多柔比星纳米载药系统逆转肿瘤多药耐药的研究进展

多柔比星是治疗乳腺癌、肺癌的1种有效的化疗药物。现存的主要问题是临床使用时肿瘤细胞产生多药耐药。为克服多药耐药,研究者们报道了一些利用纳米载药系统传递多柔比星的方法。纳米载药系统生物相容性好,稳定性高,具有药物控释和靶向性的优点,在药物传递中应用广泛。纳米载药系统可分为无机物纳米系统、基于脂质的纳米系统和聚合物纳米系统3种类型,在多柔比星载药中均有应用。综述近年来有关纳米载药系统最新研究文献,对其研究进展作了分析,并展望了其发展前景。     

叶酸受体介导的肿瘤靶向纳米递药系统

叶酸受体在上皮源性的恶性肿瘤细胞膜表面高度表达。叶酸靶向纳米递药系统具有叶酸-叶酸受体主动靶向和纳米递药系统被动靶向的双重优势,可实现化疗药物对肿瘤组织的靶向递送,有效提高药物疗效,减少毒副作用。本文就近年来研究较多的叶酸-脂质体、叶酸-树枝状聚合物、叶酸-聚合物胶束、叶酸-纳米球等叶酸受体介导的肿瘤靶向递药系统进行综述。     

空心多孔纳米ZrO_2载体材料载药性能的研究

目的为了寻找新型的药物控释载体材料,采用空心多孔ZrO2纳米球作为控释载体对阿维菌素的载药性能进行研究。方法利用反溶剂法将阿维菌素包埋到空心多孔纳米ZrO2载体中,制备空心多孔ZrO2纳米控释剂,并利用热分析仪、智能溶出仪、紫外分光光度计等对其整体载药量、载体内外载药量分布以及载药后的缓释性能进行了分析。结果空心多孔ZrO2纳米颗粒对阿维菌素有较强的吸附能力,包埋率高达65.5%;其对阿维菌素的吸附主要为物理吸附;阿维菌素纳米控释剂(Av-PHZN)在体积分数30%乙醇溶出介质中的控制释放时间可长达72 h以上,结果表明空心多孔ZrO2纳米控释剂对阿维菌素缓释效果良好。结论空心多孔ZrO2纳米球可望作为理想的新一代药物保护型控释载体。     

PLA-PEG-PLA的微波合成及其磁性载药微球的表征、释药性

目的 采用微波法合成PLA-PEG-PLA,并以该嵌段共聚物为基质制备ASA/PLA-PEG-PLA载药微球和ASA-Fe3O4/PLA-PEG-PLA载药微球,考察磁性载药微球和非磁性载药微球的药物缓释性能.方法 通过傅立叶变换红外光谱(FT-IR)、核磁(NMR)对微波法合成的PLA-PEG-PLA的微观结构进行了表征分析.采用乳化-溶剂挥发法制备了ASA/PLA-PEG-PLA载药微球,通过正交设计实验优选载药微球的最佳制备条件,在此基础上利用单微乳法制备的Fe3O4纳米粒子制备了ASA-Fe3O4/PLA-PEG-PLA载药微球.通过透射电子显微镜(TEM)、X-射线衍射(XRD)对Fe3O4纳米粒子进行微观结构表征和性能分析.采用傅立叶变换红外光谱(FT-IR),扫描电子显微镜(SEM)对制备的载药微球进行了微观结构的表征和分析.结果 微波法合成的PLA-PEG-PLA是一种三嵌段共聚物.载药微球呈规则球形,表面光滑,粒径分布较均匀,平均粒径约为20μm.体外模拟释药试验表明ASA/PLA-PEG-PLA载药微球和ASA-Fe3O4/PLA-PEG-PLA载药微球24h释药率分别为69.16％和100％.结论 以微波法合成的PLA-PEG-PLA作为药物载体具有明显的缓释作用.ASA-Fe3O4/PLA-PEG-PLA磁性载药微球比ASA/PLA-PEG-PLA非磁性载药微球具有较快的药物释放速率.     

