载紫杉醇聚乳酸-羟基乙酸纳米粒的体外释药研究

以生物可降解材料聚乳酸-羟基乙酸(PLGA)为载体制备了载紫杉醇纳米粒,重点考察了纳米粒的体外释放特性.采用乳化-溶剂挥发法制备了载紫杉醇PLGA纳米粒,其平均粒径为200nm,载药量为21%,包封率为89.44%;体外释药符合Higuchi方程:Q=3.8796t1/2+30.4649(r=0.9397),同时载紫杉醇纳米粒具有一定的缓释作用.     

羟基喜树碱叶酸-壳聚糖纳米粒的制备及其性能研究

为了提高羟基喜树碱对肿瘤组织的靶向性,增强其抗肿瘤活性,延长其在体内的作用时间,以壳聚糖为药物载体,叶酸为肿瘤靶向配体,三聚磷酸钠为聚阴离子,利用静电相互作用的原理,通过离子交联法合成载羟基喜树碱的叶酸-壳聚糖(FA-CTS/HCPT)纳米粒。利用动态光散射、透射电镜以及红外等技术对纳米粒的结构、平均粒径及粒径分布、形态特征、表面电位、稳定性、对药物的包封率及载药量、体外释放等特点进行了初步研究。结果表明,所制得的纳米粒平均粒径为150nm;粒子形态圆整,大小均匀;表面电位+50.1mV;放置数十天纳米粒粒径几乎无变化,纳米粒具有很好的粒度稳定性;对羟基喜树碱包封率最高为89.9%,载药量最高为19.8%;在人工体液pH值为7.4条件下具有很好的缓释作用,用Higuchi方程拟合其体外释放曲线,得Higuchi方程:Q=14.529t1/2+8.3589(R2=0.9247),说明HCPT在人工体液的释放量与时间的平方根成直线关系,符合水不溶性骨架的释药性能。     

野皂荚多糖修饰羟基磷灰石材料的制备及载药性能研究

靶向载药材料是实现靶向治疗癌症的有效途径之一,新型靶向载药材料的制备和性能提高具有重要研究价值。以四水合硝酸钙、磷酸二氢铵为原料,野皂荚多糖为修饰剂,采用乙醇-水混合溶剂热法,制备得到羟基磷灰石(HAP)材料。用红外(IR)、X射线衍射(XRD)和扫描电镜(SEM)对材料进行结构形貌表征,采用四唑盐(MTT)比色法评价材料细胞毒性,并进行体外载抗癌药物盐酸阿霉素(DOX)性能研究。IR和XRD表征均表明野皂荚多糖修饰剂将多糖有机官能团引入到HAP材料中,野皂荚多糖的结晶成核作用使材料有自组装为棒状花球趋势,所得HAP材料结晶度高,HAP材料对hela细胞基本无毒且对DOX的载药量可高达142.37μg/mg;且所得材料对DOX具有pH响应释放性能,在pH值为7.4和5.0的体外环境下,释放差异15%左右,表明野皂荚多糖修饰的HAP材料具有一定靶向载药的潜在应用价值。     

叶酸修饰的氧化石墨烯装载阿霉素的载药性能评价

制备了负载阿霉素的叶酸修饰的氧化石墨烯材料,并对其性能进行研究。首先制备由叶酸修饰的氧化石墨烯,记为FA/GO,然后将该复合物对药物阿霉素进行负载,记为FA/GO/DOX,通过与空白组(FA/GO)的对比分析,观察其药物负载和释放行为,选择Hela细胞作为模型进行细胞实验,考察其细胞形态、细胞毒性和生物安全性,对FA/GO/DOX载药系统的靶向性、细胞毒性和安全性能进行研究和评价,发现该材料性能良好,具有广阔的应用前景。     

环糊精功能化多壁碳纳米管对芒柄花素的装载及其细胞毒性研究

利用羟丙基-β-环糊精(HP-β-CD)修饰羧基化多壁碳纳米管(CD-MWCNTs),通过红外光谱证明了CDMWCNTs的成功合成,并经溶液共混法将CD-MWCNTs装载芒柄花素(FMN)。选用激光粒径仪,X射线衍射、扫描电镜对载药CD-MWCNTs(CD-MWCNTs-FMN)进行表征,并考察其释药特性。采用水溶性四唑盐试剂(WST-1)测定CD-MWCNTs-FMN的抗肿瘤活性。研究结果表明CD-MWCNTs对FMN的包封率为(50.60±1.92)%,载药率为(7.20±0.98)%。FMN在CD-MWCNTs的释放行为具有pH值依赖。细胞毒性结果表明载药CD-MWCNTs的抗肿瘤活性强于游离药物。这说明环糊精修饰的多壁碳纳米管是一种良好的缓释性载药系统,并且能提高芒柄花素的抗肿瘤活性。     

