脂质体修饰性材料应用研究进展

脂质体作为低毒性与免疫原性的药物载体已被应用于难溶性、不稳定、毒性等药物的递送，但传统脂质体仍存在稳定性差、体内循环时间不足、主动靶向性不明显等缺陷，因此选择适宜的修饰性材料制备脂质体已成为必要手段。修饰脂质体的方法主要有：在膜材中加入表面活性剂或改性物质，在膜表面嵌插靶向配体物质，将配体与膜材偶联共同组成脂质体结构。通过总结近年来脂质体常用的修饰性材料，阐释修饰原理并分析其优势及弊端，为脂质体的研究与开发提供借鉴。     

主动靶向脂质体研究进展

目的 介绍主动靶向脂质体最新研究进展。方法 查阅近年来国内外相关文献,对主动靶向脂质体的表面修饰、配体选择及应用进行进行总结和归纳。结果 主动靶向脂质体的表面修饰有三种方法：作为组份直接制备;键合到脂质体表面;后插入法。主动靶向脂质体可以将药物传递到靶组织、靶向细胞或靶细胞器,提高药物的生物利用度,而不增加对正常组织或细胞的毒性,是近年研究最为广泛的主动靶向给药系统。结论 主动靶向脂质体是一种非常有前途的给药系统。     

新型脂质体的研究进展

作为药物传递系统的载体,几种新型脂质体如膜融合脂质体、柔性脂质体、表面修饰脂质体等的研究己取得显著进展.本文归纳和分析了近期有关脂质体稳定性、靶向性及修饰材料的文献.     

免疫脂质体作为靶向给药系统的研究进展

免疫脂质体是用抗体或其片段修饰的脂质体,能与靶细胞表面抗原或受体结合,从而对靶细胞具有分子水平上的识别能力。与游离药物、非特异抗体脂质体、单独单抗等相比,免疫脂质体有更好的选择性和更强的杀伤活性。在动物体内,免疫脂质体可使药物特异性分布在病灶部位,从而增强药物疗效、减轻不良反应,并且表面聚乙二醇化还增强了体内的循环时间。本文综述了用于修饰的不同种类抗体、抗体与免疫脂质体偶联方式,并总结了免疫脂质体在抗肿瘤药、基因治疗、活体成像技术以及在传染病、自身免疫和神经退行性疾病治疗方面的应用。     

用于抗肿瘤药物递送的脂质体表面修饰策略

脂质体作为一种传统的药物传递系统,因其在药物及蛋白质、基因、核酸等生物活性物质的高效传递方面的应用而备受研究领域的关注。脂质体给药系统在抗肿瘤药物研究领域经历了常规脂质体、长循环脂质体、配体功能脂质体、刺激响应型脂质体等4个阶段。现结合相关文献,综述了这4种脂质体给药系统常用的表面修饰靶向策略和研究进展,以期为脂质体的进一步研究和基本靶向修饰提供参考。     

pH值敏感型脂质体表面修饰技术的研究进展

pH 值敏感型脂质体表面修饰已成为脂质体制剂的研究热点,经过表面修饰的pH值敏感型脂质体进入人体后,在此特异性片段的介导下,被靶细胞识别,达到在靶细胞有针对性地释放药物和减少对机体正常组织损害的目的.对pH值敏感型脂质体进行表面修饰的主要目的有3个:延长体循环时间、增强pH值敏感性和提高靶向性.主要从这3方面综述近十年来pH值敏感型脂质体表面修饰的研究进展,为pH值敏感型脂质体表面修饰的进一步研究提供参考.     