ZnS-壳聚糖海藻酸钠包裹布洛芬纳米微球的制备和性能研究

目的以壳聚糖-海藻酸钠为基质材料,掺杂入纳米ZnS包裹非甾体抗炎药物布洛芬,制备缓、控释性能优异的载药纳米微球;为研发四代新剂型打下基础。方法利用复凝聚法,通过调整添加基质材料速度、反应温度、搅拌速度等,制备含ZnS的壳聚糖海藻酸钠布洛芬纳米微球,透射电镜观察纳米微球的形态,测试纳米微球的载药量与包封率,拟肠液条件下测试所致纳米微球的释放特性。结果含ZnS壳聚糖海藻酸钠布洛芬纳米载药微球的粒径约为80~100nm,载药量为40.2%药物包封率78.2%,ZnS粒径3nm。在水溶液、0.9%NaCl和磷酸盐缓冲液中的吸水膨胀程度小于不含ZnS的载药纳米微球;体外拟肠条件溶出表明含ZnS的载药纳米微球具有良好的缓控释性能,药代动力学特征为被动扩散。结论掺入了ZnS的壳聚糖海藻酸钠布洛芬纳米微球,形状圆整,包封率理想,具有良好的缓控释性能。     

卡铂碳包铁纳米壳聚糖微球的制备和特征

目的制备卡铂碳包铁纳米壳聚糖微球,检测其性能,并与卡铂纯铁纳米壳聚糖微球进行比较。方法以吸附药物的碳包铁纳米磁粉为磁性内核,壳聚糖为基质,卡铂为负载药物,采用反相微乳法制备卡铂碳包铁纳米壳聚糖微球。卡铂纯铁纳米壳聚糖微球的制备方法相似,不同的是以无吸附药物能力的纯铁纳米磁粉为磁性内核。检测和比较两种纳米药物微球的形态、粒径、磁响应性、载药量、包封率和体外释药。结果两种药物微球的球形圆整,平均粒径(210±26)nm,粒径分布150~300nm,磁响应性强。碳包铁纳米微球的载药量(11.15±1.03)%,纯铁纳米微球载药量(9.21±1.10)%。碳包铁纳米微球1,2,3,4d的体外释药量分别为60%、74%、84%、92%;纯铁纳米微球1,2d的释药量分别为81%,91%。结论通过活性碳吸附和物理基质包裹双重物理机制载药载药的卡铂碳包铁纳米壳聚糖微球不但载药量高,而且释药速度平稳。多重机制的有机结合是优化纳米微球性能的有效方法。     

硫酸庆大霉素/壳聚糖纳米球的制备及其释药性能

目的 制备具有预防和降低硫酸庆大霉素耳毒性的壳聚糖纳米球.方法 采用离子交联法,以三聚磷酸钠为离子交联剂,制备了硫酸庆大霉素/壳聚糖纳米球,用透射电子显微镜,X-射线衍射仪和紫外分光光度计考察了其理化性质和释药性能.结果 纳米球的粒径为50～80nm,载药包封率为39.8%,载药量为18.3%,体外60h释药90%左右,释放过程符合双相动力学方程.结论 这可能预示硫酸庆大霉素/壳聚糖纳米球缓释效果可降低硫酸庆大霉素的耳毒性.     

抗肿瘤药物靶向载体系统的研究与开发

综述肿瘤靶向给药的基础和抗肿瘤药物靶向载体系统的发展。分类介绍普通被动靶向载药系统（如微乳、传统脂质体、聚合物纳米粒、固体脂质纳米粒、纳米脂质载体、药-脂结合物纳米粒等）、表面修饰的被动靶向载药系统及主动靶向载药系统（如免疫脂质体、免疫聚合物纳米粒及受体-配体介导靶向纳米载体）的研究与开发。在传统药物制剂的基础上，发展抗肿瘤药物的新型靶向载体系统，改善药物在体内的代谢动力学特性，增加药物定向富集到肿瘤部位甚至肿瘤细胞内，提高疗效，降低毒副作用，是近年来备受关注的课题。     

正交试验优选羧甲基壳聚糖-醋甲唑胺纳米微球的制备方案

目的：制备羧甲基壳聚糖载药纳米微球,醋甲唑胺为模型药物,测量药物的包封率和纳米微球形态.方法：采用乳化交联法,在微乳液的基础上制备载药纳米微球,对可能影响药物包封率的处方因素进行优化设计,筛选出最优配方.结果：羧甲基壳聚糖溶液的浓度对包封率有显著性影响,三聚磷酸钠溶液浓度和醋甲唑胺药量对包封率未见影响.优化方案的载药纳米微球包封率为49.36％,其电镜下为较规整的球型纳米微球,平均粒径386.0 nm.结论：采用乳化交联法,可形成较高包封率的羧甲基壳聚糖-醋甲唑胺纳米微球.     

