膀胱癌用BCG/Fe_3O_4/温敏凝胶集成材料靶向贴壁和缓释功能研究
|
摘要
膀胱肿瘤(tumor of bladder)是泌尿系统中最常见的肿瘤,绝大多数来自上皮组织,其中90%以上为移行上皮肿瘤。在男性中位居第四位,女性中居第十位。肿瘤的扩散主要向膀胱壁内浸润,直至累及膀胱外组织及邻近器官。为防止肿瘤复发,术后可采用膀胱内药物灌注治疗。常用药物有丝裂霉素、阿霉素、羟基喜树碱及卡介苗(bacillus Calmette-Guerin即BCG)等,目前认为BCG效果最好。膀胱癌在灌注治疗过程中通常存在药物作用时间短,严重影响疗效,灌注次数多等问题。本研究拟利用冻干BCG设计一种新的灌注制剂治疗膀胱肿瘤----BCG靶向缓释集成材料。该制剂将药物的靶向贴壁与缓释治疗引入到膀胱肿瘤治疗过程中,使BCG在膀胱内靶区停留时间超过48小时,可在一定程度上有效解决以上问题。
Fe3O4属于尖晶石类铁氧体,其纳米粒子具备优良的超顺磁性。本文制备纳米Fe3O4采用了化学共沉淀法,并采用水浴、微波辐照、水热等方法对Fe3O4进行熟化处理,借助)CRD、TEM、VSM等方法进行测试分析。研究发现采用化学共沉淀法制备纳米Fe3O4时,Fe3+与Fe2+配比为1.75：1时最优,Fe3O4经熟化后其晶粒结晶度有所提高,颗粒尺寸在25nm以下,晶粒尺寸增大；比饱和磁化强度随熟化的温度或时间的延长而增大；纳米Fe3O4的比饱和磁化强度和结晶度经水热熟化处理后较高；纳米Fe3O4经200℃水热处理4h后,Ms可达80.0emu/g;微波辐照后的Fe3O4的Hc、Mr都较小,辐照20min后Fe3O4的Ms、Hc、Mr分别为74.6emu/g、14.5Oe、2.02emu/g。通过数据对比能够发现,化学共沉淀-微波辐照制备的Fe3O4超顺磁性较好。
壳聚糖(CS)是甲壳素的脱乙酰基产物,由于其独特的生物活性、可生物降解性、生物相容性,在工业、农业、医药等领域得到广泛应用。壳聚糖-β-甘油磷酸钠(GP)温敏凝胶具有良好的组织相容性、无毒副作用、在生物体内可降解,使得CS/GP温敏水凝胶广泛应用到药剂学、组织工程等领域。壳聚糖-β-甘油磷酸钠温敏凝胶作为纳米磁性Fe3O4的载体材料,研究确定了其制备工艺参数。在壳聚糖温敏凝胶制备过程中加入纳米Fe3O4微粒,再经干燥粉碎得到Fe3O4/壳聚糖温敏凝胶磁性颗粒。SEM结果显示,由于凝胶粘度较大以及凝胶化过程中的疏水作用,Fe304产生比较严重的团聚,包覆凝胶后的Fe304颗粒粒径明显增大；XRD与IR结果显示,Fe304与凝胶基体并未发生反应；磁性能曲线表明制备的颗粒磁性能下降较大,Ms下降约80%,但颗粒仍然保持了一定的磁响应特性,且随着Fe304的含量的增加,复合颗粒的磁性能相应增大。
采用分光光度计法和四唑鎓盐(XTT钠盐)法进行了BCG浓度的检测方法探究。冻干BCG为白色疏松体或粉末,复溶后为均匀悬液。其主要成份为卡介菌,辅料包括明胶、蔗糖、氯化钾、味精。XTT作为线粒体脱氢酶的作用底物,被活细胞还原成水溶性的橙黄色甲臢产物。当XTT与电子偶合剂(例如PMS)联合应用时,其所产生的水溶性的甲臢产物的吸光度与活细胞的数量成正比。实验结果表明,单纯的采用分光光度计进行BCG浓度检测,不同浓度的BCG溶液没有固定的吸收峰,无法准确的测定BCG的浓度；XTT钠盐由于其水溶性的显色反应能够反映细胞的活力,能够应用于细菌的活力检测。测定的吸光度值与配置的BCG溶液浓度呈现良好的线性比例关系,XTT方法将BCG浓度检测周期缩短为24小时,方法简单易行。
在壳聚糖温敏凝胶制备过程中加入Fe304和BCG,充分搅拌分散均匀,获得载药靶向缓释复合凝胶,将凝胶高速机械粉碎得到BCG/Fe3O4/壳聚糖温敏凝胶磁性颗粒,并配制成灌注缓释液,探究BCG载药磁性复合颗粒的缓释性能。采用XTT法进行BCG缓释液浓度的检测,结果表明缓释液缓释初期在较短的时间内达到一个较高浓度,出现“突释”现象,约12小时后浓度变化逐渐趋于稳定,缓释至48小时仍能保持一定浓度,具有较好的缓释效果。由于其载药量不同,BCG药物包封率随着药物含量的增加呈现先增后降的趋势,药物含量10mg时包封率最高。基于扩散原理对缓释集成颗粒的一级方程缓释模型进行修饰,提出了靶向贴壁缓释集成颗粒的5参数对数缓释模型。对提出的5参数对数模型,以及常用的缓释模型从模拟精度、方差、预测精度等方面进行分析与比较。结果表明,构造的函数模型能准确地反映靶向载药颗粒的缓释性能。
采用同样的方法制备BCG/Fe3O4/壳聚糖温敏凝胶靶向缓释颗粒,进行缓释集成颗粒靶向贴壁实验。首先在漏斗中进行体外贴壁实验,将载药靶向缓释颗粒悬浊液注入锥形漏斗,轻晃摇匀,用铷铁硼强磁体靠近漏斗侧壁,靶向磁性载药颗粒在外磁场的作用下能够聚集到漏斗侧壁上,实现可靠贴壁,漏斗内得澄清溶液；撤掉外磁场,再次轻晃漏斗,载药靶向缓释颗粒在液流作用下全部排出。其次,利用新西兰大白兔动物模型进行载药靶向缓释颗粒膀胱灌注,并通过X光及CT进行检查,可见复合材料在膀胱内部分散成堆聚集,BCG/Fe3O4/壳聚糖温敏凝胶复合颗粒贴壁效果良好。实验组按照每隔24小时处死,观察膀胱内BCG/Fe3O4/壳聚糖温敏凝胶复合颗粒情况。实验结果发现,膀胱贴壁24小时后仍有大量复合材料聚集,48小时后膀胱内材料随尿液排走较多,72小时膀胱内无材料残留。实验结果表明设计人体体外强磁体固定装置,利用强磁场作用,确保载药靶向缓释复合材料在人体膀胱内可靠贴壁,并维持48小时是切实可行和必须的。
Tumor of bladder is the most common tumors of the urinary system, the vast majority of which come from epithelial tissue, and of which more than90%are transitional cell tumors. Tumor of bladder ranks fourth in men and tenth in women. The spread of the cancer heads to the bladder wall until involving the bladder tissue and adjacent organs. According to clinical habits, we refer Tis carcinoma in situ, papillary carcinoma of Ta non-infiltration and the lamina propria tumor of T1infiltration as superficial bladder cancers. General treatment of superficial bladder cancer is endoscopic laser or photodynamic therapy. To prevent the recurrence of tumor, intravesical infusion of drug can be used after treatment. The drugs commonly used are mitomycin, doxorubicin, HCPT, BCG and so on. Now it is generally considered that BCG works best. In infusion therapy process, due to the short duration of action, its efficacy is affect seriously, which result in multiple perfusion. High perfusion number and many other problems often bring patients a great deal of physical suffering and economic burden. Introducing of drug targeting adherent with sustained-release treatment bladder cancer treatment process, this study intends to design a new target sustained release integrated materials with BCG composite by freeze-dried BCG to make the BCG stay in the bladder more than48hours to attain effective solution to the above problem in a certain extent.
Fe3O4belongs spinel ferrite, and its nanoparticles possess excellent superparamagnetic property. Firstly, Fe3O4nanoparticles were prepared by chemical coprecipitation. After aging treatment by heated in water bath, heated by microwave irradiation and hydrothermal, we analysis them with methods such as XRD, TEM, VSM. Using chemical coprecipitation method to prepare Fe3O4, Fe3+and Fe2+best ratio of1.75:1, the degree of crystallinity improve after curing Fe3O4grain, the grain size increases, the particle size of less than25nm; ratio of the saturation magnetization increases with the extension of the temperature or time of ripening; saturation magnetization and the degree of crystallinity of Fe3O4nanoparticles are higher after by hydrothermal aging treatment; after nano Fe3O4heat treatment at200℃water for4hours, Ms up to80.0emu/g. The He and Mr of Fe3O4treated with the microwave irradiation are small. And Ms, Hc, Mr were74.6emu/g,14.5Oe,2.02emu/g which irradiated for20min. Comparative data, we find that they have good superparamagnetic Fe3O4coprecipitation-prepared by microwave irradiation.
Chitosan (CS) is deacetylated product of chitin. Because of its unique biological activity, biodegradability and biocompatibility, it has been widely used in industry, agriculture,medicine,and other fields.Chitosan-β-glycerophosphate(GP) thermosensitive hydrogel has good histocompatibility, non-toxic side effects in vivo biodegradable, which makes CS/GP temperature-sensitive hydrogels be widely applied to pharmacy, tissue engineering, and other fields. We put Chitosan-β-glycerophosphate thermo-sensitive gel as BCG and nano-magnetic ferrite carrier materials. We identified the preparation process parameters by study.90-100mg Chitosan with a deacetylation degree of95%was dissolved in4.5mL O.lmol/L of dilute hydrochloric acid, the400-500mg GP was dissolved in0.5mL of deionized water, and was added dropwise to the CS solution accompanied by stirring constantly. According to the different needs of adjusting the pH value in a37℃water bath, formation of a gel can be controlled within the time. Add the nano Fe3O4particles to the the chitosan in the thermosensitive gel preparation process, then dry and crush to get Fe3O4/chitosan thermosensitive hydrogel magnetic particles. SEM results show that, due to the gel viscosity and the hydrophobic interaction in the gelation process, Fe3O4produce more serious reunion, and the size of Fe3O4particle coated gel significantly increases. XRD and IR results show that Fe3O4didn't react with gel matrix. Magnetic curves showed that the magnetic property of particles decline seriously, and Ms decreases by approximately80%, but the particles are still maintained a certain magnetic response characteristics and magnetic properties of the composite particles can be correspondingly increased with increasing the content of Fe3O4.