壳聚糖修饰的PLGA纳米粒作为蛋白多肽类药物载体的研究

采用溶剂挥发法,以乳酸羟基乙酸共聚物(PLGA)制备了载牛血清白蛋白(BSA)的PLGA纳米粒(PLGA NP),采用两种修饰方式(直接吸附法和共价交联法)以壳聚糖(chitosan,CS)修饰纳米粒表面,通过考察修饰方法对纳米粒的理化性质、释药性质以及对BSA构型的影响,吸附法修饰的纳米粒(ADCS NP)包封率提高...     

近红外荧光磁性复合载药脂质体的制备及应用

拟建立以近红外荧光磁性复合脂质体(NFMSLs)为模型药物载体、盐酸多柔比星(DOX)为包封药物的药物输送系统,研究了近红外荧光磁性载药复合脂质体(DOX-NFMSLs)的制备、性质及初步应用.采用共沉淀法制备FeO4磁流体,CdTe掺杂Se制备近红外量子点CdSeTe,薄膜分散法制备DOX-NFMSLs.用DOX荧光分光光度法测定DOX-NFMSLs的包封率和体外药物释放率;用DOX-NFMSLs与HepG2肝癌细胞共孵育来进行细胞成像和细胞毒性实验.结果表明,近红外CdSeTe量子点粒径约为5nm,闪锌矿结构,发射波长824 nm.磷脂与胆固醇质量比为8∶1,药脂比为1∶20的DOX-NFMSLs平均粒径为252.9 nm,Zeta电位为-48.6 mV,理想释放药物温度为41℃,平均包封率为(74.84±0.89)％.DOX-NFMSLs对HepG2肝癌细胞有一定的抗癌效果.得到了具有良好磁响应、释药温度T=41℃、可近红外成像的载药脂质体.     

山核桃仁鞣质叶酸-PEG修饰纳米粒的制备和性能研究

为了提高山核桃仁鞣质的肿瘤靶向性,增强其抗肿瘤活性,采用薄膜分散法制备山核桃仁鞣质叶酸-PEG修饰纳米粒,通过核磁共振、透射电镜等方法对纳米粒的结构、粒径和粒径分布、形态、稳定性、包封率以及肿瘤靶向性进行了初步研究。结果表明,山核桃仁鞣质叶酸-PEG修饰纳米粒平均粒径为166.8nm;包封率为74.5%,粒子呈大小均匀的球形;放置50d纳米粒粒径和包封率变化轻微,具有很好的稳定性;叶酸-PEG修饰纳米粒小鼠尾静脉注射后0.25,1和4h肿瘤分布分别为20.8%,36.2%和50.2%,具备明显的肿瘤靶向作用。     

一种pH响应型Y形两亲聚合物的合成表征及药物释放性能EI北大核心CSCD

乙氧基乙基缩水甘油醚作为聚合单体,采用阴离子活性聚合(AROP)的方法合成了一种Y形两亲性聚合物聚乙二醇-聚乙氧基乙基缩水甘油醚(PEG-b-PEEGE),并在支点位置引入对弱酸敏感的缩酮结构。采用核磁共振和凝胶渗透色谱对其结构和相对分子质量进行表征。通过旋蒸法制备聚合物胶束,采用透射电镜和动态光散射对胶束的形貌及尺寸进行表征,结果显示聚合物胶束呈球形,平均粒径为88.36 nm。以阿霉素为模型药物考察聚合物的载药及在不同pH环境下的释放行为,结果表明这种缩酮结构的两亲性聚合物具有良好的pH响应性释放能力,即在酸性条件下(pH 4.0)的释放速率比生理pH环境下明显加快。     