聚合物纳米粒子作为药物载体的研究与应用

目的:介绍聚合物纳米粒子作为药物载体的研究与应用现状。方法:参阅国内外文献,进行分析、归纳和总结。结果:聚合物纳米粒子可作为疏水药物、靶向药物和生物大分子药物的载体制备聚合物纳米粒的材料与方法具有多样性。结论:可生物降解的聚合物纳米粒载药系统具有可控释、靶向、保护生物大分子药物的活性等优势,是一个很有发展潜力的药物传递系统。     

Drug-loaded, magnetic, hollow silica nanocomposites for nanomedicine

Magnetic, hollow silica nanocomposites (MHSNC), including nanospheres and nanotubes, have been successfully synthesized using a coating of Fe(3)O(4) magnetic nanoparticles (NPs) ( approximately 10 nm) and silica on nanosized spherical and nanoneedle-like calcium carbonate (CaCO(3)) surfaces under alkaline conditions. The nanosized CaCO(3) surfaces were used as nanotemplates, and tetraethoxysilane and magnetic NPs were used as precursors. The as-synthesized MHSNC were immersed in an acidic solution to remove the CaCO(3), forming magnetic, hollow silica nanospheres and nanotubes. The MHSNC were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), x-ray powder diffraction, and superconducting quantum interference device (SQUID) magnetometer. SEM and TEM results showed that a smooth surface of MHSNC and a thin layer of silica ( approximately 10 nm) embedded with the magnetic NPs were successfully formed, and that the CaCO(3) nanotemplates appeared to be dissolved. SQUID measurement demonstrated that magnetization of MHSNC was dependent on temperature, exhibiting superparamagnetism. The MHSNC were immersed in ibuprofen solution. The amount of the loaded drug was determined to be 12 wt% for nanospheres, and 8 wt% for nanotubes by UV measurement, respectively. Drug-loaded MHSNC have potential applications in nanomedicine.     

载环孢素纳米球的制备及释放特性*

目的：制备一种环孢素A（CsA）缓释纳米体系。方法：以PLA-co-PEG共聚物材料作为环孢素药物的释放载体；采用超声振荡技术制备载环孢素的PLA—PEG—PLA纳米球；分析纳米球的粒径与分布以及纳米球降解过程中的形貌变化；体外释放试验探讨制备的纳米球的降解特性以及与载体材料、介质pH值之间的影响关系；小鼠灌胃后HPLC法测定血药浓度。结果：采用PLA—PEG—PLA共聚材料装载CsA，药物包封率达到89．2％。纳米球平均粒径为242．3nm，载药后平均粒径增大到320．2nm。扫描电镜分析发现纳米球在磷酸缓冲液中溶胀程度与降解速率依赖于介质pH值。体外模拟释放表明载药纳米球的药物释放速率与载体降解速率一致，持续稳定释药时间〉7d。动物模型也证实该载CsA纳米球可维持血液中稳定的药物浓度5d以上。结论：利用本方法制备的载CsA纳米球是一种较理想的环孢素药物剂型，具有临床应用价值。     

Mucoadhesive DL-Lactide/Glycolide Copolymer Nanospheres Coated with Chitosan to Improve Oral Delivery of Elcatonin

The purpose of this work was to develop a novel mucoadhesive DL-lactide/glycolide copolymer (PLGA) nanosphere system to improve peptide absorption and prolong the physiological activity following oral administration. The desired PLGA nanospheres with elcatonin were prepared by the emulsion solvent diffusion method to coat the surface of the resultant nanospheres with a mucoadhesive polymer such as chitosan, poly(acrylic acid), and sodium alginate. Their mucoadhesive properties were evaluated by measuring the nanospheres adsorbed to a rat everted intestinal sac (in vitro). The chitosan-coated nanospheres showed higher mucoadhesion to the everted intestinal tract in saline than the other polymer-coated nanospheres. There was no mucoadhesion site-specificity of the chitosan-coated nanospheres between duodenal, jejunal, and ileal sacs. The payload of drug in the chitosan-coated nanospheres was successfully increased by using the solvent diffusion method in oil. The pattern of drug release of the resultant nanospheres did not differ markedly from that of uncoated nanospheres. The chitosan-coated nanospheres with elcatonin were administered intragastrically to fasted Wistar rats. The chitosan-coated nanosphere reduced significantly the blood calcium level compared with elcatonin solution and uncoated nanospheres, and the reduced calcium level was sustained for a period of 48 hr. Even under nonfasting conditions, the mucoadhesion of chitosan-coated nanospheres was unaltered and the reduction in blood Ca levels was maintained satisfactorily.     