Spectrophotometer method and the method of the tetrazolium salt (XTT sodium salt) are used to explore the detection method of BCG concentration. The freeze-dried BCG is white loose body powder, and uniform suspension after reconstituted. Its main components are the BCG, and its excipients include gelatin, sucrose, potassium chloride and monosodium glutamate. As the substrate of mitochondrial dehydrogenase, XTT is restored to the water-soluble orange formazan product by living cells. When XTT combines with the electronic coupling agent (such as PMS), the absorbance of water-soluble formazan product is proportional to the number of living cells. Experimental results show that simply detect BCG concentration by spectrophotometer, BCG solutions with different concentrations don't have fixed absorption peaks. So the concentration of BCG can not be accurately measured. Due to its water-soluble color reaction, XTT sodium salt can reflect the vitality of cells, which can be applied to the vitality of detection of bacteria. The absorbance value and the BCG concentration of the solution showed a good linear proportional relationship. The XTT method will shorten the cycle of the detection of BCG concentration to24hours, which is simple.
Adding Fe3O4and BCG to the chitosan thermosensitive gel in the the process of the preparation, and fully stirring to make the drug-loaded targeted sustained-release composite gel. We obtain BCG/Fe3O4/chitosan thermosensitive gel magnetic particles with high-speed mechanical crushing, and configure to release liquid perfusion. Then we explore the drug release properties of the BCG uploader magnetic composite particles. We take XTT method to detect the concentration of BCG release liquid. The results showed that in the early sustained release phase, a higher concentration can be achieved in a short period of time, and there is the "burst release" phenomenon. The concentration changes gradually stabilized after about12hours. And substantially maintaining a certain concentration to48hours, it has preferably sustained-release effect. Because of different drug loadings, the encapsulation efficiency of BCG drug first increased and then decreased with increasing drug content. When the drug content is10mg, the encapsulation efficiency is highest. Based on the diffusion theory, we modified the first class equation. And we put up with5parameters logarithmic slow-release model of targeted adherent integrated sustained release particles. For the5parameters logarithmic model as well as commonly used slow-release model, we conduct analysis and comparison from the simulation accuracy, variance, and forecast accuracy. The results show that the constructed function model can accurately reflect the release properties of the targeted drug particles.
Using the same method, we prepared of BCG/Fe3O4/chitosan thermosensitive hydrogel target sustained release particles. Firstly, we conduct the vitro adherent experiments in the funnels. Inject the drug target sustained release particles suspension into the cone-shaped funnel, sway and shake. Putting NdFeB strong magnet close to the lateral wall of the funnel, we can find that the targeted magnetic drug-loaded particles can gather adherent to the side wall of the funnel. And there was clear solution in the funnel. After removed the external magnetic field, and shaked the funnel again, the targeted magnetic drug-loaded particles all discharged under the action of the flow. We take New Zealand white rabbits animal models to targeted release granules intravesical instillation, and detect by X-ray and CT. We can find that composite materials gathered in the bladder, and BCG/Fe3O4/chitosan thermosensitive hydrogel composite particles have good adherent effect. Every experimental group were put to death per24hours. Observing the BCG/Fe3O4/chitosan temperature-sensitive gel composite particles in the bladder, we can find that there are still a large number of composite material together after24hours, more material drain away with the urine after48hours, and there isn't residual material in the bladder after72hours. The results show that the design of vitro strong magnet fixtures to ensure that the drug targeted sustained release composite particles in human bladder target adherent and maintain48hours is feasible and necessary.
Fe3O4属于尖晶石类铁氧体,其纳米粒子具备优良的超顺磁性。本文制备纳米Fe3O4采用了化学共沉淀法,并采用水浴、微波辐照、水热等方法对Fe3O4进行熟化处理,借助)CRD、TEM、VSM等方法进行测试分析。研究发现采用化学共沉淀法制备纳米Fe3O4时,Fe3+与Fe2+配比为1.75：1时最优,Fe3O4经熟化后其晶粒结晶度有所提高,颗粒尺寸在25nm以下,晶粒尺寸增大；比饱和磁化强度随熟化的温度或时间的延长而增大；纳米Fe3O4的比饱和磁化强度和结晶度经水热熟化处理后较高；纳米Fe3O4经200℃水热处理4h后,Ms可达80.0emu/g;微波辐照后的Fe3O4的Hc、Mr都较小,辐照20min后Fe3O4的Ms、Hc、Mr分别为74.6emu/g、14.5Oe、2.02emu/g。通过数据对比能够发现,化学共沉淀-微波辐照制备的Fe3O4超顺磁性较好。
壳聚糖(CS)是甲壳素的脱乙酰基产物,由于其独特的生物活性、可生物降解性、生物相容性,在工业、农业、医药等领域得到广泛应用。壳聚糖-β-甘油磷酸钠(GP)温敏凝胶具有良好的组织相容性、无毒副作用、在生物体内可降解,使得CS/GP温敏水凝胶广泛应用到药剂学、组织工程等领域。壳聚糖-β-甘油磷酸钠温敏凝胶作为纳米磁性Fe3O4的载体材料,研究确定了其制备工艺参数。在壳聚糖温敏凝胶制备过程中加入纳米Fe3O4微粒,再经干燥粉碎得到Fe3O4/壳聚糖温敏凝胶磁性颗粒。SEM结果显示,由于凝胶粘度较大以及凝胶化过程中的疏水作用,Fe304产生比较严重的团聚,包覆凝胶后的Fe304颗粒粒径明显增大；XRD与IR结果显示,Fe304与凝胶基体并未发生反应；磁性能曲线表明制备的颗粒磁性能下降较大,Ms下降约80%,但颗粒仍然保持了一定的磁响应特性,且随着Fe304的含量的增加,复合颗粒的磁性能相应增大。
采用分光光度计法和四唑鎓盐(XTT钠盐)法进行了BCG浓度的检测方法探究。冻干BCG为白色疏松体或粉末,复溶后为均匀悬液。其主要成份为卡介菌,辅料包括明胶、蔗糖、氯化钾、味精。XTT作为线粒体脱氢酶的作用底物,被活细胞还原成水溶性的橙黄色甲臢产物。当XTT与电子偶合剂(例如PMS)联合应用时,其所产生的水溶性的甲臢产物的吸光度与活细胞的数量成正比。实验结果表明,单纯的采用分光光度计进行BCG浓度检测,不同浓度的BCG溶液没有固定的吸收峰,无法准确的测定BCG的浓度；XTT钠盐由于其水溶性的显色反应能够反映细胞的活力,能够应用于细菌的活力检测。测定的吸光度值与配置的BCG溶液浓度呈现良好的线性比例关系,XTT方法将BCG浓度检测周期缩短为24小时,方法简单易行。
在壳聚糖温敏凝胶制备过程中加入Fe304和BCG,充分搅拌分散均匀,获得载药靶向缓释复合凝胶,将凝胶高速机械粉碎得到BCG/Fe3O4/壳聚糖温敏凝胶磁性颗粒,并配制成灌注缓释液,探究BCG载药磁性复合颗粒的缓释性能。采用XTT法进行BCG缓释液浓度的检测,结果表明缓释液缓释初期在较短的时间内达到一个较高浓度,出现“突释”现象,约12小时后浓度变化逐渐趋于稳定,缓释至48小时仍能保持一定浓度,具有较好的缓释效果。由于其载药量不同,BCG药物包封率随着药物含量的增加呈现先增后降的趋势,药物含量10mg时包封率最高。基于扩散原理对缓释集成颗粒的一级方程缓释模型进行修饰,提出了靶向贴壁缓释集成颗粒的5参数对数缓释模型。对提出的5参数对数模型,以及常用的缓释模型从模拟精度、方差、预测精度等方面进行分析与比较。结果表明,构造的函数模型能准确地反映靶向载药颗粒的缓释性能。
采用同样的方法制备BCG/Fe3O4/壳聚糖温敏凝胶靶向缓释颗粒,进行缓释集成颗粒靶向贴壁实验。首先在漏斗中进行体外贴壁实验,将载药靶向缓释颗粒悬浊液注入锥形漏斗,轻晃摇匀,用铷铁硼强磁体靠近漏斗侧壁,靶向磁性载药颗粒在外磁场的作用下能够聚集到漏斗侧壁上,实现可靠贴壁,漏斗内得澄清溶液；撤掉外磁场,再次轻晃漏斗,载药靶向缓释颗粒在液流作用下全部排出。其次,利用新西兰大白兔动物模型进行载药靶向缓释颗粒膀胱灌注,并通过X光及CT进行检查,可见复合材料在膀胱内部分散成堆聚集,BCG/Fe3O4/壳聚糖温敏凝胶复合颗粒贴壁效果良好。实验组按照每隔24小时处死,观察膀胱内BCG/Fe3O4/壳聚糖温敏凝胶复合颗粒情况。实验结果发现,膀胱贴壁24小时后仍有大量复合材料聚集,48小时后膀胱内材料随尿液排走较多,72小时膀胱内无材料残留。实验结果表明设计人体体外强磁体固定装置,利用强磁场作用,确保载药靶向缓释复合材料在人体膀胱内可靠贴壁,并维持48小时是切实可行和必须的。
Tumor of bladder is the most common tumors of the urinary system, the vast majority of which come from epithelial tissue, and of which more than90%are transitional cell tumors. Tumor of bladder ranks fourth in men and tenth in women. The spread of the cancer heads to the bladder wall until involving the bladder tissue and adjacent organs. According to clinical habits, we refer Tis carcinoma in situ, papillary carcinoma of Ta non-infiltration and the lamina propria tumor of T1infiltration as superficial bladder cancers. General treatment of superficial bladder cancer is endoscopic laser or photodynamic therapy. To prevent the recurrence of tumor, intravesical infusion of drug can be used after treatment. The drugs commonly used are mitomycin, doxorubicin, HCPT, BCG and so on. Now it is generally considered that BCG works best. In infusion therapy process, due to the short duration of action, its efficacy is affect seriously, which result in multiple perfusion. High perfusion number and many other problems often bring patients a great deal of physical suffering and economic burden. Introducing of drug targeting adherent with sustained-release treatment bladder cancer treatment process, this study intends to design a new target sustained release integrated materials with BCG composite by freeze-dried BCG to make the BCG stay in the bladder more than48hours to attain effective solution to the above problem in a certain extent.
Fe3O4belongs spinel ferrite, and its nanoparticles possess excellent superparamagnetic property. Firstly, Fe3O4nanoparticles were prepared by chemical coprecipitation. After aging treatment by heated in water bath, heated by microwave irradiation and hydrothermal, we analysis them with methods such as XRD, TEM, VSM. Using chemical coprecipitation method to prepare Fe3O4, Fe3+and Fe2+best ratio of1.75:1, the degree of crystallinity improve after curing Fe3O4grain, the grain size increases, the particle size of less than25nm; ratio of the saturation magnetization increases with the extension of the temperature or time of ripening; saturation magnetization and the degree of crystallinity of Fe3O4nanoparticles are higher after by hydrothermal aging treatment; after nano Fe3O4heat treatment at200℃water for4hours, Ms up to80.0emu/g. The He and Mr of Fe3O4treated with the microwave irradiation are small. And Ms, Hc, Mr were74.6emu/g,14.5Oe,2.02emu/g which irradiated for20min. Comparative data, we find that they have good superparamagnetic Fe3O4coprecipitation-prepared by microwave irradiation.
