雷公藤红素纳米脂质体的制备及抗胶质瘤的实验研究
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摘要
第一部分雷公藤红素纳米脂质体的制备和小鼠体内的组织分布
目的:研究包封率高,稳定性好的雷公藤红素纳米脂质体的制备方法和小鼠腹腔给药后血药浓度及药物在主要脏器的分布。
方法:用薄膜分散法,以磷脂+脱氧胆酸钠为膜材制备成了包封率较高,稳定性较好雷公藤红素纳米脂质体。并建立了雷公藤红素纳米脂质体的高效液相含量测定方法;建立了葡聚糖凝胶柱层析法雷公藤红素纳米脂质体包封率测定方法。采用液相色谱质谱联动方法测定小鼠血液及体内不同组织中雷公藤红素的含量。
结果:雷公藤红素纳米脂质体包封率为71.67%,纳米脂质体的粒径测定结果表明,粒径分布较窄,平均粒径为128.1nm。载药率为2.19%。电镜示雷公藤红素纳米脂质体形态为圆形,大小比较均匀,内核为雷公藤红素,外围为磷脂成分。雷公藤红素纳米脂质体较其裸药最高血药浓度(C_(max))、曲线下面积(AUC)有显著提高,而平均驻留时间(MRT)和消除相半衰期(t_(1/2))显著延长。体内分布显示纳米脂质体在肺、脑、心靶向指数较高,分别为3.54、2.79、2.66。
结论:纳米脂质体可以作为雷公藤红素的有效药物载体。药代动力学实验显示纳米脂质体制剂能够提高雷公藤红素血药浓度,以及延长半衰期。体内分布的实验结果显示雷公藤红素纳米脂质体的具有较好的肺、脑、心靶向性。
第二部分雷公藤红素纳米脂质体抗胶质瘤的实验研究
目的:研究雷公藤红素纳米脂质体体内外对胶质瘤的抑制作用,以及比较雷公藤红素裸药和纳米脂质体的毒副作用。
方法:使用SRB法测定雷公藤红素裸药和其纳米脂质体在体外对三株胶质瘤细胞的抑制作用。将人脑胶质瘤SHG44细胞移植到BALB/c裸鼠右侧腋下,一周后分别给予雷公藤红素裸药及其纳米脂质体、顺铂、以及空白纳米脂质体。用药时间为四周,测定其肿瘤直径,裸鼠体重,观察裸鼠的一般情况。四周后在末次给药后2小时断头取血测定肝肾功能和心肌酶谱。剔出移植瘤标本,肿瘤一半速冻后用液相色谱质谱联动仪进行雷公藤红素含量的测定。另一半肿瘤固定后,常规石蜡包埋标本,4um石蜡切片,行HE染色。并取裸鼠心肝肾做常规病理切片。
结果:在体外纳米脂质体并不能增强雷公藤红素抑制胶质瘤细胞生长的作用。在SHG44胶质瘤移植模型中发现:雷公藤红素纳米脂质体低剂量组对移植瘤有抑制作用,抑制率达32.8%,显著高于雷公藤红素裸药低剂量组的18.2%。两者之间有显著差异。雷公藤红素纳米脂质体和裸药高剂量组对抑制瘤均有明显抑制作用,分别68.4%和66.5%。两者之间无差异。用药期间雷公藤红素裸药组的裸鼠体重有明显下降,而纳米脂质体组对体重的影响轻微。顺铂组显示有轻度肾损害,其余各组的肝肾功能,心肌酶谱,血常规均无明显变化。但雷公藤红素裸药组肝脏病理切片显示有早期肝损伤,汇管区有淋巴细胞浸润;裸药组肾脏切片示有轻度淤血表现。雷公藤红素纳米脂质体具有肿瘤靶向性,药物靶向指数为2.51。
结论:本研究制备的雷公藤红素纳米脂质体具有增强抗胶质瘤生长的效果,具有肿瘤靶向性,并能降低药物的毒性作用。
Part one:Preparation of nano-sized Liposomal celastrol and distribution of nano-sized Liposomal celastrol in mice
Objective:To prepare nano-sized liposomal Celastrol with high encapsulation efficiency and good stability,study the distribution of nano-sized Liposomal celastrol in mice.