聚乙二醇修饰的立体稳定脂质体

立体稳定脂质体（长效脂质体）是一种表面含有天然或合成聚合物修饰的类脂衍生物的新型脂质体。它在血液中驻留时间延长，从而延长药物作用时间，具有长效作用。将抗体或其他配体连接于长效脂质体表面的聚合物末端，可得到立体稳定的免疫脂质体，从而达到长效与靶向的完善结合。     

壳聚糖修饰绿原酸脂质体的制备及其体外透皮性能考察

采用Box-Behnken设计结合响应面法优化了绿原酸(1)脂质体的处方，再采用壳聚糖对1脂质体进行表面修饰。透射电镜观测结果显示，未表面修饰或表面修饰脂质体均为球形，表面修饰后的制品具有明显的核-壳结构。所得脂质体和表面修饰脂质体的粒径分别为(185.0±10.8)和(265.0±11.9)nm,ζ电位为(–18.3±2.1)和(45.6±3.5)mV。体外释放试验表明，1脂质体的体外释药行为用Higuchi模型拟合效果较好，而壳聚糖修饰脂质体则采用Korsmeyer-Peppas模型拟合的效果较好。采用改良的Franz扩散池法考察制品对小鼠皮肤的体外透皮性能。结果显示，1溶液、1脂质体和壳聚糖修饰1脂质体的稳态渗透通量分别为1.77、0.98、0.73μg·cm^-2·h^-1,36 h时的皮肤滞留量分别为(113.4±7.4)、(399.6±5.5)、(519.6±13.1)μg/cm²。可见，与1溶液和1脂质体相比，壳聚糖修饰1脂质体的皮肤渗透量减小，但皮肤滞留量增加，作为1皮肤给药载体具有较大潜力。     

双重修饰的主动靶向脂质体研究进展

主动靶向脂质体是靶向递药体系的一个重要角色。由于传统的单一基团修饰的主动靶向脂质体存在靶向效率不高、细胞摄取率不高等缺点,人们不断探索采用两种或多种不同识别分子或其他协同分子共同修饰脂质体。本文拟针对双重修饰脂质体技术的研究进展进行综述。通过对两种特异性配体或抗体共同修饰、特异性配体与细胞穿透肽共同修饰、两种细胞穿透肽共同修饰等不同类型的双重修饰脂质体的综述分析,我们发现双重修饰技术具有提高靶向准确性和靶向效率,提高药物摄取,提高对靶点的黏附能力和血流稳定性等优势,尤其在跨膜穿越屏障系统的应用中凸显作用。     

脂质体靶向肿瘤相关巨噬细胞的研究进展

肿瘤相关巨噬细胞(TAM)在肿瘤生长和促进血管生成上有重要作用.脂质体是新型的给药系统,通过改变脂质组成,改变粒径电位或表面修饰,特异性靶向巨噬细胞.负载药物的脂质体可以有效地减少TAM的数量或通过调节TAM的功能抑制肿瘤的生长.TAM在肿瘤中的作用已成为共识,脂质体给药系统介导的肿瘤相关巨噬细胞的靶向治疗也成为癌症治疗的新热点.     

PEG修饰鳖甲肽HGRFG脂质体的药动学研究

目的 制备鳖甲肽HGRFG脂质体以及聚乙二醇（polyethylene glycol,PEG）修饰后的长循环脂质体,考察经修饰的脂质体较未修饰脂质体在动物体内分布及滞留情况。方法 采用BLB/c裸鼠荧光活体成像实验,进行脂质体体内分布及代谢研究;采用药动学实验,初步探究2种载药脂质体在血浆内的滞留时间。结果 2种载药脂质体均能广泛分布于实验动物体内。与未经修饰的脂质体载药组相比,经PEG修饰的长循环脂质体载药组中裸鼠荧光全部消失的时间明显延长,药物在血浆滞留时间也明显延长。结论 经PEG修饰后的长循环脂质体可以延长药物在实验动物体内的滞留时间,延长药物半衰期。     

Effect of surface ligand density on cytotoxicity and pharmacokinetic profile of docetaxel loaded liposomes