Mucoadhesive DL-lactide/glycolide copolymer nanospheres coated with chitosan to improve oral delivery of elcatonin

The purpose of this work was to develop a novel mucoadhesive DL-lactide/glycolide copolymer (PLGA) nanosphere system to improve peptide absorption and prolong the physiological activity following oral administration. The desired PLGA nanospheres with elcatonin were prepared by the emulsion solvent diffusion method to coat the surface of the resultant nanospheres with a mucoadhesive polymer such as chitosan, poly(acrylic acid), and sodium alginate. Their mucoadhesive properties were evaluated by measuring the nanospheres adsorbed to a rat everted intestinal sac (in vitro). The chitosan-coated nanospheres showed higher mucoadhesion to the everted intestinal tract in saline than the other polymer-coated nanospheres. There was no mucoadhesion site-specificity of the chitosan-coated nanospheres between duodenal, jejunal, and ileal sacs. The payload of drug in the chitosan-coated nanospheres was successfully increased by using the solvent diffusion method in oil. The pattern of drug release of the resultant nanospheres did not differ markedly from that of uncoated nanospheres. The chitosan-coated nanospheres with elcatonin were administered intragastrically to fasted Wistar rats. The chitosan-coated nanosphere reduced significantly the blood calcium level compared with elcatonin solution and uncoated nanospheres, and the reduced calcium level was sustained for a period of 48 hr. Even under nonfasting conditions, the mucoadhesion of chitosan-coated nanospheres was unaltered and the reduction in blood Ca levels was maintained satisfactorily.     

透明质酸修饰的空腔靶向纳米载体制备及其体内外性能评价

目的： 制备具有pH响应性的透明质酸衍生物修饰的主动靶向载药空腔纳米球载体,并进行相关性能测定。方法： 采用One-pot法制备空腔碳酸钙纳米球,并用透明质酸与壳聚糖的偶联物进行修饰,得到具有pH响应性的靶向给药载体;以阿霉素作为模型药物,对载体的粒径及Zeta电位、包封率、载药量及体外释放进行考察;以人肝癌HepG2细胞,通过MTT实验进行细胞毒性验证;以H22荷瘤小鼠为模型验证载体在体内及肿瘤部位的靶向性作用。结果： 所制备的靶向给药载体呈球状,平均粒径（376.8±12.4）nm,PDI为（0.295±0.080）,Zeta电位为（-45.1±0.3）mV,包封率（80.45±2.35）%及载药量（15.65±0.25）%;体外释放显示出此载体具有良好的pH响应性,且具有明显的缓释特征;细胞毒性实验证明了此载体具有低毒性;荷瘤小鼠实验证明了此载体具有良好的肝靶向和肝肿瘤靶向能力。结论： 成功制备了透明质酸衍生物修饰的碳酸钙空腔纳米球靶向给药载体,此载体具有良好肝癌靶向治疗的能力。     

载血卟啉单甲醚中空金纳米球的光热光动力联合抗肿瘤研究

目的 设计基于中空金纳米球的新型纳米给药系统(HMME-PEI-HAuNS),在近红外光照射下研究其同步光热光动力联合抗肿瘤作用。方法 以钴纳米粒为模板制备中空金纳米球(HAuNS),将血卟啉单甲醚(HMME)通过枝状聚乙烯亚胺(PEI)装载到HAuNS表面,形成纳米给药系统(HMME-PEI-HAuNS);采用核磁共振氢谱、红外光谱、紫外光谱分析对HMME-PEI-HAuNS进行结构确证。建立荷瘤(SKOV3)小鼠模型,通过荧光活体成像仪考察其体内分布情况。将对肿瘤细胞表面EphB4受体具有特异性亲和力的靶向多肽TNYL修饰于其表面以增强该纳米体系的靶向性,用核染试剂Hoechst染色SKOV3细胞,在激光共聚焦显微镜下观察细胞内的荧光强度,用MTT比色法进行细胞毒性评价。结果 HAuNS能对HMME进行成功装载,装载率达63.4±5.2%。由于肿瘤的高通透性和滞留效应(EPR 效应),HMME-PEI-HAuNS较游离HMME和HMME-PEI胶束在肿瘤部位有更多的累积量和更长的滞留时间,累计效率约为1.6%。荧光定量统计显示在TNYL多肽的介导下纳米球的靶向性更高,在808 nm激光照射下,TNYL-HMME-PEI-HAuNS发挥光热和光动力协同作用产生强大的肿瘤杀伤作用,在高浓度时,细胞存活率不到10%。结论 主动靶向纳米球(TNYL-HMME-PEI-HAuNS)在808 nm近红外光照射下具有较强的光热光动力联合抗肿瘤作用。     

Preparation of tin-albumin nanospheres for labelling with 99mTc and application in liver scintigraphy

A modified method is described for the preparation of albumin nanospheres for labelling with 99mTc by investigating the absorption behaviour of tin as a reducing agent on albumin nanospheres. These albumin nanospheres can be used for studying the reticuloendothelial system, especially that of the liver. The labelling method is very simple, and the efficiency of labelling with 99mTc is higher than 97 per cent.     