Methods:we obtained nano-sized liposomal celastrol by the thin film dispersed method.The RP-HPLC-UV analysis method of celastrol was studied and proved to be accurate and reliable for quantitative analysis in vitro through methodology investigation. Sephadex column chromatography was created to be an encapsulation efficiency determination method of nano-sized liposomal celastrol.Durg concentration in tissue of mice was determined by the method of LC-MS/MS.
Result:The encapsulation efficiency was 71.67%,the particle size of the liposome was 128.1nm.Loading efficiency was 2.19%.Observation of TEM showed that nano-sized liposomal celastrol was round with smooth surfaces.Inner core was Celastrol,surrounding was phosphatides.C_(max) and AUC and MRT and t_(1/2) of nano-sized liposomal celastrol was increased compared with active compound Celastrol.Target index in of nano-sized liposomal celastrol in lung and brain and heart was 3.54 and 2.79 and 2.66.
Conclusion:Nano-sized liposomal may serve as availability carrier of Celastrol. Nano-sized liposomal Celastrol could increase blood concentration and half life. Nano-sized liposomal Celastrol had good targeting efficiency in brain and lung and heart.
Part two:Nano-sized liposomal Celastrol on the inhibition of a human malignant glioma cell line SHG-44 in vivo
Objective:To investigate antitumor effects of nano-sized liposomal Celastrol on the growth of a human malignant glioma cell line SHG-44 in vivo.To compare the toxic effect between nano-sized liposomal Celastrol and active compound of Celastrol.
Methods:SRB colorimetric assay was used to evaluate antitumor effect on three glioma cell lines.Animal models were constructed on BALB/c nude mice with subcutaneously transplanted neoplasma of SHG-44 glioma.The nude mice bearing with SHG44 glioma were divided into six groups by random selection,which were treated with different doses of nano-sized liposomal Celastrol or active compound of Celastrol(4mg/kg,and 1mg/kg,every day for four weeks)or with Cisplatin(2 mg/kg,) or blank nanoliposomes.The dimension of xenografts was measured and the living state and weight of nude mice with SHG-44 glioma were observed.The concentration of Celastrol in xenografts was determined by liquid chromatography-trandem mass spectrometry.The parameters concerning heart,liver and kidney function were measured and the morphology of organ tissues was observed pathologically.
Results:Nano-sized liposomal Celastrol and active compound Celastrol have the similar cytotoxicity in vitro assay.Nano-sized liposomal Celastrol and active compound Celastrol at 4mg/kg can inhibit the growth of xenografts in nude mice with SHG44 glioma (P＜0.05) compared with the control and the tumor volume was reduced by 68.4%and 66.5%.Nano-sized liposomal Celastrol at 1mg/kg can inhibit the growth of xenografts in nude mice with SHG44 glioma while active compound Celastrol at 1mg/kg cannot.Active compound Celastrol reduce the weight of nude mice with SHG-44 glioma while nano-sized liposomal Celastrol haven' the same the toxic effect.
Conclusion:It is demonstrated that nano-sized liposomal Celastrol can achieved the same therapeutic effects with lower dosage.The side-effect of nano-sized liposomal Celastrol is less than the same dosage of active compound Celastrol.Nano-sized liposomal Celastrol had good targeting efficiency in xenograft,DTI was 2.51.