Chitosan (CS) is deacetylated product of chitin. Because of its unique biological activity, biodegradability and biocompatibility, it has been widely used in industry, agriculture,medicine,and other fields.Chitosan-β-glycerophosphate(GP) thermosensitive hydrogel has good histocompatibility, non-toxic side effects in vivo biodegradable, which makes CS/GP temperature-sensitive hydrogels be widely applied to pharmacy, tissue engineering, and other fields. We put Chitosan-β-glycerophosphate thermo-sensitive gel as BCG and nano-magnetic ferrite carrier materials. We identified the preparation process parameters by study.90-100mg Chitosan with a deacetylation degree of95%was dissolved in4.5mL O.lmol/L of dilute hydrochloric acid, the400-500mg GP was dissolved in0.5mL of deionized water, and was added dropwise to the CS solution accompanied by stirring constantly. According to the different needs of adjusting the pH value in a37℃water bath, formation of a gel can be controlled within the time. Add the nano Fe3O4particles to the the chitosan in the thermosensitive gel preparation process, then dry and crush to get Fe3O4/chitosan thermosensitive hydrogel magnetic particles. SEM results show that, due to the gel viscosity and the hydrophobic interaction in the gelation process, Fe3O4produce more serious reunion, and the size of Fe3O4particle coated gel significantly increases. XRD and IR results show that Fe3O4didn't react with gel matrix. Magnetic curves showed that the magnetic property of particles decline seriously, and Ms decreases by approximately80%, but the particles are still maintained a certain magnetic response characteristics and magnetic properties of the composite particles can be correspondingly increased with increasing the content of Fe3O4.
Spectrophotometer method and the method of the tetrazolium salt (XTT sodium salt) are used to explore the detection method of BCG concentration. The freeze-dried BCG is white loose body powder, and uniform suspension after reconstituted. Its main components are the BCG, and its excipients include gelatin, sucrose, potassium chloride and monosodium glutamate. As the substrate of mitochondrial dehydrogenase, XTT is restored to the water-soluble orange formazan product by living cells. When XTT combines with the electronic coupling agent (such as PMS), the absorbance of water-soluble formazan product is proportional to the number of living cells. Experimental results show that simply detect BCG concentration by spectrophotometer, BCG solutions with different concentrations don't have fixed absorption peaks. So the concentration of BCG can not be accurately measured. Due to its water-soluble color reaction, XTT sodium salt can reflect the vitality of cells, which can be applied to the vitality of detection of bacteria. The absorbance value and the BCG concentration of the solution showed a good linear proportional relationship. The XTT method will shorten the cycle of the detection of BCG concentration to24hours, which is simple.
Adding Fe3O4and BCG to the chitosan thermosensitive gel in the the process of the preparation, and fully stirring to make the drug-loaded targeted sustained-release composite gel. We obtain BCG/Fe3O4/chitosan thermosensitive gel magnetic particles with high-speed mechanical crushing, and configure to release liquid perfusion. Then we explore the drug release properties of the BCG uploader magnetic composite particles. We take XTT method to detect the concentration of BCG release liquid. The results showed that in the early sustained release phase, a higher concentration can be achieved in a short period of time, and there is the "burst release" phenomenon. The concentration changes gradually stabilized after about12hours. And substantially maintaining a certain concentration to48hours, it has preferably sustained-release effect. Because of different drug loadings, the encapsulation efficiency of BCG drug first increased and then decreased with increasing drug content. When the drug content is10mg, the encapsulation efficiency is highest. Based on the diffusion theory, we modified the first class equation. And we put up with5parameters logarithmic slow-release model of targeted adherent integrated sustained release particles. For the5parameters logarithmic model as well as commonly used slow-release model, we conduct analysis and comparison from the simulation accuracy, variance, and forecast accuracy. The results show that the constructed function model can accurately reflect the release properties of the targeted drug particles.
Using the same method, we prepared of BCG/Fe3O4/chitosan thermosensitive hydrogel target sustained release particles. Firstly, we conduct the vitro adherent experiments in the funnels. Inject the drug target sustained release particles suspension into the cone-shaped funnel, sway and shake. Putting NdFeB strong magnet close to the lateral wall of the funnel, we can find that the targeted magnetic drug-loaded particles can gather adherent to the side wall of the funnel. And there was clear solution in the funnel. After removed the external magnetic field, and shaked the funnel again, the targeted magnetic drug-loaded particles all discharged under the action of the flow. We take New Zealand white rabbits animal models to targeted release granules intravesical instillation, and detect by X-ray and CT. We can find that composite materials gathered in the bladder, and BCG/Fe3O4/chitosan thermosensitive hydrogel composite particles have good adherent effect. Every experimental group were put to death per24hours. Observing the BCG/Fe3O4/chitosan temperature-sensitive gel composite particles in the bladder, we can find that there are still a large number of composite material together after24hours, more material drain away with the urine after48hours, and there isn't residual material in the bladder after72hours. The results show that the design of vitro strong magnet fixtures to ensure that the drug targeted sustained release composite particles in human bladder target adherent and maintain48hours is feasible and necessary.
引文
1. 孔秋菊,刘广德,李佰玲.膀胱癌术后膀胱灌注联用高频热疗的护理体会[J].河北医科大学学报.2010,31(10).
2. 林文彬.膀胱癌治疗方法的选择[J].当代医学.2012,18(8).
3. 金保庚,李光,向丛明,陈平康,陈葳,沈德炘,赵锡生.22例晚期膀胱癌患者术中放疗随访报告[J].临床泌尿外科杂志.2002,17(6)：p.2.
4. 张鸣,陈朝晖.浸润性膀胱癌的最佳治疗方法[J].临床泌尿外科杂志.2007,22(4)：p.1.
5. 王宇.卡介苗联合化疗药物膀胱灌注预防表浅性膀胱癌TURB-t术后复发及进展的系统评价.2007,四川大学.
6. 赵纪宇,陈立军.膀胱癌免疫治疗研究进展[J].军事医学科学院院刊.2009(04)：p.395-397.
7. 史久华.膀胱癌的卡介苗免疫治疗[J].国外医学.预防.诊断.治疗用生物制品分册.2000(01)：p.7-9.
8. 黄啸,陈一戎,刘国栋.卡介苗激活杀伤细胞抗膀胱肿瘤作用研究[J].中华泌尿外科杂志.1997(11)：p.25-27.
9. 蒋翡翎,单保恩.卡介苗治疗膀胱癌的免疫机制与研究进展[J].中国热带医学.2005(03)：p.640-642.
10. 黄剑辉,陆俊沛.药物运输系统机制的研究进展[J].中国当代医药.2012,v.19；No.285(14)：p.16-17.
11. 郁正艳,金明飞,左翼,卞慧芳,吴自荣.药物传输系统(DDS)的研究现状与发展前景[J].生命的化学.2004(05)：p.428-431.
12. 张钧寿.浅谈药物传输系统研究的几个热点[J].中国新药杂志.1999(03)：p.3-7.
13. 余耀庭.生物医用材料[M].天津：天津大学出版社.2000.
14. 颜耀东.缓释控释制剂的设计与开发[M].北京：中国医药科技出版社.2006.
15. 纪立伟.药物剂型知识系列介绍(2)缓释制剂与控释制剂[J].中国临床医生. 2005,33(6)：p.2.
16. 盘登科.LDH型核壳结构磁性纳米载药粒子的组装及其体外释放性能研究.2010,北京化工大学.
17. 马丽微.pH/温度敏感的水凝胶粒子/微球的制备、表征及其在药物缓释中的应用.2010,兰州大学.
18. 崔启华,崔京浩,张进进.结肠定位释放甘草次酸-羟丙基-β-环糊精包合物包衣片的制备[J].中国中药杂志.2008,33(20)：p.5.
19. 魏农农,陆彬.结肠定位壳聚糖包衣氟尿嘧啶脂质体的制备、形态与体外释放[J].药学学报.2003,38(1)：p.4.
20. 董虹美,王志刚,冉海涛,李攀,钟世根,张辉.超声辐照载10-HCPT微泡在小鼠H22肝癌移植瘤的定位释放研究[J].中国超声医学杂志.2010,26(7).
21. 刘洪英,郑小林,皮喜田,彭承琳,侯文生,刘洋,唐伟,崔建国.消化道定位药物释放技术及其在新药开发中的应用[J].中国药学杂志.2005,40(13)：p.3.
22. 曹文疆,程江,王昶光.纳米靶向给药系统载体材料的研究进展[J].中国组织工程研究与临床康复.2007,No.278(22)：p.4380-4383.
23. Kearney, A.S. Prodrugs and targeted drug delivery[J]. Advanced Drug Delivery Reviews.1996,19(2):p.225-239.
24. Kumar, A.,Zhang, X.,Liang, X.-J. Gold nanoparticles:Emerging paradigm for targeted drug delivery system[J]. Biotechnology Advances. (0).
25. 张景勃,张志荣,谭群友.磁靶向给药系统的研究进展[J].中国医药工业杂志.2001(12)：p.38-41.
26. 武鑫.PSMA靶向的纳米主动靶向给药系统构建及其抗前列腺癌作用研究.2012,第二军医大学.
27. 吴寿荣,程刚.脑靶向给药系统的研究进展[J].中国医药工业杂志.2002(05)：p.41-45.
28. 王兰,杨芳,齐香君.肠道疾病治疗中的口服结肠靶向给药系统[J].中国新药杂志.2003(12)：p.995-998.
29. 莫韫,张钧寿.结肠靶向给药系统研究进展[J].中国新药杂志.1999(06)：p. 10-13.
30. 李超英,蒋学华,侯世祥.淋巴靶向给药系统研究与应用[J].中国新药杂志.2001(12)：p.903-907.
31. 刘朝晖,王栋.脂质体技术及其在生物医学中的应用[J].承德医学院学报.2004,21(2)：p.2.
32. 时念秋,张大同,李树英,刘书庆,张永春,万文珠,陈宇洲.脂质体与新型脂质体在药物传递系统中的应用[J].山东轻工业学院学报(自然科学版).2008,22(1)：p.4.
33. 王浩红,李自成.征服肿瘤的定向导弹--磁性靶向药物简介[J].化学教学.2004(1)：p.3.
34. Freichels, H.Jerome, R.Jerome, C. Sugar-labeled and PEGylated (bio)degradable polymers intended for targeted drug delivery systems[J]. Carbohydrate Polymers.2011,86(3):p.1093-1106.
35. 王蕾.水溶性单壁碳纳米管肿瘤靶向给药系统的构建和热疗研究.2012,郑州大学.
36. 魏赞,李娟,张钧寿.天然药物靶向给药系统的研究[J].药学进展.2005(01)：p.10-15.
37. 陈闪山,朱银华,李伟,刘维佳,李力成,杨祝红,刘畅,姚文俊,陆小华,冯新.含TiO_2(B)介孔氧化钛材料的制备、特性和应用[J].催化学报.201 0,v.3 1(06)：p.605-614.
38. 胡延臣,王彦竹,王思玲.纳米多孔二氧化硅作为药物载体的研究进展[J].沈阳药科大学学报.2010,v.27；No.179(12)：p.961-967.