赖氨酸超小纳米粒的制备及胶质瘤细胞荧光成像

利用N-芴甲氧羰基-L-赖氨酸分子接枝异硫氰基荧光素,合成赖氨酸-荧光素小分子,在反相微乳液中京尼平作为交联剂交联赖氨酸-荧光素分子制备超小纳米粒。所得纳米粒纯化后进行紫外-近红外可见光扫描分析,确定荧光素交联到纳米粒上及未反应小分子被完全洗脱。动态光散射考察所得纳米粒径为(198.33±0.03)nm、透射电子显微镜观察到纳米粒呈球形,平均粒径为39.78nm。荧光光谱表征所得纳米粒与荧光素荧光光谱完全吻合。利用胶质瘤U87细胞进行纳米粒荧光成像,细胞被染色。利用CHO细胞考察纳米粒的毒性,在一定浓度下(小于8mg/mL)纳米粒对细胞无明显毒副作用。     

Preparation and characterization of galactosylated glycol chitosan micelles and its potential use for hepatoma-targeting delivery of doxorubicin

This study aimed to develop novel galactosylated cholesterol modified-glycol chitosan (Gal-CHGC) micelles for targeting delivery of doxorubicin (DOX) in live cancer cells. Three kinds of Gal-CHGC conjugates were synthesized and characterized. The mean particle size and critical aggregation concentration of these polymeric micelles increased with the increase of galactose substitution degree. The DOX-loaded micelles were prepared by an o/w method. The mean diameters of DOX-loaded galactosylated micelles were in the range of 387–497 nm. DOX released from drug-loaded micelles displayed a biphasic way. Cellular uptake studies demonstrated that DOX-loaded galactosylated micelles could enhance the uptake of DOX into HepG2 cells. Moreover, the cytotoxicity of DOX-loaded galactosylated micelles against HepG2 cells significantly improved in contrast with free DOX and DOX-loaded micelles without galactosylation. These results suggested that Gal-CHGC micelles could be a potential carrier for hepatoma-targeting drug delivery.     

Overcoming multidrug resistance of breast cancer cells by the micellar doxorubicin nanoparticles of mPEG-PCL-graft-cellulose

The amphiphilic block copolymer methoxy-poly(ethylene glycol)-poly(epsilon-caprolactone) (mPEG-PCL) was grafted to 2-hydroxyethyl cellulose (HEC) to produce nano-sized micellar nanoparticles. The nanoparticles were loaded with anti-tumor drug, doxorubicin (DOX) and the size of the DOX-loaded nanoparticles were determined by dynamic light scattering (DLS) in aqueous solution to be from 197.4 to 230 nm. The nanoparticles subjected to co-culture with macrophage cells showed that these nanoparticles used as drug carrier are not recognized as foreign bodies. Overexpression of P-glycoprotein (P-gp) is an important factor in the development of multidrug resistance (MDR) in many cancer cells. In this study, Western blot and Rhodamine 123 were used to monitor the relative P-glycoprotein expression in human breast cancer cell lines MCF-7/WT and MCF-7/ADR. The endocytosis of the DOX-loaded nanoparticles by breast cancer cells is more efficient observed under a confocal laser scanning microscopy (CLSM) and a flow cytometry in MCF7/ADR cells, compared to the diffusion of the free drug into the cytoplasm of cells. Based on these findings, we concluded that the nanoparticles made from mPEG-PCL-g-cellulose were effective in overcoming P-gp efflux in MDR breast cancer cells.     

M13 bacteriophage-polymer nanoassemblies as drug delivery vehicles

Poly(caprolactone-b-2-vinylpyridine) (PCL-P2VP) coated with folate-conjugated M13 (FA-M13) provides a nanosized delivery system which is capable of encapsulating hydrophobic antitumor drugs such as doxorubicin (DOX). The DOX-loaded FA-M13-PCL-P2VP assemblies had an average diameter of approximately 200 nm and their structure was characterized using transmission electron microscopy, scanning electron microscopy, and dynamic light scattering. The particles were stable at physiological pH but could be degraded at a lower pH. The release of DOX from the nanoassemblies under acidic conditions was shown to be significantly faster than that observed at physiological pH. In addition, the DOX-loaded FA-M13-PCL-P2VP particles showed a distinctly greater cellular uptake and cytotoxicity against folate-receptor-positive cancer cells than folate-receptor-negative cells, indicating that the receptor facilitates folate uptake via receptor-mediated endocytosis. Furthermore, the DOX-loaded particles also had a significantly higher tumor uptake and selectivity compared to free DOX. This study therefore offers a new way to fabricate nanosized drug delivery vehicles.     