目的:研究包封率高,稳定性好的雷公藤红素纳米脂质体的制备方法和小鼠腹腔给药后血药浓度及药物在主要脏器的分布。
方法:用薄膜分散法,以磷脂+脱氧胆酸钠为膜材制备成了包封率较高,稳定性较好雷公藤红素纳米脂质体。并建立了雷公藤红素纳米脂质体的高效液相含量测定方法;建立了葡聚糖凝胶柱层析法雷公藤红素纳米脂质体包封率测定方法。采用液相色谱质谱联动方法测定小鼠血液及体内不同组织中雷公藤红素的含量。
结果:雷公藤红素纳米脂质体包封率为71.67%,纳米脂质体的粒径测定结果表明,粒径分布较窄,平均粒径为128.1nm。载药率为2.19%。电镜示雷公藤红素纳米脂质体形态为圆形,大小比较均匀,内核为雷公藤红素,外围为磷脂成分。雷公藤红素纳米脂质体较其裸药最高血药浓度(C_(max))、曲线下面积(AUC)有显著提高,而平均驻留时间(MRT)和消除相半衰期(t_(1/2))显著延长。体内分布显示纳米脂质体在肺、脑、心靶向指数较高,分别为3.54、2.79、2.66。
结论:纳米脂质体可以作为雷公藤红素的有效药物载体。药代动力学实验显示纳米脂质体制剂能够提高雷公藤红素血药浓度,以及延长半衰期。体内分布的实验结果显示雷公藤红素纳米脂质体的具有较好的肺、脑、心靶向性。
第二部分雷公藤红素纳米脂质体抗胶质瘤的实验研究
目的:研究雷公藤红素纳米脂质体体内外对胶质瘤的抑制作用,以及比较雷公藤红素裸药和纳米脂质体的毒副作用。
方法:使用SRB法测定雷公藤红素裸药和其纳米脂质体在体外对三株胶质瘤细胞的抑制作用。将人脑胶质瘤SHG44细胞移植到BALB/c裸鼠右侧腋下,一周后分别给予雷公藤红素裸药及其纳米脂质体、顺铂、以及空白纳米脂质体。用药时间为四周,测定其肿瘤直径,裸鼠体重,观察裸鼠的一般情况。四周后在末次给药后2小时断头取血测定肝肾功能和心肌酶谱。剔出移植瘤标本,肿瘤一半速冻后用液相色谱质谱联动仪进行雷公藤红素含量的测定。另一半肿瘤固定后,常规石蜡包埋标本,4um石蜡切片,行HE染色。并取裸鼠心肝肾做常规病理切片。
结果:在体外纳米脂质体并不能增强雷公藤红素抑制胶质瘤细胞生长的作用。在SHG44胶质瘤移植模型中发现:雷公藤红素纳米脂质体低剂量组对移植瘤有抑制作用,抑制率达32.8%,显著高于雷公藤红素裸药低剂量组的18.2%。两者之间有显著差异。雷公藤红素纳米脂质体和裸药高剂量组对抑制瘤均有明显抑制作用,分别68.4%和66.5%。两者之间无差异。用药期间雷公藤红素裸药组的裸鼠体重有明显下降,而纳米脂质体组对体重的影响轻微。顺铂组显示有轻度肾损害,其余各组的肝肾功能,心肌酶谱,血常规均无明显变化。但雷公藤红素裸药组肝脏病理切片显示有早期肝损伤,汇管区有淋巴细胞浸润;裸药组肾脏切片示有轻度淤血表现。雷公藤红素纳米脂质体具有肿瘤靶向性,药物靶向指数为2.51。
结论:本研究制备的雷公藤红素纳米脂质体具有增强抗胶质瘤生长的效果,具有肿瘤靶向性,并能降低药物的毒性作用。
Part one:Preparation of nano-sized Liposomal celastrol and distribution of nano-sized Liposomal celastrol in mice
Objective:To prepare nano-sized liposomal Celastrol with high encapsulation efficiency and good stability,study the distribution of nano-sized Liposomal celastrol in mice.
Methods:we obtained nano-sized liposomal celastrol by the thin film dispersed method.The RP-HPLC-UV analysis method of celastrol was studied and proved to be accurate and reliable for quantitative analysis in vitro through methodology investigation. Sephadex column chromatography was created to be an encapsulation efficiency determination method of nano-sized liposomal celastrol.Durg concentration in tissue of mice was determined by the method of LC-MS/MS.
Result:The encapsulation efficiency was 71.67%,the particle size of the liposome was 128.1nm.Loading efficiency was 2.19%.Observation of TEM showed that nano-sized liposomal celastrol was round with smooth surfaces.Inner core was Celastrol,surrounding was phosphatides.C_(max) and AUC and MRT and t_(1/2) of nano-sized liposomal celastrol was increased compared with active compound Celastrol.Target index in of nano-sized liposomal celastrol in lung and brain and heart was 3.54 and 2.79 and 2.66.
Conclusion:Nano-sized liposomal may serve as availability carrier of Celastrol. Nano-sized liposomal Celastrol could increase blood concentration and half life. Nano-sized liposomal Celastrol had good targeting efficiency in brain and lung and heart.
Part two:Nano-sized liposomal Celastrol on the inhibition of a human malignant glioma cell line SHG-44 in vivo
Objective:To investigate antitumor effects of nano-sized liposomal Celastrol on the growth of a human malignant glioma cell line SHG-44 in vivo.To compare the toxic effect between nano-sized liposomal Celastrol and active compound of Celastrol.