39. 王艳丽,谈顺,吴秋霞,王佳.二氧化钛纳米管作为肿瘤药物载体系统的体外负载及释放[J].上海大学学报(自然科学版).2010,v.16；No.96(06)：p.582-586+596.
40. Hsieh, B.T.,Ting, G.,Hsieh, H.T.,Shen, L.H. Preparation of carrier-free yttrium-90 for medical applications by solvent extraction chromatography[J]. Applied Radiation and Isotopes.1993,44(12):p.1473-1480.
41. 段康颖,王从容,李琦.新型的药物载体——脂质体[J].中国医院药学杂志.2010,v.30(10)：p.864-866.
42. 李文渊,童丽,热增才旦.纳米胶束作为药物载体的研究进展[J].中国执业药师.2009,v.6(12)：p.36-40.
43. 孙维彤,于莲,苏瑾.改性壳聚糖作为药物载体材料的研究[J].生命的化学.2010,v.30；No.177(06)：p.964-967.
44. 吴承尧,权静,李树白,朱利民.高分子药物载体的应用及研究趋势[J].化学世界.2009,v.50(09)：p.561-563+560.
45. 杨琼,张来新,周立生.高分子药物载体的机理应用及展望[J].化学工程师.2010,v.24；No.181(10)：p.27-30+33.
46. Jain, K.K. Strategies and technologies for drug delivery systems[J]. Trends in Pharmacological Sciences.1998,19(5):p.155-157.
47. Costas Kaparissides, S.A., Katerina Kotti and Sotira Chaitidou. Recent Advances in Novel Drug Delivery Systems[J]. Recent Advances in Novel Drug Delivery Systems.2006,2:p.11-21.
48. 何宇,杨述华.温敏凝胶聚-N-异丙基丙烯酰胺-co-N-羟甲基丙烯酰胺的制备及体内生物相容性评价[J].中国组织工程研究与临床康复.2008,12(1)：p.69-72.
49. 董晓燕,付敏玲,陆晨星,张萌.利用温敏性凝胶的缓释作用促进变性溶菌酶复性[J].天津大学学报.2006,39(10)：p.1193-1198.
50. Gutowska, A.,Bae, Y.H.,Feijen, J.,Kim, S.W. Heparin release from thermosensitive hydrogels[J]. Journal of Controlled Release.1992,22(2):p. 95-104.
51. 邢宝玲,张东生.纳米As203磁性脂质体的制备及表征[J].南京医科大学学报(自然科学版).2005,25(1)：p.6.
52. 贾秀鹏,张东生,郑杰,顾宁,丁安伟,樊祥山,王子妤,邢宝玲,颜士岩.As203磁性纳米微球的研制及表征[J].东南大学学报(自然科学版).2004,34(6)：p.5.
53. 辛胜昌,吴新荣,周丽珍.紫杉醇磁性脂质体纳米粒的制备[J].药学学报. 2006,41(10)：p.6.
54. 林巧平,郭仁平,许向阳,刘春晖.注射用姜黄素脂质体的制备及其质量评价[J].中国天然药物.2007(03)：p.207-210.
55. 吴红兵,霍东风,蒋新国.脂质立方液晶纳米粒作为药物载体的研究进展[J].药学学报.2008,43(5)：p.6.
56. 张琰,汪长春,杨武利,沈锡中,府寿宽.聚合物胶束作为药物载体的研究进展[J].高分子通报.2005(2)：p.5.
57. 孙维彤,黄桂华,叶杰胜,张娜.鱼精蛋白凝聚法测定脂质体和纳米脂质体包封率[J].中国药学杂志.2006(22)：p.1716-1720.
58. 王健,李明轩.冷冻干燥对提高脂质体稳定性的研究概况[J].中国医药工业杂志.2005(09)：p.576-580.
59. 王健松,朱家壁,吕瑞勤,沈伟.肺靶向阿奇霉素脂质体的制备及其在小鼠体内的分布[J].药学学报.2005(03)：p.274-278.
60. 肖超菊,齐宪荣,艾尼瓦尔,魏树礼.顺铂缓释多囊脂质体的制备和体外释放性能研究[J].药学学报.2003(02)：p.133-137.
61. 郭亮,熊向源,李玉萍,李资玲,龚妍春.叶酸修饰聚合物和脂质体药物载体及其靶向治疗的研究现状[J].中国组织工程研究.2012,16(21).
62. 李欣玮,孙立新,林晓宏,郑利强.固体脂质纳米粒作为药物载体[J].化学进展.2007,19(1)：p.6.
63. 蒋挺大.壳聚糖[M].北京：化学工业出版社.2007.
64. 罗华丽,鲁在君.壳聚糖作为药物缓释载体的研究进展[J].高分子通报.2006(07).
65. 罗华丽,鲁在君.壳聚糖作为药物载体的缓释机理的研究进展[J].天中学刊.2006(02).
66. 马志伟,张勇杰,吴织芬,王荣,朱浩,李媛,许杰,刘青.缓释骨形态发生蛋白-2的壳聚糖温敏凝胶促进牙周组织再生的实验研究[J].华西口腔医学杂志.2008,26(1)：p.23-26.
67. 马志伟,王荣,吴织芬,陈栋,张邦乐,何炜,王晓娟,王勤涛,周威,刘青,董广英.壳 聚糖温敏凝胶共混环糊精缓释氯己定的体外实验[J].中国组织工程研究与临床康复,2007(18).
68. Du, Y.-Z.,Ying, X.-Y.,Wang, L.,Zhai, Y.,Yuan, H.,Yu, R.-S.,Hu, F.-Q. Sustained release of ATP encapsulated in chitosan oligosaccharide nanoparticles[J]. International Journal of Pharmaceutics.2010,392(1-2):p.164-169.
69. 朱雪燕,陈明清,刘晓亚,倪忠斌,杨成.温敏性凝胶的合成与药物缓释模拟[J].江南大学学报(自然科学版).2002(02).
70. 赵凯,孙庆申,李国新,金媛媛,魏海霞,童光志,周东坡.伊维菌素缓释微球片剂的体外释放评价[J].高分子通报.2008(05).
71. 姜玲海,冯怡,沈岚,徐德生.温敏凝胶释药模式及机制研究进展[J].中国中药杂志.2008(01)：p.105-107.
72. 常翠,杨宏图,董淳,毕殿洲.缓释控释制剂的释放度测定方法的研究进展[J].广东药学.2003(02).
73. 陈红丽,唐红波,杨文智,陈汉,王银松,梅林,张彤,熊青青,张其清.生物素化壳聚糖修饰的PLGA纳米粒的制备及表征[J].高等学校化学学报.2010,31(8).
74. Lee, S.J.,Park, K.,Oh, Y.-K.,Kwon, S.-H.,Her, S.,Kim, I.-S.,Choi, K.,Lee, S.J.,Kim, H.,Lee, S.G.,Kim, K.,Kwon, I.C. Tumor specificity and therapeutic efficacy of photosensitizer-encapsulated glycol chitosan-based nanoparticles in tumor-bearing mice[J]. Biomaterials.2009,30(15):p.2929-2939.
75. Nanaki, S.G,Koutsidis, I.A.,Koutri, I.,Karavas, E.,Bikiaris, D. Miscibility study of chitosan/2-hydroxyethyl starch blends and evaluation of their effectiveness as drug sustained release hydrogels[J]. Carbohydrate Polymers.2012,87(2):p. 1286-1294.
76. 金鑫,张阳德,王吉伟,张丽华,杨璞,张旭,胡玉,于丽.荧光标记的叶酸修饰壳聚糖纳米载体研制[J].中南大学学报(自然科学版).2010,41(1).
77. 余慧,梁淑彩,钟海迪,付婷,鄢国平.新型壳聚糖荧光纳米粒的制备及pH敏感性能研究[J].分析化学.2011,39(3).
78. 李和平,肖华伍,肖子丹,阮建明.磁性壳聚糖-5-氟尿嘧啶纳米粒的制备及体 外释药性能[J].高分子材料科学与工程.2007,23(1)：p.4.
79. 应晓英,胡富强,袁弘.胰岛素壳聚糖纳米粒的制备[J].中国药学杂志.2003,38(12)：p.4.
80. 袁弘,胡富强,应晓英,韩钢.胰岛素纳米粒的制备[J].中国药学杂志.2002,37(5)：p.4.
81. 蒋海明,夏金兰,聂珍媛.壳聚糖基复合控释膜的制备及其渗透性能[J].中南大学学报(自然科学版).2006,37(1)：p.5.
82. 董陈,徐靖宏,蔡镭,胡巧玲,林军.可吸收复合壳聚糖引导药膜的研究[J].稀有金属材料与工程.2008,37(z2)：p.4.
83. 陈莉,李世庚,肖飞,张爱华,姚康德.温敏性壳聚糖共聚膜的制备与细胞吸附/脱附行为[J].高等学校化学学报.2008,29(5)：p.4.
84. 吴燕,曲波,赵瑾,邝清林,成国祥.温敏性壳聚糖/甘油磷酸盐配合物凝胶的研究[J].功能材料.2004,35(z1)：p.3.
85. 马志伟,张勇杰,吴织芬,王荣,朱浩,李媛,许杰,刘青.缓释骨形态发生蛋白-2的壳聚糖温敏凝胶促进牙周组织再生的实验研究[J].华西口腔医学杂志.2008,26(1)：p.4.
86. 张杰,褚良银,张诗博,陈文梅,王海东,巨晓洁.可生物降解温度/pH双重感应型壳聚糖凝胶载体的制备和性能研究[J].四川大学学报(工程科学版).2006,38(1)：p.5.
87. 唐金春,黄可龙,于金刚,刘素琴.壳聚糖-碳纳米管/壳聚糖半互穿网络水凝胶的机械性能及pH敏感性[J].化学学报.2008,66(5)：p.4.
88. 谭学才,翟海云,李荫,邹小勇,蔡沛祥.基于溶胶-凝壳聚糖/Si02杂化材料的安培型葡萄糖生物传感器[J].高等学校化学学报.2004,25(9)：p.3.
89. 郭英,李酽,吴瑶,杨琨,刘雪燕.超声波辅助水热合成条件对Fe_30_4纳米微粒生长及磁性的影响[J].天津师范大学学报(自然科学版).2007(02).
90. 黄小忠,申小海,冯春祥.磁性涂层碳化硅纤维的电磁特性研究[J].磁性材料及器件.2007(04).
91. 颜旭,李世梁,韩相华,王建波,薛德胜.钴铁氧体复合纳米颗粒的制备及其磁 性[J].兰州大学学报(自然科学版).2006(01).
92. 赵义恒,陈福厚,张药西.铁氧体磁性元件的稳定性问题[J].电子元器件应用.2007(03).
93. 陈辉,方庆清,李雁,黄凯,杨景景,王翠平.钴铁氧体Co_xFe_(3-x)O_4结构和磁性研究[J].安徽大学学报(自然科学版).2007(04).
94. 丁清.两种药物控释载体的体外释药性能[J].中国组织工程研究与临床康复.2008(32).
95. 刘利萍,李苹,吴泽志,蔡绍皙.5-Fu壳聚糖/丝素复合磁微球的制备及体外性质研究[J].中国药学杂志.2003(10).