Preparation and characterization of nanoparticles based on histidine–hyaluronic acid conjugates as doxorubicin carriers

Histidine-hyaluronic acid (His-HA) conjugates were synthesized using hyaluronic acid (HA) as a hydrophilic segment and histidine (His) as hydrophobic segment by 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC) mediated coupling reactions. The structural characteristics of the His-HA conjugates were investigated using (1)H NMR. His-HA nanoparticles (HH-NPs) were prepared based on His-HA conjugates, and the characteristics of HH-NPs were investigated using dynamic light scattering, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and fluorescence spectroscopy. The particles were between 342 and 732 nm in size, depending on the degree of substitution (DS) of the His. TEM and SEM images indicated that the morphology of HH-NPs was spherical in shape. The critical aggregation concentrations of HH-NPs ranged from 0.034 to 0.125 mg/ml, which decreased with an increase in the DS of the His. Images of fluorescence microscopy indicate that HH-NPs were taken up by the cancer cell line (MCF-7), and significantly decreased by competition inhibition of free HA. From the cytotoxicity test, it was found that DOX-loaded HH-NPs exhibited similar dose and time-dependent cytotoxicity against MCF-7 cells with free DOX.     

Glucose-conjugated chitosan nanoparticles for targeted drug delivery and their specific interaction with tumor cells

A novel targeted drug delivery system, glucose-conjugated chitosan nanoparticles （GCNPs）, was developed for specific recognition and interaction with glucose transporters （Gluts） over-expressed by tumor cells. GC was synthesized by using succinic acid as a linker between glucosamine and chitosan （CS）, and successful synthesis was confirmed by NMR and elemental analysis. GCNPs were prepared by ionic crosslinking method, and characterized in terms of morphology, size, and zeta potential. The optimally prepared nanoparticles showed spherical shapes with an average particle size of （187.9 ± 3.8） nm and a zeta potential of （-15.43 ± 0.31） mV. The GCNPs showed negligible cytotoxicity to mouse embryo fibroblast and 4T1 cells. Doxorubicin （DOX） could be efficiently entrapped into GCNPs, with a loading capacity and encapsulation efficiency of 20.11% and 64.81%, respectively. DOX-Ioaded nanoparticles exhibited sustained-release behavior in phosphate buffered saline （pH 7.4）. In vitro cellular uptake studies showed that the GCNPs had better endocytosis ability than CSNPs, and the antitumor activity of DOX/GCNPs was 4-5 times effectiveness in 4T1 cell killing than that of DOX/CSNPs. All the results demonstrate that nanoparticles decorated with glucose have specific interactions with cancer cells via the recognition between glucose and Gluts. Therefore, Gluts-targeted GCNPs may be promising delivery agents in cancer therapies.     

Nanoparticles of deoxycholic acid,polyethylene glycol and folic acid-modified chitosan for targeted delivery of doxorubicin

Chitosan (CS) was first modified hydrophobically with deoxycholic acid (DCA) and then with polyethylene glycol (PEG) to obtain a novel amphiphilic polymer (CS–DCA–PEG). This was covalently bound to folic acid (FA) to develop nanoparticles (CS–DCA–PEG–FA) with tumor cell targeting property. The structure of the conjugates was characterised using Fourier transform infrared and ¹H nuclear magnetic resonance spectroscopy and X-ray diffraction. Based on self-aggregation, the conjugates formed nanoparticles with a low critical aggregation concentration of 0.035 mg/ml. The anti-cancer drug doxorubicin (DOX) was encapsulated into the nanoparticles with a drug-loading capacity of 30.2 wt%. The mean diameter of the DOX-loaded nanoparticles was about 200 nm, with a narrow size distribution. Transmission electron microscopy images showed that the DOX-loaded nanoparticles were spherical. The drug release was studied under different conditions. Furthermore, the cytotoxic activities of DOX in CS–DCA–PEG–FA nanoparticles against folate receptor (FR)-positive HeLa cells and FR-negative fibroblast 3T3 cells were evaluated. These results suggested that the CS–DCA–PEG–FA nanoparticles may be a promising vehicle for the targeting anticancer drug to tumor cells.     

Preparation and properties of a novel drug delivery system with both magnetic and biomolecular targeting

By loading doxorubicin (DOX) on 5-carboxyl-fluorescein (FAM) labeled AGKGTPSLETTP peptide (A54) coupled starch-coated iron oxide nanoparticles (SIONs), we prepared a novel aqueous drug delivery system with both magnetic and biomolecular targeting, which was specific to human hepatocellular carcinoma cell line BEL-7402. The saturated extent of adsorption reached 2.0 mg DOX/mg A54-SIONs at 28°C, which provided a rather high dose of DOX loading for application. Tests in vitro demonstrated the specificity of DOX-loaded A54-SIONs to BEL-7402 cells. The microscopy images proved that DOX-loaded A54-SIONs were successfully targeted to tumor tissue of nude mice with an external magnetic field in vivo. MTT assay showed higher cytostatic effect of DOX-loaded A54-SIONs to hepatocellular carcinoma cells BEL-7402 than that of DOX-loaded SIONs.     

Co-delivery of doxorubicin and TRAIL plasmid by modified PAMAM dendrimer in colon cancer cells,in vitro and in vivo evaluation

Abstract

One strategy for cancer treatment is combination therapy using nanoparticles (NPs), which has resulted in enhanced anti-cancer effects and reduced cytotoxicity of therapeutic agents. Polyamidoamine dendrimer (PAMAM) has attracted considerable attention because of its potential applications ranging from drug delivery to molecular encapsulation and gene therapy. In this study, PAMAM G5 modified with cholesteryl chloroformate and alkyl-PEG was applied for co-delivery of doxorubicin (DOX) and plasmid encoding TRAIL into colon cancer cells, in vitro and in vivo. The results showed DOX was efficiently encapsulated in modified carrier (M-PAMAM) with loading level about 90%, and the resulting DOX-loaded M-PAMAM complexed with TRAIL plasmid showed much stronger antitumor effect than M-PAMAM containing DOX or TRAIL plasmid. On the other hand, the obtained results demonstrated that the treatment of mice bearing C26 colon carcinoma with this developed co-delivery system significantly decreased tumor growth rate. Thus, this modified PAMAM G5 can be considered as a potential carrier for co-delivery of drug and gene in cancer therapy.     

Preparation and characterization of self-assemblied nanoparticles based on folic acid modified carboxymethyl chitosan

Folate (FA) modified carboxymethyl chitosan (FCC) has been synthesized and the hydrogel nanoparticles can be prepared after the sonication. Formation and characteristics of nanoparticles of FCC were studied by fluorescence spectroscopy and dynamic light scattering methods. The critical aggregation concentration value of FCC in water was 9.34 × 10⁻² mg/ml and the mean hydrodynamic diameter of particle was 267.8 nm. The morphology of nanoparticles was observed by transmission electron microscopy which had spherical shape. Loading capacity (LC), loading efficiency (LE) and the in vitro release profiles of nanoparticles were investigated by doxorubicin (DOX) as a model drug. When the initially added amount of DOX versus the constant amount of FCC polymer was increased, the LC in the nanoparticles was gradually increased and the LE decreased. The in vitro release profile of the DOX from the FCC nanoparticles exhibited sustained release. Cellular uptake of FCC nanoparticles was found to be higher than that of nanoparticles based on linoleic acid (LA) modified carboxymethyl chitosan because of the FA-receptor-mediated endocytosis, thereby providing higher cytotoxicity against Hela cells.     

具有吗啉侧基的聚氨基酸嵌段共聚物的控制释放研究

通过大分子引发开环聚合和侧基改性,制备了一种侧链含有吗啉丙基的聚乙二醇-聚(吗啉丙基-天冬酰胺)-聚丙氨酸三嵌段共聚物。利用肿瘤细胞外、细胞内和正常组织pH值环境的差异,调节聚合物载药纳米粒子的结构和性能实现肿瘤部位靶向释放的目的。在水溶液中,此聚合物可自组装形成一种核-壳-冠型的3层共聚物胶束,其中疏水性的聚丙氨酸链段自聚集形成胶束的核,聚(吗啉丙基-天冬酰胺)链段形成具有pH值-响应性的壳层,用于包埋和释放药物,外围的聚乙二醇链段可以提供一个稳定的水合冠层,延长药物的体内循环时间。以阿霉素作为模型药物在自组装的过程中包埋到胶束内。研究发现,由于吗啉环在酸性条件下的质子化导致链段亲疏水性质发生明显变化,载药胶束的药物释放能力随环境pH值的降低药物的释放速率显著增加。