Methods:SRB colorimetric assay was used to evaluate antitumor effect on three glioma cell lines.Animal models were constructed on BALB/c nude mice with subcutaneously transplanted neoplasma of SHG-44 glioma.The nude mice bearing with SHG44 glioma were divided into six groups by random selection,which were treated with different doses of nano-sized liposomal Celastrol or active compound of Celastrol(4mg/kg,and 1mg/kg,every day for four weeks)or with Cisplatin(2 mg/kg,) or blank nanoliposomes.The dimension of xenografts was measured and the living state and weight of nude mice with SHG-44 glioma were observed.The concentration of Celastrol in xenografts was determined by liquid chromatography-trandem mass spectrometry.The parameters concerning heart,liver and kidney function were measured and the morphology of organ tissues was observed pathologically.
Results:Nano-sized liposomal Celastrol and active compound Celastrol have the similar cytotoxicity in vitro assay.Nano-sized liposomal Celastrol and active compound Celastrol at 4mg/kg can inhibit the growth of xenografts in nude mice with SHG44 glioma (P＜0.05) compared with the control and the tumor volume was reduced by 68.4%and 66.5%.Nano-sized liposomal Celastrol at 1mg/kg can inhibit the growth of xenografts in nude mice with SHG44 glioma while active compound Celastrol at 1mg/kg cannot.Active compound Celastrol reduce the weight of nude mice with SHG-44 glioma while nano-sized liposomal Celastrol haven' the same the toxic effect.
Conclusion:It is demonstrated that nano-sized liposomal Celastrol can achieved the same therapeutic effects with lower dosage.The side-effect of nano-sized liposomal Celastrol is less than the same dosage of active compound Celastrol.Nano-sized liposomal Celastrol had good targeting efficiency in xenograft,DTI was 2.51.
引文
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(1) 张阳德.纳米药物学[M].北京.化学工业出版社.2005.10
(2) Thrall JH.Nanotechnology and medicine.Radiology,2004,230(2):315-318.
(3) Whitesides GM.The "right" size in nanobiotechnology.Nat Biotechnol,2003,21(10):1161-1165.
(4) Liu Y,Miyoshi H,Nakamura M.Nanomedicine for drug delivery and imaging:a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles.Int J Cancer,2007,120(12):2527-2537
(5) 王子好,张东生.纳米药物的研究进展[J].东南大学学报(医学版),2004,23(2):13
(6) 易明,陈汇,曾繁典.纳米技术在药学研究中的应用进展[J].中国临床药理学杂志,2001,9(17):5
(7) 王晓波,袭荣刚,李忠亮,等.纳米级雄黄粉体的制备[J].解放军药学学报.2002,18(3):129-134
(8) 王晓波,袭荣刚,张怡然,等.纳米级雄黄粉体药代动力学研究[J].解放军药学 学报. 2002,18(6):324-326
(9) Furlani EP, Ng KC. Analytical model of magnetic nanoparticle transport and capture in the microvasculature. Phys Rev E Stat Nonlin Soft Matter Phys, 2006, 73(6 Pt 1): 061919.
(10) Yang J, Park SB, Yoon HG, et al. Preparation of poly epsilon—caprolactone nanoparticles containing magnetite for magnetic drug carrier. Int J Pharm, 2006, 324(2): 185-190.
(11) Sinha V, Singh A, Kumar RV, Singh S, Kumria R, Bhinge J. Oral colon-specific drug delivery of protein and peptide drugs. Crit Rev Ther Drug Carrier Syst. 2007;24(1):63-92.
(12) Cecconi D, Donadelli M, Rinalducci S, Zolla L, Scupoli MT, Scarpa A, Palmieri M, Righetti PG. Proteomic analysis of pancreatic endocrine tumor cell lines treated with the histone deacetylase inhibitor trichostatin A. Proteomics. 2007 May; 7(10): 1644-53.
(13 ) Pasqualini R, Arap W ,McDonald DM .Probing the structural and molecular diversity of tumour vasculature. Trends Mol Med, 2002, 8(12): 563-571.
(14) Montet X, Montet-Abou K, Reynolds F, et al. Nanoparticle imaging of integrins on tumor cells. Neoplasia, 2006, 8(3): 214—222.
(15) Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetrationin tumours by vascular targeting and barrier alteration. J Clin Invest, 2002, 110(4): 475-482.
(16) Ran S, Gao B, Duffy S, etal. Infarction of solid Hodgk in's tumors in mice by antibody—directed targeting of tissue factor to tumour vasculature. Cancer Res, 1998, 58(20): 4646—4653.
(17) Gabizon AA. Liposomal anthracyclines. Hematol Oncol Clin North Am. 1994; 8(2):431-50
(18) Nikanjam M,Gibbs AR,Hunt CA,Budinger TF,Forte TM.Synthetic nano-LDL with paclitaxel oleate as a targeted drug delivery vehicle for glioblastoma multiforme.J Control Release.2007;124(3):163-71
(19) Lo Prete AC,Maris DA,Rodrigues DG,et al.Evaluation in melanoma—bearing mice of an etoposide derivative associated to a cholesterolrich nano-emulsion.J Pharm Pharmacol,2006,58(6):801-808.
(20) Luo Y,Chen D,Ren L,et al.Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability.J Control Release,2006,114(1):53-59.
(21) Hamaguchi T,Matusmura Y,Suzuki M,et al.NK105,a paclitaxel—incorporating micellar nanoparticle formulation,can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel.Br J Cancer,2005,92(7):1240-1246.
(22) Shen LF,Zhang YD,Shen HJ,et al.Liver targeting and the delayed drug release of the nanoparticles of adriamycin polybutylcyanoacrylate in mice.Chin Med J,2006,119(15):1287-1293.
(23) Wollina U,Dummer R,Brockmeyer NH,Konrad H,Busch JO,Kaatz M,Knopf B,KochHJ,Hauschild A.Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma.Cancer.2003 Sep 1;98(5):993-1001.
(24) Negishi T,Koizumi F,Uchino H,et al.NK105,a paclitaxel-incorporating micellar nanoparticle,is a more potent radiosensitising agent compared to free paclitaxel.Br J Cancer,2006,95(5):601-606.
(25) Xing J,Zhang D,Tan T.Studies on the oridonin—loaded poly(D,L-lactic acid)nanoparticles in vitro and in vivo.Int J Biol Macromol,2007,40(2):153-158.
(26) 赵慧君,王德平,张娟等..磁性纳米微粒的特性及其在生物医学中的应用[J].同济大学学报(医学版),2003,8(24):4
(27) 张阳德,张洋,潘一峰.磁性纳米颗粒靶向性肿瘤热疗的研究进展[J].中国医学工程,2004,4(14):2
(28) 李静,秦晓民,丁焕平等.磁性纳米微粒分离中药蛋白质的实验研究[J].生物磁性,2005,(5):2
(29) Sarciaux JM,Acar L,Sado PA.Using mciroemulsion formulations for oral drug delivery of therapeutic peptides.J Int J Pharm,1995,120(2):127-136
(30) 张阳德,龚连生.阿霉素白蛋白磁纳米粒在正常肝脏的靶向性[J].中国现代医学杂志,2001,11(3):4-7
(31) 张俊山,陈晓青,蒋新宇等.纳米药物研究进展[J].中国现代医学杂志,2002,12(14):45-48.
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(1) 张阳德.纳米药物学[M].北京.化学工业出版社.2005.10
(2) Thrall JH.Nanotechnology and medicine.Radiology,2004,230(2):315-318.
(3) Whitesides GM.The "right" size in nanobiotechnology.Nat Biotechnol,2003,21(10):1161-1165.
(4) Liu Y,Miyoshi H,Nakamura M.Nanomedicine for drug delivery and imaging:a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles.Int J Cancer,2007,120(12):2527-2537
(5) 王子好,张东生.纳米药物的研究进展[J].东南大学学报(医学版),2004,23(2):13
(6) 易明,陈汇,曾繁典.纳米技术在药学研究中的应用进展[J].中国临床药理学杂志,2001,9(17):5
(7) 王晓波,袭荣刚,李忠亮,等.纳米级雄黄粉体的制备[J].解放军药学学报.2002,18(3):129-134
(8) 王晓波,袭荣刚,张怡然,等.纳米级雄黄粉体药代动力学研究[J].解放军药学 学报. 2002,18(6):324-326
(9) Furlani EP, Ng KC. Analytical model of magnetic nanoparticle transport and capture in the microvasculature. Phys Rev E Stat Nonlin Soft Matter Phys, 2006, 73(6 Pt 1): 061919.
(10) Yang J, Park SB, Yoon HG, et al. Preparation of poly epsilon—caprolactone nanoparticles containing magnetite for magnetic drug carrier. Int J Pharm, 2006, 324(2): 185-190.