Various biotin-modified liposomes incorporated with docetaxel (DTX) were prepared to study the effect of surface biotin density on the pharmacokinetic profile of the liposome. Four types of liposomes such as PEG modified liposome (PDL), 0.5% (mol) biotin modified liposome (0.5BDL), 1% (mol) biotin modified liposome (1BDL) and 2% (mol) biotin modified liposome (2BDL) were prepared using thin film dispersion method. The prepared liposomes were characterized by measuring encapsulation efficiency (EE), particle size, Zeta-potential, physical stability and drug release profiles in vitro. MTT assay was performed to elevate the cytotoxicity of liposomes on MCF-7 cells. In vivo evaluation was further performed to investigate the effect of biotin surface density on the pharmacokinetic profiles. All the prepared liposomes exhibited high encapsulation efficiency, small particle size, narrow particle distribution and sustained release profiles in vitro. In MTT assay, 0.5BDL showed largest tumor cell toxicity, compared with DTX solution. All liposomes containing DTX showed prolonged blood circulation in vivo, and 0.5BDL showed the longest circulation time among the biotin modified liposome. Surface modification of liposome had a negative impact on the circulation of liposomes in the blood, which needs to be considered when designing the ligand mediated targeting delivery systems. A proper amount of biotin liposome with 0.5% molar ratio is expected to produce the best anti-tumor effect.     

超氧化物歧化酶脂质体在大鼠体内的药代动力学和组织分布

目的考察3种超氧化物歧化酶(SOD)脂质体静脉给药后在大鼠体内的药代动力学和组织分布。方法 用反相蒸发法制备SOD脂质体，采用黄嘌呤氧化酶法检测SOD活力，静脉注射给药后，测定大鼠血中SOD含量变化和不同组织中SOD含量变化。结果在血浆中，SOD水溶液、SOD普通脂质体、用DSPE-PEG2000修饰的SOD脂质体、用Tween 80修饰的SOD脂质体的半衰期分别为0.25，0.34，0.66和0.41 h；AUC分别为12.48，24.66，41.16和33.02 μg·h·mL^-1。与普通脂质体比较，经过DSPE-PEG和Tween 80修饰后的脂质体，使肝、脾中SOD的含量有不同程度的降低，脑中含量有所提高。结论3种SOD脂质体均可不同程度地延长SOD的血浆半衰期，并以用DSPE-PEG2000修饰的SOD脂质体效果最好。与普通脂质体相比，用Tween 80修饰的SOD脂质体可以提高进入脑中的SOD量，用DSPE-PEG2000修饰的SOD脂质体可以减少肝脾对SOD的摄取。     

Liposome formulated with TAT-modified cholesterol for improving brain delivery and therapeutic efficacy on brain glioma in animals

The treatment of central nervous system diseases such as brain glioma is a major challenge due to the presence of the blood-brain barrier (BBB). A cell-penetrating peptide TAT (AYGRKKRRQRRR), which appears to enter cells with alacrity, was employed to enhance the delivery efficiency of normal drug formulation to the brain. Targeting liposomal formulations often apply modified phospholipids as anchors. However, cholesterol, another liposomal component more stable and cheaper, has not been fully investigated as an alternative anchor. In our study, TAT was covalently conjugated with cholesterol for preparing doxorubicin-loaded liposome for brain glioma therapy. Cellular uptake by brain capillary endothelial cells (BCECs) and C6 glioma cells was explored. The anti-proliferative activity against C6s confirmed strong inhibitory effect of the liposomes modified with doxorubicin-loaded TAT. The bio-distribution findings in brains and hearts were evident of higher efficiency of brain delivery and lower cardiotoxic risk. The results on survival of the brain glioma-bearing animals indicate that survival time of the glioma-bearing rats treated with TAT-modified liposome was much longer than in the other groups. In conclusion, the potency of the TAT-modified liposome to enter the BBB appears to be related with the TAT on the liposome's surface. The TAT-modified liposome may improve the therapeutic efficacy on brain glioma in vitro and in vivo.     

脂质体载药系统与抗肿瘤药物

目的:介绍脂质体载药系统在抗肿瘤药物治疗中的应用.方法:采用文献综述方法,主要介绍普通脂质体和一些经过修饰后的脂质体作为药物载体的研究情况.结果:脂质体作为抗肿瘤药物的载体是可行的,可显著降低抗肿瘤药物的毒副作用,增加血药浓度并延长作用时间,还可明显提高抗肿瘤药物作用的靶向性.结论:脂质体是抗肿瘤药物的理想载体,在抗肿瘤治疗中有广泛的应用前景.     

Liposomal drug delivery systems: an update review

The discovery of liposome or lipid vesicle emerged from self forming enclosed lipid bi-layer upon hydration; liposome drug delivery systems have played a significant role in formulation of potent drug to improve therapeutics. Recently the liposome formulations are targeted to reduce toxicity and increase accumulation at the target site. There are several new methods of liposome preparation based on lipid drug interaction and liposome disposition mechanism including the inhibition of rapid clearance of liposome by controlling particle size, charge and surface hydration. Most clinical applications of liposomal drug delivery are targeting to tissue with or without expression of target recognition molecules on lipid membrane. The liposomes are characterized with respect to physical, chemical and biological parameters. The sizing of liposome is also critical parameter which helps characterize the liposome which is usually performed by sequential extrusion at relatively low pressure through polycarbonate membrane (PCM). This mode of drug delivery lends more safety and efficacy to administration of several classes of drugs like antiviral, antifungal, antimicrobial, vaccines, anti-tubercular drugs and gene therapeutics. Present applications of the liposomes are in the immunology, dermatology, vaccine adjuvant, eye disorders, brain targeting, infective disease and in tumour therapy. The new developments in this field are the specific binding properties of a drug-carrying liposome to a target cell such as a tumor cell and specific molecules in the body (antibodies, proteins, peptides etc.); stealth liposomes which are especially being used as carriers for hydrophilic (water soluble) anticancer drugs like doxorubicin, mitoxantrone; and bisphosphonate-liposome mediated depletion of macrophages. This review would be a help to the researchers working in the area of liposomal drug delivery.     

多肽GRGDS修饰的紫杉醇长循环靶向脂质体的体外评价

目的:本研究以甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸(glycine-arginine-glycine-aspartic acid-serine,GRGDS)五肽修饰的脂质体作为抗癌药物.紫杉醇的载体,对其体外理化性质和细胞毒作用进行评览价.方法:采用化学偶联合成DSPE-PEG-GRGDS,以此作为导向性材料,采用薄膜分散法制备载紫杉醇的PEG修饰长循环脂质体(GRGDS-SSL-PTX),并对脂质体的包封率、粒径和体外释放率等性质进行了考察,同时采用人卵巢癌SKOV-3细胞和人乳腺癌MCF-7细胞进行了体外细胞生长抑制的评价.结果:与普通紫杉醇长循环脂质体(SSL-PTX)相比,本研究制备的紫杉醇主动靶向脂质体(GRGDS-SSL-PTX)的粒径、包封率、载药量、体外释放及稳定性等理化性质无显著差异,包封率约为95%,平均粒径为(115.5±2.2)和(117.5±1.3)nm.冰冻蚀刻透射电镜观察结果表明,脂质体外观基本圆整且均匀分散.体外释放结果表明,12 h内分别有67.9%和72.3%的PTX从SSL-PTX和GRGDS-SSL-PTX中释放.体外细胞毒实验结果表明,GRGDS-SSL-PTX对人卵巢癌SKOV-3细胞和人乳腺癌MCF-7细胞的生长抑制作用均有增强,分别为SSL-PTX的1.42倍和2.12倍.结论:GRGDS五肽修饰的紫杉醇靶向脂质体成功制备,将有利于体内肿瘤的靶向治疗效果.     

Development and pharmacokinetics of nimodipine-loaded liposomes

In order to improve the water solubility of nimodipine and prolong the time of the drug in the circulation, nimodipine-loaded liposomes with a small size and high entrapment efficiency were prepared by a method that was easy to scale up (the modified ethanol injection method). The nimodipine liposome dispersions were characterized with respect to particle size distribution, zeta potential and entrapment efficiency. Liposomal nimodipine and nimodipine solution were intravenously administered to mice as a single dose of 4 mg kg-1. The pharmacokinetic parameters of nimodipine changed significantly when encapsulated in liposomes. The clearance of nimodipine encapsulated in liposomes was reduced and the elimination half-life was prolonged. The ratios of the area under the curve values of nimodipine liposomes to nimodipine solution were 1.78 and 1.90 in plasma and cerebral tissue, respectively. The drug concentration in cerebral tissue and in plasma showed a good linear correlation, which showed that liposomes could efficiently deliver nimodipine into brain tissue. These findings suggest that intravenous administration of liposomal nimodipine produces higher and more stable plasma and cerebral drug concentrations compared with nimodipine solution. In conclusion, liposomal nimodipine is a promising alternative to the solution preparation.     

Rheological characterization and permeation behavior of poloxamer 407-based systems containing 5-aminolevulinic acid for potential application in photodynamic therapy

Although anti-retroviral therapy is the most efficient disease management strategy for HIV-AIDS, its applications are limited by several factors including the low bioavailability and first pass metabolism of the drugs. Nanocarriers such as liposomes have been developed to circumvent some of these problems. We report here preparation of novel liposome formulations for efficient delivery of anti-retroviral drugs to mammalian cells in culture. The liposomes were prepared and surface was modified using poly (ethylene glycol). Encapsulation efficiency of the anti-retroviral drug saquinavir was found to be approximately 33% and also exhibited sustained release of the drug. Although PEGylated liposomes were more stable in protein-supplemented media, had better colloidal stability and exhibited lesser sonochemical stability due to lower cavitation threshold. The cell viability studies using Jurkat T-cells revealed that the PEGylated liposomes loaded with saquinavir were less cytotoxic as compared to the non-PEGylated liposomes or free drug confirming the potential of the liposomes as a sustained drug-release system. The drug delivery potential of the liposomes loaded with Alexa flour 647 was evaluated using Jurkat T-cells and flow cytometry showing uptake upto 74%. Collectively, our data demonstrate efficient targeting of mammalian cells using novel liposome formulations with insignificant levels of cytotoxicity.     

Effects of lipid composition and preparation conditions on physical-chemical properties, technological parameters and in vitro biological activity of gemcitabine-loaded liposomes

The effects of lipid composition and preparation conditions on the physicochemical and technological properties of gemcitabine-loaded liposomes, as well as the in vitro anti-tumoral activity of various liposome formulations were investigated. Three liposome formulations were investigated: DPPC/Chol/Oleic acid (8:3:1 molar ratio, liposomes A), DPPC/Chol/DPPS (6:3:1 molar ratio, liposomes B) and DPPC/Chol/DSPE-MPEG (6:3:1 molar ratio, liposomes C). Multilamellar liposomes were prepared by using the TLE, FAT and DRV methods, while small unilamellar liposomes were obtained by extrusion through polycarbonate filters. Light scattering techniques were used to characterize liposome formulations. Loading capacity and release profiles of gemcitabine from various liposome formulations were also investigated. Caco-2 cells were used to evaluate in vitro the antitumoral activity of gemcitabine-loaded liposomes with respect to the free drug and also the intracellular drug uptake. Preparation methods and liposome lipid composition influenced both physicochemical parameters and drug delivery features. Liposomes with a size ranging from 200 nm to 7 microm were obtained. The gemcitabine entrapment was higher than that expected probably due to an interaction with the liposome lipid components. The following decreasing loading capacity order was observed: liposome B>liposome C>liposome A. Gemcitabine release from various liposome formulations is modulated by two different processes, i.e. desorption from and permeation through liposomal bilayers. MTT assay showed a greater cytotoxic effect of gemcitabine-loaded liposomes with respect to the free drug. The following decreasing anticancer activity order was observed between the various liposome formulations: liposome C>liposome A>liposome B. The increased anticancer activity is correlated to the ability of the colloidal carrier to increase the intracellular drug uptake. Due to the encouraging results and to the high liposome modularity various applications of potential therapeutic relevance can be envisaged for liposomes.