Nimodipine loaded lipid nanospheres prepared by solvent diffusion method in a drug saturated aqueous system

To overcome the disadvantages such as lower drug entrapment efficiency (EE) of lipid nanospheres prepared by conventional solvent diffusion method, a solvent diffusion method in drug saturated aqueous system was developed. Nimodipine was used as a model drug to incorporate into lipid nanospheres. The monostearin (MS) solid lipid nanoparticles (SLN) produced by conventional method under different production temperature only showed 24.40-30.21wt% EE, and relatively higher EE was achieved when the production temperature was 0 degrees C. The EE could be enhanced by the incorporation of liquid lipid (caprylic/capric triglycerides, CT) into SLN and the employing of drug saturated dispersion medium. The nanostructured lipid carrier (NLC) with higher CT content indicated the highest EE as the drug saturated aqueous solution was used as dispersion medium. The differential scanning calorimetry (DSC) results demonstrated the present method could improve the drug encapsulation into lipid nanospheres. In vitro drug release experiments indicated the present preparation method could delay the drug release rate from lipid nanospheres, and the drug release rate could adjust by the CT content in lipid nanospheres. The highest drug loading (DL) was reached up to 4.22wt% when 8wt% drug was charged in the preparation of lipid nanospheres.     

Enhancement of gene transfection into human dendritic cells using cationic PLGA nanospheres with a synthesized nuclear localization signal

Effective delivery of DNA encoding antigen into the dendritic cells (DCs), which are non-dividing cells, is very important for the development of DNA vaccines. In a previous study, we developed the PLGA nanospheres that contained a cationic nanomaterial and showed high transfection efficiency in COS7 cells, which divide. In the present study, to produce an effective vector for the DNA vaccines, the gene expression and intracellular trafficking of pDNA complexed with PLGA/PEI nanospheres, in combination with an NF-κB analog as a nuclear localization signal (NLS) and electroporation were evaluated in human monocyte-derived DCs (hMoDCs). Cellular uptake of pDNA both in COS7 cells and hMoDCs was enhanced using the PLGA/PEI nanospheres. On the other hand, the PLGA/PEI nanospheres significantly promoted the transfection in COS7 cells, but had almost no effect on transfection in hMoDCs. The intranuclear transport of pDNA by PLGA/PEI nanospheres in COS7 cells was significantly higher than that in hMoDCs. These results indicate that pDNA complexed with PLGA/PEI nanospheres cannot enter into the nuclei of non-dividing cells. However, PLGA/PEI nanospheres combinated with NLS and electroporation (experimental permeation enhancer) greatly elevated the transfection efficiency by improvement of not only intracellular uptake but also intranuclear transport of pDNA in the hMoDCs. Thus, this delivery system using nanospheres combined with synthesized NLS might be applicable to DC-based gene vaccines when much non-invasive application such as needle-free injector should be required.     

Properties of poly(lactic-co-glycolic acid) nanospheres containing protease inhibitors: camostat mesilate and nafamostat mesilate

Poly(lactic-co-glycolic acid) (PLGA) nanospheres containing protease inhibitors, camostat mesilate (CM) and nafamostat mesilate (NM), were prepared by the emulsion solvent diffusion methods in water or in oil, and the w/o/w emulsion solvent evaporation method. The average diameter of PLGA nanospheres prepared in the water system were about 150-300 nm, whereas those prepared in the oil system were 500-600 nm. Among the three methods, these drugs were the most efficiently encapsulated up to 60-70% in PLGA nanospheres in the oil system. Other factors that may influence drug encapsulation efficiency and in vitro release such as drug load, molecular weight of polymer were also investigated. Both the CM- and NM-loaded nanospheres prepared in the water system immediately released about 85% of the drug upon dispersed in the release medium while the drug initial burst of nanospheres prepared by the emulsion solvent diffusion in oil method reduced to 30% and 60% for CM and NM, respectively. Poly(aspartic acid) (PAA), a complexing agent for cationic water soluble drugs, showed little effect on the encapsulation efficiency and release behavior for CM and NM. The DSC study and AFM pictures of nanospheres demonstrated that temperature-dependent drug release behavior was ascribable to the glass transition temperature of the polymer, which also affected the morphology of nanospheres upon dispersed in the release medium and influenced the drug release consequently.