(11) Sinha V, Singh A, Kumar RV, Singh S, Kumria R, Bhinge J. Oral colon-specific drug delivery of protein and peptide drugs. Crit Rev Ther Drug Carrier Syst. 2007;24(1):63-92.
(12) Cecconi D, Donadelli M, Rinalducci S, Zolla L, Scupoli MT, Scarpa A, Palmieri M, Righetti PG. Proteomic analysis of pancreatic endocrine tumor cell lines treated with the histone deacetylase inhibitor trichostatin A. Proteomics. 2007 May; 7(10): 1644-53.
(13 ) Pasqualini R, Arap W ,McDonald DM .Probing the structural and molecular diversity of tumour vasculature. Trends Mol Med, 2002, 8(12): 563-571.
(14) Montet X, Montet-Abou K, Reynolds F, et al. Nanoparticle imaging of integrins on tumor cells. Neoplasia, 2006, 8(3): 214—222.
(15) Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetrationin tumours by vascular targeting and barrier alteration. J Clin Invest, 2002, 110(4): 475-482.
(16) Ran S, Gao B, Duffy S, etal. Infarction of solid Hodgk in's tumors in mice by antibody—directed targeting of tissue factor to tumour vasculature. Cancer Res, 1998, 58(20): 4646—4653.
(17) Gabizon AA. Liposomal anthracyclines. Hematol Oncol Clin North Am. 1994; 8(2):431-50
(18) Nikanjam M,Gibbs AR,Hunt CA,Budinger TF,Forte TM.Synthetic nano-LDL with paclitaxel oleate as a targeted drug delivery vehicle for glioblastoma multiforme.J Control Release.2007;124(3):163-71
(19) Lo Prete AC,Maris DA,Rodrigues DG,et al.Evaluation in melanoma—bearing mice of an etoposide derivative associated to a cholesterolrich nano-emulsion.J Pharm Pharmacol,2006,58(6):801-808.
(20) Luo Y,Chen D,Ren L,et al.Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability.J Control Release,2006,114(1):53-59.
(21) Hamaguchi T,Matusmura Y,Suzuki M,et al.NK105,a paclitaxel—incorporating micellar nanoparticle formulation,can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel.Br J Cancer,2005,92(7):1240-1246.
(22) Shen LF,Zhang YD,Shen HJ,et al.Liver targeting and the delayed drug release of the nanoparticles of adriamycin polybutylcyanoacrylate in mice.Chin Med J,2006,119(15):1287-1293.
(23) Wollina U,Dummer R,Brockmeyer NH,Konrad H,Busch JO,Kaatz M,Knopf B,KochHJ,Hauschild A.Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma.Cancer.2003 Sep 1;98(5):993-1001.
(24) Negishi T,Koizumi F,Uchino H,et al.NK105,a paclitaxel-incorporating micellar nanoparticle,is a more potent radiosensitising agent compared to free paclitaxel.Br J Cancer,2006,95(5):601-606.
(25) Xing J,Zhang D,Tan T.Studies on the oridonin—loaded poly(D,L-lactic acid)nanoparticles in vitro and in vivo.Int J Biol Macromol,2007,40(2):153-158.
(26) 赵慧君,王德平,张娟等..磁性纳米微粒的特性及其在生物医学中的应用[J].同济大学学报(医学版),2003,8(24):4
(27) 张阳德,张洋,潘一峰.磁性纳米颗粒靶向性肿瘤热疗的研究进展[J].中国医学工程,2004,4(14):2
(28) 李静,秦晓民,丁焕平等.磁性纳米微粒分离中药蛋白质的实验研究[J].生物磁性,2005,(5):2
(29) Sarciaux JM,Acar L,Sado PA.Using mciroemulsion formulations for oral drug delivery of therapeutic peptides.J Int J Pharm,1995,120(2):127-136
(30) 张阳德,龚连生.阿霉素白蛋白磁纳米粒在正常肝脏的靶向性[J].中国现代医学杂志,2001,11(3):4-7
(31) 张俊山,陈晓青,蒋新宇等.纳米药物研究进展[J].中国现代医学杂志,2002,12(14):45-48.
(32) 平其能.纳米药物与纳米载体系统[J].中国新药杂志,2002,11(1):43-46
(33) 常津、纳米高分子材料在抗癌药物释控方面的应用[J].中国生物医学工程学报,1996,15(2):7-11
(34) 苏莉,宋宏淘.药物研究中的纳米技术[J].湘南学院学报,2006,10(27):5