96. 周永国,杨越冬,郭学民,齐印阁,白继海.磁性壳聚糖微球的制备、表征及其靶向给药研究[J].应用化学.2002(12).
97. 赵大庆,高明.磁性壳聚糖微球的释药和靶向研究[J].中国新药杂志.2006(09)：p.698-701.
98. Grasso, M. Bladder Cancer:A Major Public Health Issue[J]. European Urology Supplements.2008,7(7):p.510-515.
99. Phull, J.S.Jefferies, E.R.,Bates, T.S.Issa, R.,McFarlane, J.P.,Howell, G.P.,Gallegos, C.R.,Persad, R.A. Modern transurethral resection in the management of superficial bladder tumours[J]. British Journal of Medical and Surgical Urology.2011,4(3):p.91-100.
100. Grimm, M.-O.,Steinhoff, C.,Simon, X.,Spiegelhalder, P.,Ackermann, R.,VOGeli, T.A. Effect of Routine Repeat Transurethral Resection for Superficial Bladder Cancer:A Long-term Observational Study[J]. The Journal of Urology.2003, 170(2, Part 1):p.433-437.
101. Gudjonsson, S.,Adell, L.,Merdasa, F.,Olsson, R.,Larsson, B.,Davidsson, T.,Richthoff, J.,Hagberg, G,Grabe, M.,Bendahl, P.O.,Mansson, W.,Liedberg, F. Should All Patients with Non-Muscle-Invasive Bladder Cancer Receive Early Intravesical Chemotherapy after Transurethral Resection? The Results of a Prospective Randomised Multicentre Study[J]. European Urology.2009,55(4): p.773-780.
102. Miladi, M.,Peyromaure, M.,Zerbib, M.,Sai□ghi, D.,Debre, B. The Value of a Second Transurethral Resection in Evaluating Patients with Bladder Tumours[J]. European Urology.2003,43(3):p.241-245.
103. Ritch, C.R.,Clark, P.E.,Morgan, T.M. Restaging Transurethral Resection for Nonmuscle-Invasive Bladder Cancer:Who, Why, When, and How?[J]. Urologic Clinics of North America. (0).
104. Solsona, E.,Iborra, I.,Collado, A.,Rubio-Briones, J.,Casanova, J.,Calatrava, A. Feasibility of Radical Transurethral Resection as Monotherapy for Selected Patients With Muscle Invasive Bladder Cancer[J]. The Journal of Urology.2010, 184(2):p.475-481.
105. Donat, S.M.,Bayuga, S.,Herr, H.W.,Berwick, M. Fluid Intake and the Risk of Tumor Recurrence in Patients With Superficial Bladder Cancer[J]. The Journal of Urology.2003,170(5):p.1777-1780.
106. van der Heijden, A.G.,Witjes, J.A. Recurrence, Progression, and Follow-Up in Non-Muscle-Invasive Bladder Cancer[J]. European Urology Supplements.2009, 8(7):p.556-562.
107. Schultz, I.J.,Witjes, J.A.,Swinkels, D.W.,de Kok, J.B. Bladder cancer diagnosis and recurrence prognosis:Comparison of markers with emphasis on survivin[J]. Clinica Chimica Acta 2006,368(1-2):p.20-32.
108. Behnsawy, H.M.,Miyake, H.,Abdalla, M.A.,Sayed, M.A.,Ahmed, A.E.-F.I.,Fujisawa, M. Expression of cell cycle-associated proteins in non-muscle-invasive bladder cancer:Correlation with intravesical recurrence following transurethral resection[J]. Urologic Oncology:Seminars and Original Investigations.2011,29(5):p.495-501.
109. 马旭东,王全好.浅表膀胱癌的治疗现状[J].广东医学.2008,29(6)：p.1055-1056.
110. Sylvester, R.J.,van der Meijden, A.P.M.,Lamm, D.L. Intravesical Bacillus Calmette-Guerin Reduces the Risk of Progression in Patients with Superficial Bladder Cancer:A Meta-analysis of the Published Results of Randomized Clinical Trials[J]. The Journal of Urology.2002,168(5):p.1964-1970.
111. Urdaneta, G,Solsona, E.,Palou, J. Intravesical Chemotherapy and BCG for the Treatment of Bladder Cancer:Evidence and Opinion[J]. European Urology Supplements.2008,7(7):p.542-547.
112. Mohanty, N.K.,Nayak, R.L.,Vasudeva, P.,Arora, R.P. Intravesicle gemcitabine in management of BCG refractory superficial TCC of urinary bladder—our experience[J]. Urologic Oncology:Seminars and Original Investigations.2008, 26(6):p.616-619.
113. 刘嘉琳,林萍萍,周炳娟,刘书哲,吴艳萍,张颖,高伟敏,薛娟.卡介苗联合药物缓释剂在抗肿瘤方面的初步研究[J].河北职工医学院学报.2007(03)：p.3-5.
114. Morales, A.,Eidinger, D.,Bruce, A.W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors[J]. The Journal of Urology.1976, 116(2):p.180-3.
115. 刘昊,王志华.浅表性膀胱癌的灌注治疗[J].肿瘤研究与临床.2006,18(12)：p.854-856.
116. 黄多斌.卡介苗膀胱灌注预防膀胱癌复发效果分析[J].中国热带医学.2007(06)：p.952+957.
117. 刘文平,白永韬,刘永连.表柔比星联合卡介苗膀胱灌注预防膀胱癌术后复发的疗效分析[J].医学信息(中旬刊).2010(12)：p.3706-3707.
118. 马顺利.膀胱癌术后灌注化疗药物预防复发82例分析[J].中国误诊学杂志.2008(10)：p.2419-2420.
119. 葛宏,葛长龙,李忠善,李英民.5种灌注药物预防膀胱癌术后复发的疗效观察[J].中国医药导报.2008(02).
120. 黄多斌.卡介苗膀胱灌注预防膀胱癌复发效果分析[J].中国热带医学.2007(06).
121. 李毅,林成楚,汪志伟.吡柔比星及卡介苗膀胱灌注预防膀胱癌术后复发的临 床观察[J].海峡药学.2008(03).
122. 吴渭贤,朱希松,孔宏伟.膀胱癌术后联合采用介入治疗和膀胱灌注预防肿瘤复发和转移的临床应用价值探讨[J].中国中西医结合急救杂志.2008(04).
123. 张怀强,周春文,马天加,王绍勇,葛南.不同剂量卡介苗膀胱灌注预防浅表性膀胱癌复发的效果[J].山东大学学报(医学版).2008(05).
124. 葛宏,葛长龙,李忠善,李英民.5种灌注药物预防膀胱癌术后复发的疗效观察[J].中国医药导报.2008(02)：p.78-79.
125. Highshaw, R.A.,Tanaka, S.T.,Evans, C.P.,deVere White, R.W. Is bladder biopsy necessary at three or six months post BCG therapy?[J]. Urologic Oncology: Seminars and Original Investigations.2003,21(3):p.207-209.
126. Bassi, P.,Milani, C.,Meneghini, A.,Garbeglio, A.,Aragona, F.,Zattoni, F.,Palma, P.D.,Rebuffi, A.,Pagano, F. Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer[J]. Urology.1992,40(2): p.175-179.
127. Kamat, M.R.,Kulkarni, J.N.,Tongaonkar, H.B.,Dalai, A.V. Intravesical bacillus Calmette-Guerin for superficial bladder cancer:experience with Danish 1331 strain[J]. The Journal of Urology.1994,152(5 Pt 1):p.1424-8.
128. ElsASser-Beile, U.,Gutzeit, O.,Bauer, S.,Katzenwadel, A.,Schultze-Seemann, W.,Wetterauer, U. Systemic and Local Immunomodulatory Effects of Intravesical BCG Therapy in Patients with Superficial Urinary Bladder Carcinomas[J]. The Journal of Urology.2000,163(1):p.296-299.
129. Davis, J.W.,Sheth, S.I.,Doviak, M.J.,Schellhammer, P.F. Superficial bladder carcinoma treated with bacillus Calmette-Guerin:Progression-free and disease specific survival with minimum 10-year follow-up[J]. Journal of Urology.2002, 167(2):p.494-500.
130. Siracusano, S.,Vita, F.,Abbate, R.,Ciciliato, S.,Borelli, V.,Bernabei, M.,Zabucchi, G. The Role of Granulocytes Following Intravesical BCG Prophylaxis[J]. European Urology.2007,51(6):p.1589-1599.
131. Simons, M.P.,O'Donnell, M.A.,Griffith, T.S. Role of neutrophils in BCG immunotherapy for bladder cancer[J]. Urologic Oncology:Seminars and Original Investigations.2008,26(4):p.341-345.
132. O'Donnell, M.A. Optimizing BCG therapy[J]. Urologic Oncology:Seminars and Original Investigations.2009,27(3):p.325-328.
133. Pan, H.,Ma, X.,Chen, J.Jiang, H. PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer?[J]. Medical Hypotheses.2009,73(4):p.559-560.
134. Gilmore, P.E.,Henderson, K.,Kutarski, P.W.,Stephenson, R.N.,Parr, N.J. A pilot study of the tolerability of two BCG maintenance regimens in the treatment of high risk superficial bladder cancer[J]. British Journal of Medical and Surgical Urology.2010,3(6):p.231-236.
135. Wilson, J.R.F.,Turney, B.W.,LeMonnier, K.,Crew, J.P. A comparison of two BCG instillation regimens for non-muscle invasive bladder cancer:A retrospective cohort analysis of side effect profiles[J]. British Journal of Medical and Surgical Urology.2010,3(6):p.241-248.
136. Bunimovich-Mendrazitsky, S.,Claude Gluckman, J.,Chaskalovic, J. A mathematical model of combined bacillus Calmette-Guerin (BCG) and interleukin (IL)-2 immunotherapy of superficial bladder cancer[J]. Journal of Theoretical Biology.2011,277(1):p.27-40.
137. Herr, H.W.,Dalbagni, G.,Donat, S.M. Bacillus Calmette-Guerin Without Maintenance Therapy for High-Risk Non-Muscle-Invasive Bladder Cancer [J]. European Urology.2011,60(1):p.32-36.
138. Tanaka, N.,Kikuchi, E.,Matsumoto, K.,Miyajima, A.,Nakagawa, K.,Oya, M. Frequency of Tumor Recurrence:A Strong Predictor of Stage Progression in Initially Diagnosed Nonmuscle Invasive Bladder Cancer[J]. The Journal of Urology.2011,185(2):p.450-455.
139. Zuiverloon, T.C.M.,Nieuweboer, A.J.M.,Vekony, H.,Kirkels, W.J.,Bangma, C.H.,Zwarthoff, E.C. Markers Predicting Response to Bacillus Calmette-Guerin Immunotherapy in High-Risk Bladder Cancer Patients:A Systematic Review[J]. European Urology.2012,61(1):p.128-145.
140. 何运兵.磁性靶向药物载体Fe_3O_4的制备及性能研究.2006,南昌大学.
