriers and targeted drugdelivering[J]. Pharmacol Res,2010,62(2):144-149.
[181] Itoh H, Sugimoto T. Systematic control of size, shape, structure, and magnetic properties ofuniform magnetite and maghemite particles[J]. J Colloid Interface Sci,2003,265(2):283-295.
[182] Tucek J, Zboril R, Petridis D. Maghemite nano carriers by view of Mossbauerspectroscopy[J]. J Nanosci Nanotechnol,2006,6(4):926-947.
[183] Reshmi G, Mohan Kumar P, Malathi M. Preparation, characterization and dielectric studieson carbonyl iron/cellulose acetate hydrogen phthalate core/shell nano carriers for drugdelivery applications[J]. Int J Pharm,2009,365(1-2):131-135.
[184] Arias JL, Lopez-Viota M, Lopez-Viota J, et al. Development of iron/ethylcellulose(core/shell) nano carriers loaded with diclofenac sodium for arthritis treatment[J]. Int J Pharm,2009,382(1-2):270-276.
[185] Pouponneau P, Leroux JC, Martel S. Magnetic nano carriers encapsulated into biodegradablemicroparticles steered with an upgraded magnetic resonance imaging system for tumorchemoembolization[J]. Biomaterials,2009,30(31):6327-6332.
[186] Hu FX, Neoh KG, Kang ET. Synthesis and in vitro anti-cancer evaluation oftamoxifen-loaded magnetite/PLLA composite nano carriers[J]. Biomaterials,2006,27(33):5725-5733.
[187] Parvin S, Matsui J, Sato E, et al. Side-chain effect on Langmuir and Langmuir-Blodgett filmproperties of poly(N-alkylmethacrylamide)-coated magnetic nano carrier[J]. J ColloidInterface Sci,2007,313(1):128-134.
[188] Shubayev VI, Pisanic TR,2nd, Jin S. Magnetic nano carriers for theragnostics[J]. Adv DrugDeliv Rev,2009,61(6):467-477.
[189] Faraji AH, Wipf P. Nano carriers in cellular drug delivery[J]. Bioorg Med Chem,2009,17(8):2950-2962.
[190] Singh R, Lillard JW, Jr. Nano carrier-based targeted drug delivery[J]. Exp Mol Pathol,2009,86(3):215-223.
[191] Arias JL, Lopez-Viota M, Ruiz MA, et al. Development of carbonyl iron/ethylcellulosecore/shell nano carriers for biomedical applications[J]. Int J Pharm,2007,339(1-2):237-245.
[192] Chertok B, Moffat BA, David AE, et al. Iron oxide nano carriers as a drug delivery vehiclefor MRI monitored magnetic targeting of brain tumors[J]. Biomaterials,2008,29(4):487-496.
[193] Kumar A, Jena PK, Behera S, et al. Multifunctional magnetic nano carriers for targeteddelivery[J]. Nanomedicine,2010,6(1):64-69.
[194] Bi F, Zhang J, Su Y, et al. Chemical conjugation of urokinase to magnetic nano carriers fortargeted thrombolysis[J]. Biomaterials,2009,30(28):5125-5130.
[195] Purushotham S, Ramanujan RV. Thermoresponsive magnetic composite nanomaterials formultimodal cancer therapy[J]. Acta Biomater,2010,6(2):502-510.
[196] Yuan Q, Venkatasubramanian R, Hein S, et al. A stimulus-responsive magnetic nano carrierdrug carrier: magnetite encapsulated by chitosan-grafted-copolymer[J]. Acta Biomater,2008,4(4):1024-1037.
[197] Skaat H, Margel S. Synthesis of fluorescent-maghemite nano carriers as multimodalimaging agents for amyloid-beta fibrils detection and removal by a magnetic field[J].Biochem Biophys Res Commun,2009,386(4):645-649.
[198] Huang WC, Hu SH, Liu KH, et al. A flexible drug delivery chip for themagnetically-controlled release of anti-epileptic drugs[J]. J Control Release,2009,139(3):221-228.
[199] Wang X, Wang L, He X, et al. A molecularly imprinted polymer-coated nanocomposite ofmagnetic nano carriers for estrone recognition[J]. Talanta,2009,78(2):327-332.
[200]任志强，巩驰昊，吴有金，等.油酸改性的二甲苯基Fe3O4磁流体的制备及表征[J].材料研究与应用，2008，2(1)：18-21.
[201]马啸华，刘瑛，任军哲，等.新型磁性纳米级油酸改性铁氧磁流体磁性粒子的制备及表征[J].化工时刊，2006，20(1)：6-8.
[202] Ozturk N, Gunay ME, Akgol S, et al. Silane-modified magnetic beads: application toimmunoglobulin G separation[J]. Biotechnol Prog,2007,23(5):1149-1156.
[203] Chertok B, David AE, Moffat BA, et al. Substantiating in vivo magnetic brain tumortargeting of cationic iron oxide nanocarriers via adsorptive surface masking[J]. Biomaterials,2009,30(35):6780-6787.
[204] Lin JJ, Chen JS, Huang SJ, et al. Folic acid-Pluronic F127magnetic nano carrier clusters forcombined targeting, diagnosis, and therapy applications[J]. Biomaterials,2009,30(28):5114-5124.
[205] Lim YT, Cho MY, Lee JM, et al. Simultaneous intracellular delivery of targeting antibodiesand functional nano carriers with engineered protein G system[J]. Biomaterials,2009,30(6):1197-1204.
[206]周宓，王志强.跨血脑屏障药物转运的研究进展[J].生命科学研究，2009，13（4）：370-376.
[207]张微.脂质纳米粒的制备及基因转染研究[D].浙江大学硕士论文，2010.