脂质体作为抗肿瘤药物载体的应用研究

目前，应用脂质体作为抗肿瘤药物载体已成为趋势。脂质体可明显提高抗肿瘤药物的靶向性，延长药物的作用时间，降低药物毒性。作者对国内外普通脂质体和修饰脂质体（包括长循环脂质体、免疫脂质体、温度敏感脂质体和pH敏感脂质体）的相关文献进行了综述。结果表明，脂质体是抗肿瘤药物的理想载体，在肿瘤治疗中有着广阔的应用前景。     

新型药物载体免疫脂质体的研究进展

介绍了免疫脂质体的分类,主要分为抗体介导型免疫脂质体和受体介导型免疫脂质体;作用特点主要有靶向性、缓释型和细胞亲和性;并介绍了抗体与脂质体的主要连接方法;实际应用主要为作为抗肿瘤药物的载体、基因治疗的载体以及治疗中枢神经系统疾病的药物载体。     

受脂质体作为药物载体的研究进展

目的 :介绍脂质体作为药物载体的应用及最新发展动态。方法 :查阅国内外文献资料 ,对脂质体作为药物载体的特性、应用及发展动态分别加以阐述。结果与结论 :脂质体作为药物载体可提高药物的治疗指数 ,降低药物毒副作用。脂质体在提高药物制剂稳定性、提高药物靶向性及多途径给药等方面有了实质性进展 ,具有广阔的应用前景     

脂质体作为药物载体研究进展

脂质体是由磷脂分散在水中形成的具有双分子层的直径仅有几十纳米至数微米的超微球状粒子.1965年Bangham等[1]发现脂质体,20世纪70年代Gregoriadis等[2]首先将脂质体作为药物载体应用.由于脂质体具有独特的作用特点,而受到越来越多的关注.靶向性是脂质体作为药物载体的主要目标之一,脂质体是治疗肝寄生虫病、利什曼病等网状内皮系统疾病理想的药物载体,在肿瘤治疗方面,利用脂质体的靶向作用,将脂质体作为抗肿瘤药物的有效载体而得到广泛应用.另外,药物被包埋在脂质体中缓慢释放,在血循环中脂质体药物要比游离药物有更长的滞留时间,因而延长了药物的作用时间,起到长效作用[3].药物由于有脂质体包封将提高被包封药物的稳定性,还能保护定向至某些需治疗的靶器官或组织中释放,使这些靶器官或组织药物浓度提高,提高了药物的疗效,以此同时,另外一些器官或组织药物浓度分布很少,避免药物对这些器官或组织的影响,从而降低了药物的毒性[4].近年来脂质体用作基因转移的有效载体[5,6],较病毒类载体有更大的优势,受到广泛的关注.     

大豆甾醇及其葡萄糖苷对脂质体生物化学性质的影响

膜稳定性及药物靶向性是脂质体作为药物载体很重要的两个方面 ,大豆甾醇及其葡萄糖苷对脂质体这两方面性质具有明显的作用。大豆甾醇能显著提高脂质体膜稳定性 ,其膜稳定作用大于胆固醇 ,大豆甾醇脂质体可作为口服药物载体 ,提高药物吸收。而大豆甾醇葡萄糖苷能明显提高脂质体肝细胞靶向性 ,从而提高抗肿瘤药物的活性 ,同时大豆甾醇葡萄糖苷脂质体可作为鼻粘膜给药载体 ,提高药物鼻粘膜吸收。由于大豆甾醇及其葡萄糖苷为纯天然产物 ,安全、来源丰富和价格便宜 ,因此 ,具有很好的应用前景。     

受脂质体作为药物载体的研究进展

目的：介绍脂质体作为药物载体的应用及最新发展动态。方法：查阅国内外文献资料,对脂质体作为药物载体的特性、应用及发展动态分别加以阐述。结果与结论：脂质体作为药物载体可提高药物的治疗指数,降低药物毒副作用。脂质体在提高药物制剂稳定性、提高药物靶向性及多途径给药等方面有了实质性进展,具有广阔的应用前景。     