141.王丽艳.纳米四氧化三铁制备的研究进展[J].科技资讯.2009(27)：p.3.
142. 刘爱红,孙康宁,李爱民.肿瘤热疗用CNTs/Fe_3O_4热种子复合材料的制备及表征[J].化工新型材料.2010(11)：p.43-45.
143. 海岩冰,袁红雁,肖丹.微波法制备纳米Fe_30_4[J].化学研究与应用.2006(06)：p.744-746.
144. 宁青菊.无机材料物理性能[M].北京：化学工业出版社.2010.
145. Hong, R.,Li, J.,Wang, J.,Li, H. Comparison of schemes for preparing magnetic Fe3O4 nanoparticles[J]. China Particuology.2007,5(1-2):p.186-191.
146. 张玉坤,罗聪,朱朝敏.超顺磁性Fe_30_4纳米粒的制备及其对小鼠的急性毒性作用[J].第三军医大学学报.2011(12)：p.1224-1227.
147. 赵爱华,贾淑珍,寇丽杰,乔来艳,王国治.应用四唑鎓盐法快速检测卡介苗活菌含量[J].中国医药生物技术.2009(01)：p.33-36.
148. 杨菊林,周长忍,田冶,田金环.壳聚糖/羟基磷灰石膜的制备及对细胞生长的影响[J].生物医学工程学杂志.2009(03)：p.580-584.
149. 张瑞,韩宝三,彭承宏.壳聚糖球形多孔微载体支持下人肝细胞L-02的高浓度细胞培养[J].中国组织工程研究与临床康复.2011(12)：p.2161-2165.
150. 陈力,刘砚韬,黄亮,张伶俐.缓控释系统药物释放的数学模型研究进展[J].中国药业.2008,17(11)：p.4.
151. 张丽杰,赵天涛,赵由才,石晓鸿.复合基质中乙炔缓释的扩散模型与工艺优化[J].化工学报.2010,61(5).
152. 齐凤林,李淑萍,张晓晴.甲氨蝶呤/层状双金属氢氧化物的粒径调控及缓释性能研究[J].化学学报.2012,70(20)：p.7.
153. 刘思峰.灰色系统理论及其应用(第五版)[M].北京：科学出版社.2010.
154. 连捷,张凯.基于AIC方法的切换神经网络模型设计[J].大连理工大学学报. 2011(06)：p.890-895.
155. 宋喜芳,李建平,胡希远.模型选择信息量准则AIC及其在方差分析中的应用[J].西北农林科技大学学报(自然科学版).2009(02)：p.88-92.
156. 周芳坚.膀胱癌[M].广州：广东科技出版社.2008.
2. 林文彬.膀胱癌治疗方法的选择[J].当代医学.2012,18(8).
3. 金保庚,李光,向丛明,陈平康,陈葳,沈德炘,赵锡生.22例晚期膀胱癌患者术中放疗随访报告[J].临床泌尿外科杂志.2002,17(6)：p.2.
4. 张鸣,陈朝晖.浸润性膀胱癌的最佳治疗方法[J].临床泌尿外科杂志.2007,22(4)：p.1.
5. 王宇.卡介苗联合化疗药物膀胱灌注预防表浅性膀胱癌TURB-t术后复发及进展的系统评价.2007,四川大学.
6. 赵纪宇,陈立军.膀胱癌免疫治疗研究进展[J].军事医学科学院院刊.2009(04)：p.395-397.
7. 史久华.膀胱癌的卡介苗免疫治疗[J].国外医学.预防.诊断.治疗用生物制品分册.2000(01)：p.7-9.
8. 黄啸,陈一戎,刘国栋.卡介苗激活杀伤细胞抗膀胱肿瘤作用研究[J].中华泌尿外科杂志.1997(11)：p.25-27.
9. 蒋翡翎,单保恩.卡介苗治疗膀胱癌的免疫机制与研究进展[J].中国热带医学.2005(03)：p.640-642.
10. 黄剑辉,陆俊沛.药物运输系统机制的研究进展[J].中国当代医药.2012,v.19；No.285(14)：p.16-17.
11. 郁正艳,金明飞,左翼,卞慧芳,吴自荣.药物传输系统(DDS)的研究现状与发展前景[J].生命的化学.2004(05)：p.428-431.
12. 张钧寿.浅谈药物传输系统研究的几个热点[J].中国新药杂志.1999(03)：p.3-7.
13. 余耀庭.生物医用材料[M].天津：天津大学出版社.2000.
14. 颜耀东.缓释控释制剂的设计与开发[M].北京：中国医药科技出版社.2006.
15. 纪立伟.药物剂型知识系列介绍(2)缓释制剂与控释制剂[J].中国临床医生. 2005,33(6)：p.2.
16. 盘登科.LDH型核壳结构磁性纳米载药粒子的组装及其体外释放性能研究.2010,北京化工大学.
17. 马丽微.pH/温度敏感的水凝胶粒子/微球的制备、表征及其在药物缓释中的应用.2010,兰州大学.
18. 崔启华,崔京浩,张进进.结肠定位释放甘草次酸-羟丙基-β-环糊精包合物包衣片的制备[J].中国中药杂志.2008,33(20)：p.5.
19. 魏农农,陆彬.结肠定位壳聚糖包衣氟尿嘧啶脂质体的制备、形态与体外释放[J].药学学报.2003,38(1)：p.4.
20. 董虹美,王志刚,冉海涛,李攀,钟世根,张辉.超声辐照载10-HCPT微泡在小鼠H22肝癌移植瘤的定位释放研究[J].中国超声医学杂志.2010,26(7).
21. 刘洪英,郑小林,皮喜田,彭承琳,侯文生,刘洋,唐伟,崔建国.消化道定位药物释放技术及其在新药开发中的应用[J].中国药学杂志.2005,40(13)：p.3.
22. 曹文疆,程江,王昶光.纳米靶向给药系统载体材料的研究进展[J].中国组织工程研究与临床康复.2007,No.278(22)：p.4380-4383.
23. Kearney, A.S. Prodrugs and targeted drug delivery[J]. Advanced Drug Delivery Reviews.1996,19(2):p.225-239.
24. Kumar, A.,Zhang, X.,Liang, X.-J. Gold nanoparticles:Emerging paradigm for targeted drug delivery system[J]. Biotechnology Advances. (0).
25. 张景勃,张志荣,谭群友.磁靶向给药系统的研究进展[J].中国医药工业杂志.2001(12)：p.38-41.
26. 武鑫.PSMA靶向的纳米主动靶向给药系统构建及其抗前列腺癌作用研究.2012,第二军医大学.
27. 吴寿荣,程刚.脑靶向给药系统的研究进展[J].中国医药工业杂志.2002(05)：p.41-45.
28. 王兰,杨芳,齐香君.肠道疾病治疗中的口服结肠靶向给药系统[J].中国新药杂志.2003(12)：p.995-998.
29. 莫韫,张钧寿.结肠靶向给药系统研究进展[J].中国新药杂志.1999(06)：p. 10-13.
30. 李超英,蒋学华,侯世祥.淋巴靶向给药系统研究与应用[J].中国新药杂志.2001(12)：p.903-907.
31. 刘朝晖,王栋.脂质体技术及其在生物医学中的应用[J].承德医学院学报.2004,21(2)：p.2.
32. 时念秋,张大同,李树英,刘书庆,张永春,万文珠,陈宇洲.脂质体与新型脂质体在药物传递系统中的应用[J].山东轻工业学院学报(自然科学版).2008,22(1)：p.4.
33. 王浩红,李自成.征服肿瘤的定向导弹--磁性靶向药物简介[J].化学教学.2004(1)：p.3.
34. Freichels, H.Jerome, R.Jerome, C. Sugar-labeled and PEGylated (bio)degradable polymers intended for targeted drug delivery systems[J]. Carbohydrate Polymers.2011,86(3):p.1093-1106.
35. 王蕾.水溶性单壁碳纳米管肿瘤靶向给药系统的构建和热疗研究.2012,郑州大学.
36. 魏赞,李娟,张钧寿.天然药物靶向给药系统的研究[J].药学进展.2005(01)：p.10-15.
37. 陈闪山,朱银华,李伟,刘维佳,李力成,杨祝红,刘畅,姚文俊,陆小华,冯新.含TiO_2(B)介孔氧化钛材料的制备、特性和应用[J].催化学报.201 0,v.3 1(06)：p.605-614.
38. 胡延臣,王彦竹,王思玲.纳米多孔二氧化硅作为药物载体的研究进展[J].沈阳药科大学学报.2010,v.27；No.179(12)：p.961-967.
39. 王艳丽,谈顺,吴秋霞,王佳.二氧化钛纳米管作为肿瘤药物载体系统的体外负载及释放[J].上海大学学报(自然科学版).2010,v.16；No.96(06)：p.582-586+596.
40. Hsieh, B.T.,Ting, G.,Hsieh, H.T.,Shen, L.H. Preparation of carrier-free yttrium-90 for medical applications by solvent extraction chromatography[J]. Applied Radiation and Isotopes.1993,44(12):p.1473-1480.
41. 段康颖,王从容,李琦.新型的药物载体——脂质体[J].中国医院药学杂志.2010,v.30(10)：p.864-866.
42. 李文渊,童丽,热增才旦.纳米胶束作为药物载体的研究进展[J].中国执业药师.2009,v.6(12)：p.36-40.
43. 孙维彤,于莲,苏瑾.改性壳聚糖作为药物载体材料的研究[J].生命的化学.2010,v.30；No.177(06)：p.964-967.
44. 吴承尧,权静,李树白,朱利民.高分子药物载体的应用及研究趋势[J].化学世界.2009,v.50(09)：p.561-563+560.
45. 杨琼,张来新,周立生.高分子药物载体的机理应用及展望[J].化学工程师.2010,v.24；No.181(10)：p.27-30+33.
46. Jain, K.K. Strategies and technologies for drug delivery systems[J]. Trends in Pharmacological Sciences.1998,19(5):p.155-157.
47. Costas Kaparissides, S.A., Katerina Kotti and Sotira Chaitidou. Recent Advances in Novel Drug Delivery Systems[J]. Recent Advances in Novel Drug Delivery Systems.2006,2:p.11-21.
48. 何宇,杨述华.温敏凝胶聚-N-异丙基丙烯酰胺-co-N-羟甲基丙烯酰胺的制备及体内生物相容性评价[J].中国组织工程研究与临床康复.2008,12(1)：p.69-72.
49. 董晓燕,付敏玲,陆晨星,张萌.利用温敏性凝胶的缓释作用促进变性溶菌酶复性[J].天津大学学报.2006,39(10)：p.1193-1198.
50. Gutowska, A.,Bae, Y.H.,Feijen, J.,Kim, S.W. Heparin release from thermosensitive hydrogels[J]. Journal of Controlled Release.1992,22(2):p. 95-104.
51. 邢宝玲,张东生.纳米As203磁性脂质体的制备及表征[J].南京医科大学学报(自然科学版).2005,25(1)：p.6.
52. 贾秀鹏,张东生,郑杰,顾宁,丁安伟,樊祥山,王子妤,邢宝玲,颜士岩.As203磁性纳米微球的研制及表征[J].东南大学学报(自然科学版).2004,34(6)：p.5.
53. 辛胜昌,吴新荣,周丽珍.紫杉醇磁性脂质体纳米粒的制备[J].药学学报. 2006,41(10)：p.6.
54. 林巧平,郭仁平,许向阳,刘春晖.注射用姜黄素脂质体的制备及其质量评价[J].中国天然药物.2007(03)：p.207-210.
55. 吴红兵,霍东风,蒋新国.脂质立方液晶纳米粒作为药物载体的研究进展[J].药学学报.2008,43(5)：p.6.
56. 张琰,汪长春,杨武利,沈锡中,府寿宽.聚合物胶束作为药物载体的研究进展[J].高分子通报.2005(2)：p.5.
57. 孙维彤,黄桂华,叶杰胜,张娜.鱼精蛋白凝聚法测定脂质体和纳米脂质体包封率[J].中国药学杂志.2006(22)：p.1716-1720.
58. 王健,李明轩.冷冻干燥对提高脂质体稳定性的研究概况[J].中国医药工业杂志.2005(09)：p.576-580.
59. 王健松,朱家壁,吕瑞勤,沈伟.肺靶向阿奇霉素脂质体的制备及其在小鼠体内的分布[J].药学学报.2005(03)：p.274-278.
60. 肖超菊,齐宪荣,艾尼瓦尔,魏树礼.顺铂缓释多囊脂质体的制备和体外释放性能研究[J].药学学报.2003(02)：p.133-137.
61. 郭亮,熊向源,李玉萍,李资玲,龚妍春.叶酸修饰聚合物和脂质体药物载体及其靶向治疗的研究现状[J].中国组织工程研究.2012,16(21).
62. 李欣玮,孙立新,林晓宏,郑利强.固体脂质纳米粒作为药物载体[J].化学进展.2007,19(1)：p.6.
63. 蒋挺大.壳聚糖[M].北京：化学工业出版社.2007.
64. 罗华丽,鲁在君.壳聚糖作为药物缓释载体的研究进展[J].高分子通报.2006(07).
65. 罗华丽,鲁在君.壳聚糖作为药物载体的缓释机理的研究进展[J].天中学刊.2006(02).
66. 马志伟,张勇杰,吴织芬,王荣,朱浩,李媛,许杰,刘青.缓释骨形态发生蛋白-2的壳聚糖温敏凝胶促进牙周组织再生的实验研究[J].华西口腔医学杂志.2008,26(1)：p.23-26.
67. 马志伟,王荣,吴织芬,陈栋,张邦乐,何炜,王晓娟,王勤涛,周威,刘青,董广英.壳 聚糖温敏凝胶共混环糊精缓释氯己定的体外实验[J].中国组织工程研究与临床康复,2007(18).
68. Du, Y.-Z.,Ying, X.-Y.,Wang, L.,Zhai, Y.,Yuan, H.,Yu, R.-S.,Hu, F.-Q. Sustained release of ATP encapsulated in chitosan oligosaccharide nanoparticles[J]. International Journal of Pharmaceutics.2010,392(1-2):p.164-169.
69. 朱雪燕,陈明清,刘晓亚,倪忠斌,杨成.温敏性凝胶的合成与药物缓释模拟[J].江南大学学报(自然科学版).2002(02).
70. 赵凯,孙庆申,李国新,金媛媛,魏海霞,童光志,周东坡.伊维菌素缓释微球片剂的体外释放评价[J].高分子通报.2008(05).
71. 姜玲海,冯怡,沈岚,徐德生.温敏凝胶释药模式及机制研究进展[J].中国中药杂志.2008(01)：p.105-107.
72. 常翠,杨宏图,董淳,毕殿洲.缓释控释制剂的释放度测定方法的研究进展[J].广东药学.2003(02).
73. 陈红丽,唐红波,杨文智,陈汉,王银松,梅林,张彤,熊青青,张其清.生物素化壳聚糖修饰的PLGA纳米粒的制备及表征[J].高等学校化学学报.2010,31(8).
74. Lee, S.J.,Park, K.,Oh, Y.-K.,Kwon, S.-H.,Her, S.,Kim, I.-S.,Choi, K.,Lee, S.J.,Kim, H.,Lee, S.G.,Kim, K.,Kwon, I.C. Tumor specificity and therapeutic efficacy of photosensitizer-encapsulated glycol chitosan-based nanoparticles in tumor-bearing mice[J]. Biomaterials.2009,30(15):p.2929-2939.
75. Nanaki, S.G,Koutsidis, I.A.,Koutri, I.,Karavas, E.,Bikiaris, D. Miscibility study of chitosan/2-hydroxyethyl starch blends and evaluation of their effectiveness as drug sustained release hydrogels[J]. Carbohydrate Polymers.2012,87(2):p. 1286-1294.
76. 金鑫,张阳德,王吉伟,张丽华,杨璞,张旭,胡玉,于丽.荧光标记的叶酸修饰壳聚糖纳米载体研制[J].中南大学学报(自然科学版).2010,41(1).
77. 余慧,梁淑彩,钟海迪,付婷,鄢国平.新型壳聚糖荧光纳米粒的制备及pH敏感性能研究[J].分析化学.2011,39(3).
78. 李和平,肖华伍,肖子丹,阮建明.磁性壳聚糖-5-氟尿嘧啶纳米粒的制备及体 外释药性能[J].高分子材料科学与工程.2007,23(1)：p.4.
79. 应晓英,胡富强,袁弘.胰岛素壳聚糖纳米粒的制备[J].中国药学杂志.2003,38(12)：p.4.
80. 袁弘,胡富强,应晓英,韩钢.胰岛素纳米粒的制备[J].中国药学杂志.2002,37(5)：p.4.
81. 蒋海明,夏金兰,聂珍媛.壳聚糖基复合控释膜的制备及其渗透性能[J].中南大学学报(自然科学版).2006,37(1)：p.5.
82. 董陈,徐靖宏,蔡镭,胡巧玲,林军.可吸收复合壳聚糖引导药膜的研究[J].稀有金属材料与工程.2008,37(z2)：p.4.
83. 陈莉,李世庚,肖飞,张爱华,姚康德.温敏性壳聚糖共聚膜的制备与细胞吸附/脱附行为[J].高等学校化学学报.2008,29(5)：p.4.
84. 吴燕,曲波,赵瑾,邝清林,成国祥.温敏性壳聚糖/甘油磷酸盐配合物凝胶的研究[J].功能材料.2004,35(z1)：p.3.
85. 马志伟,张勇杰,吴织芬,王荣,朱浩,李媛,许杰,刘青.缓释骨形态发生蛋白-2的壳聚糖温敏凝胶促进牙周组织再生的实验研究[J].华西口腔医学杂志.2008,26(1)：p.4.
86. 张杰,褚良银,张诗博,陈文梅,王海东,巨晓洁.可生物降解温度/pH双重感应型壳聚糖凝胶载体的制备和性能研究[J].四川大学学报(工程科学版).2006,38(1)：p.5.
87. 唐金春,黄可龙,于金刚,刘素琴.壳聚糖-碳纳米管/壳聚糖半互穿网络水凝胶的机械性能及pH敏感性[J].化学学报.2008,66(5)：p.4.
88. 谭学才,翟海云,李荫,邹小勇,蔡沛祥.基于溶胶-凝壳聚糖/Si02杂化材料的安培型葡萄糖生物传感器[J].高等学校化学学报.2004,25(9)：p.3.
89. 郭英,李酽,吴瑶,杨琨,刘雪燕.超声波辅助水热合成条件对Fe_30_4纳米微粒生长及磁性的影响[J].天津师范大学学报(自然科学版).2007(02).
90. 黄小忠,申小海,冯春祥.磁性涂层碳化硅纤维的电磁特性研究[J].磁性材料及器件.2007(04).
91. 颜旭,李世梁,韩相华,王建波,薛德胜.钴铁氧体复合纳米颗粒的制备及其磁 性[J].兰州大学学报(自然科学版).2006(01).
92. 赵义恒,陈福厚,张药西.铁氧体磁性元件的稳定性问题[J].电子元器件应用.2007(03).
93. 陈辉,方庆清,李雁,黄凯,杨景景,王翠平.钴铁氧体Co_xFe_(3-x)O_4结构和磁性研究[J].安徽大学学报(自然科学版).2007(04).
94. 丁清.两种药物控释载体的体外释药性能[J].中国组织工程研究与临床康复.2008(32).
95. 刘利萍,李苹,吴泽志,蔡绍皙.5-Fu壳聚糖/丝素复合磁微球的制备及体外性质研究[J].中国药学杂志.2003(10).
96. 周永国,杨越冬,郭学民,齐印阁,白继海.磁性壳聚糖微球的制备、表征及其靶向给药研究[J].应用化学.2002(12).
97. 赵大庆,高明.磁性壳聚糖微球的释药和靶向研究[J].中国新药杂志.2006(09)：p.698-701.
98. Grasso, M. Bladder Cancer:A Major Public Health Issue[J]. European Urology Supplements.2008,7(7):p.510-515.
99. Phull, J.S.Jefferies, E.R.,Bates, T.S.Issa, R.,McFarlane, J.P.,Howell, G.P.,Gallegos, C.R.,Persad, R.A. Modern transurethral resection in the management of superficial bladder tumours[J]. British Journal of Medical and Surgical Urology.2011,4(3):p.91-100.
100. Grimm, M.-O.,Steinhoff, C.,Simon, X.,Spiegelhalder, P.,Ackermann, R.,VOGeli, T.A. Effect of Routine Repeat Transurethral Resection for Superficial Bladder Cancer:A Long-term Observational Study[J]. The Journal of Urology.2003, 170(2, Part 1):p.433-437.
101. Gudjonsson, S.,Adell, L.,Merdasa, F.,Olsson, R.,Larsson, B.,Davidsson, T.,Richthoff, J.,Hagberg, G,Grabe, M.,Bendahl, P.O.,Mansson, W.,Liedberg, F. Should All Patients with Non-Muscle-Invasive Bladder Cancer Receive Early Intravesical Chemotherapy after Transurethral Resection? The Results of a Prospective Randomised Multicentre Study[J]. European Urology.2009,55(4): p.773-780.
102. Miladi, M.,Peyromaure, M.,Zerbib, M.,Sai□ghi, D.,Debre, B. The Value of a Second Transurethral Resection in Evaluating Patients with Bladder Tumours[J]. European Urology.2003,43(3):p.241-245.
103. Ritch, C.R.,Clark, P.E.,Morgan, T.M. Restaging Transurethral Resection for Nonmuscle-Invasive Bladder Cancer:Who, Why, When, and How?[J]. Urologic Clinics of North America. (0).
104. Solsona, E.,Iborra, I.,Collado, A.,Rubio-Briones, J.,Casanova, J.,Calatrava, A. Feasibility of Radical Transurethral Resection as Monotherapy for Selected Patients With Muscle Invasive Bladder Cancer[J]. The Journal of Urology.2010, 184(2):p.475-481.