大豆甾醇及葡萄糖苷对脂质体生物化学性质的影响

膜稳定性及药物靶向性是脂质体作为药物载体很重要的两个方面,大豆甾醇及其葡萄糖苷对脂质体这两方面性质具有明显的作用。大豆甾醇能显著提高脂质体膜稳定性,其膜稳定作用大于胆固醇,大豆甾醇脂质体可作为口服药物载体,提高药物吸收。而大豆甾醇葡萄糖苷能明显提高脂质体肝细胞靶向性,从而提高抗肿瘤药物的活性,同时大豆甾醇葡萄糖苷脂质体可作为鼻粘膜给药载体,提高药物鼻粘膜吸收。由于大豆甾醇及其葡萄糖苷为天然产物,安全、来源丰富和价格便宜,因此,具有很好的应用前景。     

热敏脂质体

目的:综述热敏脂质体的原理和它作为靶向药物载体的应用。方法:论述了脂质体相变的原理和热敏脂质体的研究概况,以及携带化疗药物的热敏脂质体和肿瘤热疗结合后治疗效果的增强作用,指出了热敏脂质体的发展前景。结果:热敏脂质体有良好的热靶向性,在肿瘤治疗方面效果明显。结论:热敏脂质体是新一代热靶向药物载体,有重要的开发价值。     

热敏脂质体

目的:综述热敏脂质体的原理和它作为靶向药物载体的应用。方法:论述了脂质体相变的原理和热敏脂质体的研究概况,以及携带化疗药物的热敏脂质体和肿瘤热疗结合后治疗效果的增强作用,指出了热敏脂质体的发展前景。结果:热敏脂质体有良好的热靶向性,在肿瘤治疗方面效果明显。结论:热敏脂质体是新一代热靶向药物载体,有重要的开发价值。     

脂质体肺部给药系统的应用

介绍脂质体作为肺部给药载体的优点及其在抗感染药物、抗哮喘药物、抗肿瘤药物、多肽蛋白类药物、基因药物及抗氧剂的应用。     

The effect of PEG coating on in vitro cytotoxicity and in vivo disposition of topotecan loaded liposomes in rats

Amphoteric drugs encapsulated in PEGylated liposomes may not show superior therapeutic antitumor activity due to increased leakage rate of these drugs in presence of PEG-lipids. In order to investigate the effect of PEG coating on in vitro and in vivo characteristics of topotecan loaded liposomes, an amphoteric anticancer drug, PEGylated and conventional liposomes were prepared by lipid film hydration method. Various properties of the prepared nanoliposomes such as encapsulation efficiency, size, zeta potential, physical stability as well as the chemical stability of lactone form of topotecan, cytotoxicity and topotecan pharmacokinetics were evaluated. In vitro cytotoxic activity was evaluated on murine Lewis lung carcinoma (LLC) and human mammary adenocarcinoma (BT20) cells. Pharmacokinetic was evaluated in Wistar rats after i.v. injection of topotecan, formulated in PBS pH 7.4 or in conventional or in PEGylated liposomes. The conventional liposome (CL) formulation was composed of DSPC/cholesterol/DSPG (molar ratio; 7:7:3), while for PEGylated liposome the composition was DSPC/cholesterol/DSPG/DSPE-PEG(2000) (molar ratio; 7:7:3:1.28). The size of both liposomes was around 100 nm with polydispersity index of about 0.1. In comparison with free drug, liposomal topotecan showed more stability for topotecan lactone form in vitro. Compared to free topotecan, PEGylated and conventional liposomes improved cytotoxic effect of topotecan against the two cancer cell line studied. The results of pharmacokinetic studies in rats showed that both CL and PEGylated liposomal formulations increased the concentration of total topotecan in plasma, however, initial concentration and the values of AUC, MRT and t(1/2 beta) were much higher (P<0.001) for PEGylated liposomal drug than for conventional one or free drug. PEGylated liposome resulted in a 52-fold and 2-fold increases in AUC(0-infinity) compared with that of free topotecan and CL, respectively. These results indicated that PEG modified liposome might be an effective carrier for topotecan.     

2-Hydroxyoleic acid-inserted liposomes as a multifunctional carrier of anticancer drugs

Studies have shown that insertion of oleic acid into lipid bilayers can modulate the membrane properties of liposomes so as to improve their function as drug carriers. Considering that 2-hydroxyoleic acid (2OHOA), a potential antitumor agent currently undergoing clinical trials, is a derivative of oleic acid, we explored the possibility of developing 2OHOA-inserted liposomes as a multifunctional carrier of antitumor drugs in the present study. The insertion of 2OHOA into lipid bilayers was confirmed by surface charge determination and differential scanning calorimetry. 2OHOA insertion greatly decreased the order of dimyristoylphosphatidylcholine packing, produced a nanosized (<100?nm) dispersion, and improved the colloidal stability of liposomes during storage. Moreover, 2OHOA-inserted liposome forms exhibited greater growth inhibitory activity against cancer cells compared with free 2OHOA, and the growth-inhibitory activity of liposomal 2OHOA was selective for tumor cells. 2OHOA insertion greatly increased the liposome-incorporated concentration of hydrophobic model drugs, including mitoxantrone, paclitaxel, and all-trans retinoic acid (ATRA). The in vitro anticancer activity of ATRA-incorporated/2OHOA-inserted liposomes was significantly higher than that of ATRA-incorporated conventional liposomes. In a B16-F10 melanoma syngeneic mouse model, the tumor growth rate was significantly delayed in mice treated with ATRA-incorporated/2OHOA-inserted liposomes compared with that in the control group. Immunohistochemical analyses revealed that the enhanced antitumor activity of ATRA-incorporated/2OHOA-inserted liposomes was due, at least in part, to increased induction of apoptosis. Collectively, our findings indicate that 2OHOA-inserted liposomes exhibit multiple advantages as antitumor drug carriers, including the ability to simultaneously deliver two anticancer drugs – 2OHOA and incorporated drug – to the tumor tissue.     

脂质体的研究进展

本文主要介绍了脂质体作为药物靶向制剂载体的研究发展。分析了近年来脂质体在各类药物中的应用及其优点 ,最后提出了目前存在的一些问题及脂质体作为药物载体良好有发展前景     

The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs

The size of liposomes has been shown to be an important factor in the efficient delivery of an antitumor agent to a tumor. In this paper, the effects of the size of liposomes on the pharmacokinetics of liposomes and liposome-encapsulated drugs are discussed with reference to: (1) the circulation amount and residence time of liposomes in the blood, (2) the accumulation of liposomes in the tumor, and (3) in vivo drug release from liposomes. In addition, the effect of size on therapeutic activity (antitumor efficacy and toxicity) of a liposomal anticancer preparation is discussed. Finally we discuss the importance of liposome size in the design of a more effective liposomal antitumor preparation.     

Enhancement of anticancer activity in antineovascular therapy is based on the intratumoral distribution of the active targeting carrier for anticancer drugs

We previously observed the enhanced anticancer efficacy of anticancer drugs encapsulated in Ala-Pro-Arg-Pro-Gly-polyethyleneglycol-modified liposome (APRPG-PEG-Lip) in tumor-bearing mice, since APRPG peptide was used as an active targeting tool to angiogenic endothelium. This modality, antineovascular therapy (ANET), aims to eradicate tumor cells indirectly through damaging angiogenic vessels. In the present study, we examined the in vivo trafficking of APRPG-PEG-Lip labeled with [2-(18)F]2-fluoro-2-deoxy-D-glucose ([2-(18)F]FDG) by use of positron emission tomography (PET), and observed that the trafficking of this liposome was quite similar to that of non-targeted long-circulating liposome (PEG-Lip). Then, histochemical analysis of intratumoral distribution of both liposomes was performed by use of fluorescence-labeled liposomes. In contrast to in vivo trafficking, intratumoral distribution of both types of liposomes was quite different: APRPG-PEG-Lip was colocalized with angiogenic endothelial cells that were immunohistochemically stained for CD31, although PEG-Lip was localized around the angiogenic vessels. These results strongly suggest that intratumoral distribution of drug carrier is much more important for therapeutic efficacy than the total accumulation of the anticancer drug in the tumor, and that active delivery of anticancer drugs to angiogenic vessels is useful for cancer treatment.     

姜黄素-3单体脂质体的研制及评价

目的制备包封率高、粒径均匀、稳定性好的姜黄素-3(双脱甲氧基姜黄素,demethoxycurcumin)单体脂质体。方法通过均匀设计筛选工艺,以乙醇注入法等制备姜黄素-3脂质体。结果制备姜黄素-3脂质体平均粒径为130.5nm,分布均匀,平均包封率为87.89%,稳定性好。结论以脂质体技术包裹姜黄素-3单体形成脂质体制剂可行,为进一步研究在肿瘤治疗中的应用提供了基础。     

Protein-coated and polysaccharide-coated liposomes as drug carriers

Saccharides on the surface of cell membranes play an important role in cell-cell recognition, which is the most important process utilizable for targeting of drugs encapsulated in an artificial cell, liposome. To design a targetable drug carrier, hence, employing synthesized or natural glycolipids as the recognition site of the liposomal drug carrier is certainly one of useful approach. On the other hand, coating the outermost surface of liposomes with polysaccharide derivatives is also another way for liposomes to be utilized as a targetable drug carrier. In this review, from such a viewpoint, the importance and usefulness of saccharide moiety on the surface of liposomes will be discussed in conjunction with the targeting of drugs.     

Pharmacokinetics of targeting with liposomes

The optimization of drug disposition in the body leads to an increase in its therapeutic effect and to a decrease in adverse effects. Liposomes can serve as a potential drug carrier for achieving this. However, the behavior of a drug carrier system under in vivo conditions is complex. Therefore, a more complete understanding of the pharmacokinetics of liposomes themselves, as well as that of the encapsulated drug, is required. The optimization of the pharmacokinetics of liposomes can be performed by linking a pharmacodynamic model of the free drugs that are encapsulated into liposomes. Sensitivity analysis was applied to optimize the delivery system to maximize the antitumor effect of liposomal doxorubicin (DOX). Advanced technology for ligand-mediated selective targeting and intracellular targeting is also introduced for antitumor agents and for gene delivery systems.     

Development and characteristics of temperature-sensitive liposomes for vinorelbine bitartrate

A novel liposome with temperature-sensitivity for vinorelbine bitartrate (VB) was designed to enhance VB targeted delivery and antitumor effect. Liposomes without drugs were prepared by thin film hydration, and then VB was entrapped into liposomes by pH gradient loading method. The mean particle size of the liposomes was about 100 nm, and the drug entrapment efficiency was more than 90%. Stability data indicated that the liposome was physically and chemically stable for at least 6 months at 4 °C. In vitro drug release study showed that drugs hardly released at 37 °C; while at 42 °C, drugs released quickly. For in vivo experiments, the lung tumor model was established by subcutaneous inoculation of cell suspension on mice, liposomes and free VB were injected i.v. in mice, followed by exposure the tumors to hyperthermia (HT) for 30 min after administration. The ratio of inhibition tumor of temperature-sensitive liposomes group was significantly higher than the normal injection group. Combining temperature-sensitive liposomes with HT enhanced the delivery of VB and, consequently, its antitumor effects. This liposome could potentially produce viable clinical strategies for improved targeting and delivery of VB for treatment of cancer.