105. Donat, S.M.,Bayuga, S.,Herr, H.W.,Berwick, M. Fluid Intake and the Risk of Tumor Recurrence in Patients With Superficial Bladder Cancer[J]. The Journal of Urology.2003,170(5):p.1777-1780.
106. van der Heijden, A.G.,Witjes, J.A. Recurrence, Progression, and Follow-Up in Non-Muscle-Invasive Bladder Cancer[J]. European Urology Supplements.2009, 8(7):p.556-562.
107. Schultz, I.J.,Witjes, J.A.,Swinkels, D.W.,de Kok, J.B. Bladder cancer diagnosis and recurrence prognosis:Comparison of markers with emphasis on survivin[J]. Clinica Chimica Acta 2006,368(1-2):p.20-32.
108. Behnsawy, H.M.,Miyake, H.,Abdalla, M.A.,Sayed, M.A.,Ahmed, A.E.-F.I.,Fujisawa, M. Expression of cell cycle-associated proteins in non-muscle-invasive bladder cancer:Correlation with intravesical recurrence following transurethral resection[J]. Urologic Oncology:Seminars and Original Investigations.2011,29(5):p.495-501.
109. 马旭东,王全好.浅表膀胱癌的治疗现状[J].广东医学.2008,29(6)：p.1055-1056.
110. Sylvester, R.J.,van der Meijden, A.P.M.,Lamm, D.L. Intravesical Bacillus Calmette-Guerin Reduces the Risk of Progression in Patients with Superficial Bladder Cancer:A Meta-analysis of the Published Results of Randomized Clinical Trials[J]. The Journal of Urology.2002,168(5):p.1964-1970.
111. Urdaneta, G,Solsona, E.,Palou, J. Intravesical Chemotherapy and BCG for the Treatment of Bladder Cancer:Evidence and Opinion[J]. European Urology Supplements.2008,7(7):p.542-547.
112. Mohanty, N.K.,Nayak, R.L.,Vasudeva, P.,Arora, R.P. Intravesicle gemcitabine in management of BCG refractory superficial TCC of urinary bladder—our experience[J]. Urologic Oncology:Seminars and Original Investigations.2008, 26(6):p.616-619.
113. 刘嘉琳,林萍萍,周炳娟,刘书哲,吴艳萍,张颖,高伟敏,薛娟.卡介苗联合药物缓释剂在抗肿瘤方面的初步研究[J].河北职工医学院学报.2007(03)：p.3-5.
114. Morales, A.,Eidinger, D.,Bruce, A.W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors[J]. The Journal of Urology.1976, 116(2):p.180-3.
115. 刘昊,王志华.浅表性膀胱癌的灌注治疗[J].肿瘤研究与临床.2006,18(12)：p.854-856.
116. 黄多斌.卡介苗膀胱灌注预防膀胱癌复发效果分析[J].中国热带医学.2007(06)：p.952+957.
117. 刘文平,白永韬,刘永连.表柔比星联合卡介苗膀胱灌注预防膀胱癌术后复发的疗效分析[J].医学信息(中旬刊).2010(12)：p.3706-3707.
118. 马顺利.膀胱癌术后灌注化疗药物预防复发82例分析[J].中国误诊学杂志.2008(10)：p.2419-2420.
119. 葛宏,葛长龙,李忠善,李英民.5种灌注药物预防膀胱癌术后复发的疗效观察[J].中国医药导报.2008(02).
120. 黄多斌.卡介苗膀胱灌注预防膀胱癌复发效果分析[J].中国热带医学.2007(06).
121. 李毅,林成楚,汪志伟.吡柔比星及卡介苗膀胱灌注预防膀胱癌术后复发的临 床观察[J].海峡药学.2008(03).
122. 吴渭贤,朱希松,孔宏伟.膀胱癌术后联合采用介入治疗和膀胱灌注预防肿瘤复发和转移的临床应用价值探讨[J].中国中西医结合急救杂志.2008(04).
123. 张怀强,周春文,马天加,王绍勇,葛南.不同剂量卡介苗膀胱灌注预防浅表性膀胱癌复发的效果[J].山东大学学报(医学版).2008(05).
124. 葛宏,葛长龙,李忠善,李英民.5种灌注药物预防膀胱癌术后复发的疗效观察[J].中国医药导报.2008(02)：p.78-79.
125. Highshaw, R.A.,Tanaka, S.T.,Evans, C.P.,deVere White, R.W. Is bladder biopsy necessary at three or six months post BCG therapy?[J]. Urologic Oncology: Seminars and Original Investigations.2003,21(3):p.207-209.
126. Bassi, P.,Milani, C.,Meneghini, A.,Garbeglio, A.,Aragona, F.,Zattoni, F.,Palma, P.D.,Rebuffi, A.,Pagano, F. Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer[J]. Urology.1992,40(2): p.175-179.
127. Kamat, M.R.,Kulkarni, J.N.,Tongaonkar, H.B.,Dalai, A.V. Intravesical bacillus Calmette-Guerin for superficial bladder cancer:experience with Danish 1331 strain[J]. The Journal of Urology.1994,152(5 Pt 1):p.1424-8.
128. ElsASser-Beile, U.,Gutzeit, O.,Bauer, S.,Katzenwadel, A.,Schultze-Seemann, W.,Wetterauer, U. Systemic and Local Immunomodulatory Effects of Intravesical BCG Therapy in Patients with Superficial Urinary Bladder Carcinomas[J]. The Journal of Urology.2000,163(1):p.296-299.
129. Davis, J.W.,Sheth, S.I.,Doviak, M.J.,Schellhammer, P.F. Superficial bladder carcinoma treated with bacillus Calmette-Guerin:Progression-free and disease specific survival with minimum 10-year follow-up[J]. Journal of Urology.2002, 167(2):p.494-500.
130. Siracusano, S.,Vita, F.,Abbate, R.,Ciciliato, S.,Borelli, V.,Bernabei, M.,Zabucchi, G. The Role of Granulocytes Following Intravesical BCG Prophylaxis[J]. European Urology.2007,51(6):p.1589-1599.
131. Simons, M.P.,O'Donnell, M.A.,Griffith, T.S. Role of neutrophils in BCG immunotherapy for bladder cancer[J]. Urologic Oncology:Seminars and Original Investigations.2008,26(4):p.341-345.
132. O'Donnell, M.A. Optimizing BCG therapy[J]. Urologic Oncology:Seminars and Original Investigations.2009,27(3):p.325-328.
133. Pan, H.,Ma, X.,Chen, J.Jiang, H. PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer?[J]. Medical Hypotheses.2009,73(4):p.559-560.
134. Gilmore, P.E.,Henderson, K.,Kutarski, P.W.,Stephenson, R.N.,Parr, N.J. A pilot study of the tolerability of two BCG maintenance regimens in the treatment of high risk superficial bladder cancer[J]. British Journal of Medical and Surgical Urology.2010,3(6):p.231-236.
135. Wilson, J.R.F.,Turney, B.W.,LeMonnier, K.,Crew, J.P. A comparison of two BCG instillation regimens for non-muscle invasive bladder cancer:A retrospective cohort analysis of side effect profiles[J]. British Journal of Medical and Surgical Urology.2010,3(6):p.241-248.
136. Bunimovich-Mendrazitsky, S.,Claude Gluckman, J.,Chaskalovic, J. A mathematical model of combined bacillus Calmette-Guerin (BCG) and interleukin (IL)-2 immunotherapy of superficial bladder cancer[J]. Journal of Theoretical Biology.2011,277(1):p.27-40.
137. Herr, H.W.,Dalbagni, G.,Donat, S.M. Bacillus Calmette-Guerin Without Maintenance Therapy for High-Risk Non-Muscle-Invasive Bladder Cancer [J]. European Urology.2011,60(1):p.32-36.
138. Tanaka, N.,Kikuchi, E.,Matsumoto, K.,Miyajima, A.,Nakagawa, K.,Oya, M. Frequency of Tumor Recurrence:A Strong Predictor of Stage Progression in Initially Diagnosed Nonmuscle Invasive Bladder Cancer[J]. The Journal of Urology.2011,185(2):p.450-455.
139. Zuiverloon, T.C.M.,Nieuweboer, A.J.M.,Vekony, H.,Kirkels, W.J.,Bangma, C.H.,Zwarthoff, E.C. Markers Predicting Response to Bacillus Calmette-Guerin Immunotherapy in High-Risk Bladder Cancer Patients:A Systematic Review[J]. European Urology.2012,61(1):p.128-145.
140. 何运兵.磁性靶向药物载体Fe_3O_4的制备及性能研究.2006,南昌大学.
141.王丽艳.纳米四氧化三铁制备的研究进展[J].科技资讯.2009(27)：p.3.
142. 刘爱红,孙康宁,李爱民.肿瘤热疗用CNTs/Fe_3O_4热种子复合材料的制备及表征[J].化工新型材料.2010(11)：p.43-45.
143. 海岩冰,袁红雁,肖丹.微波法制备纳米Fe_30_4[J].化学研究与应用.2006(06)：p.744-746.
144. 宁青菊.无机材料物理性能[M].北京：化学工业出版社.2010.
145. Hong, R.,Li, J.,Wang, J.,Li, H. Comparison of schemes for preparing magnetic Fe3O4 nanoparticles[J]. China Particuology.2007,5(1-2):p.186-191.
146. 张玉坤,罗聪,朱朝敏.超顺磁性Fe_30_4纳米粒的制备及其对小鼠的急性毒性作用[J].第三军医大学学报.2011(12)：p.1224-1227.
147. 赵爱华,贾淑珍,寇丽杰,乔来艳,王国治.应用四唑鎓盐法快速检测卡介苗活菌含量[J].中国医药生物技术.2009(01)：p.33-36.
148. 杨菊林,周长忍,田冶,田金环.壳聚糖/羟基磷灰石膜的制备及对细胞生长的影响[J].生物医学工程学杂志.2009(03)：p.580-584.
149. 张瑞,韩宝三,彭承宏.壳聚糖球形多孔微载体支持下人肝细胞L-02的高浓度细胞培养[J].中国组织工程研究与临床康复.2011(12)：p.2161-2165.
150. 陈力,刘砚韬,黄亮,张伶俐.缓控释系统药物释放的数学模型研究进展[J].中国药业.2008,17(11)：p.4.
151. 张丽杰,赵天涛,赵由才,石晓鸿.复合基质中乙炔缓释的扩散模型与工艺优化[J].化工学报.2010,61(5).
152. 齐凤林,李淑萍,张晓晴.甲氨蝶呤/层状双金属氢氧化物的粒径调控及缓释性能研究[J].化学学报.2012,70(20)：p.7.
153. 刘思峰.灰色系统理论及其应用(第五版)[M].北京：科学出版社.2010.
154. 连捷,张凯.基于AIC方法的切换神经网络模型设计[J].大连理工大学学报. 2011(06)：p.890-895.
155. 宋喜芳,李建平,胡希远.模型选择信息量准则AIC及其在方差分析中的应用[J].西北农林科技大学学报(自然科学版).2009(02)：p.88-92.
156. 周芳坚.膀胱癌[M].广州：广东科技出版社.2008.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |