多肽修饰脂质体靶向药物递送系统研究进展

目的 介绍近年来多肽修饰脂质体靶向药物递送系统的研究进展。方法 查阅和归纳总结近几年相关文献。结果 阐述了精氨酸-甘氨酸-天冬氨酸(RGD)多肽、丙氨酸-脯氨酸-精氨酸-脯氨酸-甘氨酸(APRPG)多肽、细胞穿透肽(CPP)、血管活性肠肽(VIP)等修饰脂质体的研究进展。多肽修饰的包载药物的脂质体可以增加药物在体内的选择性,减少药物毒副作用,提高药物治疗指数。结论 多肽分子是机体内一类重要的生物活性物质,将其作为导向物以配体-受体特异性结合的方式应用于靶向药物递送系统,具有良好的研究价值和应用前景。     

RGD肽在肿瘤靶向纳米给药系统中的应用

RGD肽是一类含有精氨酸一甘氨酸一天冬氨酸(Arg-Gly-Asp)的短肽,作为肿瘤细胞或者新生血管特异表达的整合素和其配体相互作用的识别位点,可介导肿瘤的靶向治疗.抗肿瘤药物及其递送系统经过RGD肽修饰.可增加药物的肿瘤主动靶向特性,达到更有效、精确和安全的治疗.本文主要综述了RGD肽在脂质体、聚合物胶束、基因载体等...     

两种RGD肽修饰的新型阿霉素脂质体的体外表征

目的作为配体,肽对于多种受体显示出良好的靶向性,例如在肿瘤表面过度表达的整合素家族受体。本文主要研究和表征分别用精氨酸-甘氨酸-天冬氨酸(RGD)三肽和甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸(GRGDS)五肽修饰的载药脂质体。方法分别采用RGD和GRGDS对包载阿霉素的立体稳定脂质体(SSL-doxorubicin)进行修饰,以制备RGD-SSL-doxorubicin和GRGDS-SSL-doxorubicin。在体外表征试验中,测定了各种脂质体的包封率、粒径、Zeta电位和释放率,采用SRB试验研究了各脂质体对卵巢癌细胞的细胞毒作用,并应用流式细胞仪和共聚焦显微镜考察了肿瘤细胞对各脂质体包封的阿霉素的摄取情况。结果所有脂质体的包封率均在95%以上,采用RGD或GRGDS进行的修饰并未影响长循环脂质体的包封率。各种脂质体的平均粒径在105.7±3.5nm和130.5±3.0nm之间,Zeta电位在–3.3±0.3和–6.1±0.3mV之间,在模仿体内环境的释放介质(含胎牛血清)中,12小时内约有2/5的阿霉素从脂质体中释放。与游离阿霉素相比,修饰后的脂质体对肿瘤细胞的抑制率略有下降;在研究对阿霉素摄取的流式细胞试验和共聚焦试验中,也有类似现象出现。将各种脂质体分别加入肿瘤细胞后,阿霉素主要分布于SKOV-3的细胞核。结论本研究成功制备了两种分别用精氨酸-甘氨酸-天冬氨酸(RGD)三肽和甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸(GRGDS)五肽修饰的阿霉素脂质体。体外表征结果显示,该修饰不会显著改变立体稳定脂质体的性质。     

复方舒郁健脑脑靶向脂质体的制备及其在大鼠体内组织分布

目的：利用Angiopep修饰复方舒郁健脑脂质体,研究复方舒郁健脑脑靶向脂质体的制备方法并考察其在大鼠体内的组织分布,为复方舒郁健脑脑靶向脂质体治疗失眠等脑部疾病提供依据。方法：采用乙醇注入法制备复方舒郁健脑脂质体,将Angiopep通过马来酰化端基聚乙二醇（PEG—MAL）与复方脂质体连接,得到脑靶向脂质体;以脑内茯苓酸含量作为检测指标,研究脂质体的脑靶向性。结果：在所选工艺条件下,复方舒郁健脑脑靶向脂质体平均粒径约500nm;与普通脂质体相比,复方舒郁健脑脑靶向脂质体在主要靶器官脑部的药物浓度显著增高（P〈0．05）。结论：用多肽Angiopep修饰所得脑靶向脂质体可使药物透过血脑屏障（BBB）,其作为脑靶向药物递送载体具有良好的应用前景。     

T7/A7R肽修饰的替莫唑胺脂质体制备与表征

摘要：目的:制备由T7、A7R肽双重修饰的替莫唑胺脂质体,并进行初步的体外表征。方法:分别将T7、A7R与DSPE-PEG2000-Mal反应生成DSPE-PEG2000-T7和DSPE-PEG2000-A7R,逆相蒸发法制备双肽修饰的脂质体（T7/A7R-LP）,并进行相应的体外表征。结果:制备的脂质体近球形,粒径均匀,平均粒径（96.6±6.5） nm, zeta电位为-（5.15±1.03） mV,包封率（36.38±3.95）%;在4～8℃条件下放置30 d,粒径和zeta电位无显著变化,体外6 h释药完毕;细胞摄取试验表明T7/A7R-LP具有较好的脑部靶向递送能力。结论:制备的T7/A7R肽修饰的脂质体理化特性良好,性质较为稳定,具有一定的脑部药物递送前景。     

多肽介导的核酸药物递送系统研究进展

核酸药物作为新型基因治疗药物备受关注,但生物学稳定性差、易被体内核酸酶降解、生物利用度低、靶组织内聚集浓度低等是制约其发展的主要因素。新的药物递送技术的快速发展在一定程度上解决了核酸药物的稳定性及靶向递送问题,极大地推动了核酸药物的研发进展。尤其是多肽蛋白类递送载体,已成为核酸药物递送系统研究领域的热点之一。介绍核酸药物递送载体多肽修饰的两种主要方式——共价缀合和非共价络合,重点综述近年来多肽缀合物和复合物以及多肽修饰的载体在核酸药物递送系统中的应用研究,探讨多肽介导的核酸药物递送系统在应用中存在的问题,为新型核酸药物递送系统研发提供参考。     

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。     

肿瘤转移靶向肽修饰的阿霉素脂质体对高转移性乳腺癌细胞的靶向特异性研究

肿瘤转移日渐成为肿瘤治疗的重要靶标。本研究采用肿瘤转移靶向肽（TMT）与脂质材料（PEG-DSPE）偶联获得靶向化合物（TMT-PEG-DSPE）,用以构建靶向阿霉素脂质体（TMT-LS-DOX）。结果表明,TMT-LS-DOX呈现出良好的药剂学性质。选用高转移性乳腺癌细胞（MDA-MB-435S和MDA-MB-231）对该转移特异性递送系统进行评价,采用非转移性乳腺癌细胞（MCF-7）作为对照。游离TMT多肽浓度达100μg/mL时仍未显示出细胞毒性。与MCF-7相比,MDA-MB-435S及MDA-MB-231细胞对TMT-LS-DOX摄取增加,并经受体竞争性实验证明该促进作用由TMT介导。因此,TMT修饰的纳米载体可能成为增加化疗药物对高转移性乳腺癌特异性的一种新策略。     

RGD多肽结合型长循环脂质体的肿瘤靶向性研究

目的 :研究RGD(精氨酸、甘氨酸、天门冬氨酸 )多肽结合型长循环脂质体的肿瘤靶向性。方法 :将长循环脂质体 ,通过共价键反应与RGD基元多肽进行结合 ,然后研究其在荷瘤小白鼠体内的肿瘤靶向性。结果 :RGD结合型长循环脂质体在Colon26荷瘤小白鼠体内具有较好的肿瘤靶向性。结论 :含RGD基元多肽结合型长循环脂质体可能成为一种新型的受体介导靶向制剂     

短肽在靶向药物递送系统中的研究进展

近年来研究发现许多肿瘤细胞表面高表达一些肽类受体，这些肽类受体与相应的配体亲和性高，能以配体-受体方式特异性结合。以小片段活性肽作为导向物形成复合物而发展的靶向药物递送系统，能够将药物定向转运到靶细胞内，显示了良好的研究价值和应用前景。如蛙皮素/胃泌素释放肽受体介导的靶向药物递送系统、生长抑素受体介导的靶向药物递送系统、十肽SynB₃受体介导的靶向药物递送系统、黄体酮释放激素受体介导的靶向药物递送系统及其他肽类受体介导的靶向药物递送系统，其中短肽作为靶向基团与阿霉素、吡咯阿霉素、甲氨蝶呤、顺铂和喜树碱等结合形成高效的复合物，用于表达有相应受体的肿瘤，获得靶向治疗的研究非常有意义。     

脑靶向脂质体的研究进展

血脑屏障的存在使得大部分药物无法进入大脑,从而加大了中枢神经系统疾病的治疗难度。表面修饰的脂质体或一些特殊性质的脂质体可以作为特定的药物载体,将药物运输到相应组织或器官内。该文介绍了近年来脂质体脑靶向制剂,包括经表面修饰的脂质体、热敏脂质体和前阳离子脂质体等的研究进展。     

肝癌靶向的阳离子脂质体共递送多西他赛和siRNA的研究

肝细胞癌是全世界最常见的恶性肿瘤之一,居癌症相关死亡原因第三位。通过存纳米载体系统上修饰靶向配体可将药物主动靶向至肿瘤细胞。随着药物制剂学的发展,采用纳米给药系统共递送化疗药物与基因药物成为了治疗肿瘤的一种手段。本研究通过薄膜超声法制备了共包载多西他赛（DTx）和小干扰RNA（siRNA）的脂质体,并用SP94对其进行修饰。血清稳定性试验表明,脂质体能较好地保护siRNA免受血清中核酸酶的降解。与未修饰的阳离子脂质体相比,SP94修饰的阳离子脂质体显著增强了制剂的在肿瘤细胞内的摄取和对肿瘤细胞的抗增殖作用,表明了SP94的主动靶向作用。本课题成功构建了主动靶向肝癌的共包载DTx和siRNA的阳离子纳米粒给药系统,为肝细胞癌的治疗提供了新的研究思路。     

Application of sterylglucoside-containing particles for drug delivery

Recent advances in biotechnology have promoted biomolecular targeting of drugs, peptides and genes in the treatment and management of major diseases and infections. Therapeutic development of drugs and delivery systems may have various objectives: Systemic drugs require optimal delivery and uptake at target sites; peptide drugs require alternative routes of administration, such as nasal or intestinal absorption; gene medicines need to be delivered efficiently, safely and selectively to diseased areas. The propensity of ligand-modified liposomes to carry drugs and genes to desirable sites has been extensively examined and current reports show considerable progress in this field. Sterylglucoside (SG) is a novel absorption-enhancer of peptide drugs across nasal and intestinal mucosae. Physico-chemical properties and biodistribution of liposomes incorporating SG were studied and compared against the profiles of aglycon and sitosterol derivatives of SG. It was shown that SG particles aided colon drug delivery and increased bioavailability of peptide drugs after nasal and intestinal administration. In addition, they were able to enhance anticancer effects in liver cancer chemotherapy. Biological fate and interaction of SG with hepatocytes support the novel proposition of liver-targeting SG-liposomes.     

Liposome-based depot injection technologies

Liposomes have proven to be versatile carriers for the delivery of drugs. These carriers are biocompatible, since they are generally made from lipids commonly found in biologic systems and are biodegradable by the usual metabolic pathways. A sustained drug delivery system is useful when the efficacy of drugs is limited by the inability to maintain therapeutic concentrations. Furthermore, a depot delivery system can offer important advantages in the clinic, such as significantly reducing dose frequency and providing efficacy without toxicity. Because of their small size (<5μ.m), conventional liposomes (unilamellar and multilamellar) are limited in their ability to provide depot delivery of drugs when administered subcutaneously or intramuscularly. The small size of these liposomes results in relatively fast clearance from the injection site and a short duration of delivery, typically 1–4 days. Multivesicular liposomes (MVLs) are distinct from conventional liposomes in composition, structure, and size and are the only class of commercial liposomes that have demonstrated depot delivery of both small molecule and protein/peptide drugs. These MVLs are characterized by the presence of a continuous bilayer membrane, with numerous internal aqueous compartments that are contiguous and separated by bilayer septums. As a result of their larger size (median diameter typically 10–30μ.m), these MVLs are not rapidly cleared by tissue macrophages and can act as a drug depot providing slow release of drugs delivered through different routes of administration. Moreover, the biocompatibility and biodegradability of the MVL lipid matrix allows for the sustained delivery of drugs to sensitive areas. The unique architecture of MVLs provides high drug loading of water-soluble drugs, reasonable stability during storage, and control over the drug-release rate. Furthermore, the lipid composition of MVLs can be altered to deliver therapeutics over periods ranging from a few days to a month, in order to meet specific therapeutic needs. The capability of altering the rate of drug release from MVLs by varying the lipid composition provides a great deal of versatility for controlled delivery of a wide variety of therapeutics. This article reviews depot delivery with conventional liposomes, demonstrates through several examples the sustained depot delivery of small and macromolecular drugs using MVLs, and summarizes some novel delivery systems that combine liposomes with polymeric matrices and have the potential to expand the platform of liposomal depot delivery.     

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

Importance of the field: Targeted liposomal drugs represent the next evolution of liposomal drug delivery in cancer treatment. In various preclinical cancer models, antibody-targeted PEGylated liposomal drugs have demonstrated superior therapeutic effects over their non-targeted counterparts. Single chain Fv (scFv) has gained popularity in recent years as the targeting agent of choice over traditional targeting agents such as monoclonal antibodies (mAb) and antibody fragments (e.g., Fab′).

Areas covered in this review: This review is focused mainly on advances in scFv-targeted liposomal drug delivery for the treatment of cancers, based on a survey of the recent literature, and on experiments done in a murine model of human B-lymphoma, using anti-CD19 targeted liposomes targeted with whole mAb, Fab′ fragments and scFv fragments.

What the reader will gain: This review examines the recent advances in PEGylated immunoliposomal drug delivery, focusing on scFv fragments as targeting agents, in comparison with Fab′ and mAb.

Take home message: For clinical development, scFv are potentially preferred targeting agents for PEGylated liposomes over mAb and Fab′, owing to factors such as decreased immunogenicity, and pharmacokinetics/biodistribution profiles that are similar to non-targeted PEGylated (Stealth^®) liposomes.     

The influence of in vivo treatment of skin with liposomes on the topical absorption of a hydrophilic and a hydrophobic drug in vitro

Hairless mice were treated in vivo with empty phospholipid and ‘skin lipid’ liposomes, respectively. The deposition of a hydrophobic drug (hydrocortisone) and a hydrophilic drug (inulin) was investigated in both treated and untreated skin. It was found that drugs should be encapsulated in liposomes or at least be administered together with the lipid, to achieve targeted drug delivery. Pretreatment of the skin with liposomes did not show the advantage of liposomally encapsulated drugs.     

Novel O-palmitoylscleroglucan-coated liposomes as drug carriers: development, characterization and interaction with leuprolide

Polysaccharide-coated liposomes have been studied for their potential use for peptide drug delivery by the oral route because they are able to minimize the disruptive influences on peptide drugs of gastrointestinal fluids. The aim of this work was to synthesize and characterize a modified polysaccharide, O-palmitoylscleroglucan (PSCG), and to coat unilamellar liposomes for oral delivery of peptide drugs. To better evaluate the coating efficiency of PSCG, also scleroglucan (SCG)-coated liposomes were prepared. We studied the surface modification of liposomes and the SCG- and PSCG-coated liposomes were characterized in terms of size, shape, zeta potential, influence of polymer coating on bilayer fluidity, stability in serum, in simulated gastric and intestinal fluids and against sodium cholate and pancreatin. Leuprolide, a synthetic superpotent agonist of luteinizing hormone releasing hormone (LHRH) receptor, was chosen as a model peptide drug. After polymer coating the vesicle dimensions increased and the zeta potential shifted to less negative values. These results indicate that both SCG- and PSCG-coated liposomes surface and DSC results showed that PSCG was anchored on the liposomal surface. The stability of coated-liposomes in SGF, sodium cholate solution and pancreatin solution was increased. From this preliminary in vitro studies, it seems that PSCG-coated liposomes could be considered as a potential carrier for oral administration.     

Drug delivery targets and systems for targeted treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that selectively attacks human joints. The common non-targeted treatment approaches lead to obvious side effect and systemtic complication for RA patients. Therefore, targeted drug delivery for treatment of RA has gained much attetntion in the past few years. In this paper, we reviewed the potential targets (folate receptor, angiogenesis, matrix metalloproteases, selectins, vasoactive intestinal peptide receptor andFc-γ receptor) that could be utilised to facilitate the specific delivery of drugs to the inflammed synovium and also presented different drug delivery systems for targeting RA, including the liposomes, various types of nanoparticles, polymeric micelles and the macromolecular prodrugs. The strategies combining nanotechnologies and ligand mediated active targeting for RA would be emphatically illustrated, which was expected to be helpful for identifying technologies and drug delivery methods for targeted treatment of RA.     

Polymeric core-shell nanoparticles for therapeutics

1. Nanobiotechnologies have recently attracted significant attention from chemists, biologists, engineers and pharmaceutical scientists. In particular, they have been widely applied to improve drug, protein/peptide and gene delivery. 2. This review presents recent advances in the field of drug, protein/peptide and gene delivery using natural and synthetic polymer nanoparticles and explains how polymeric nanoparticles are specifically designed to suit the needs for targeted delivery of small molecular drugs, proteins/peptides and genes. In addition, some of the challenges and prospects for these technologies are discussed.     

Encapsulation enhancement and stabilization of insulin in cationic liposomes

The purpose of this study was to enhance encapsulation efficiency and sustained-release delivery for parenteral administration of a protein drug. To reduce the administration frequency of protein drugs, it is necessary to develop sustained delivery systems. In this study, protein drug-loaded cationic liposomes were formulated with dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), dioleoyl-3-trimethylammonium-propane (DOTAP), and cholesterol (CH) at a molar ratio of DOPE/DOTAP/CH of 2/1.5/2. Five mol% of distearoylphosphatidyl ethanolamine polyethylene glycol (DSPE-PEG) was added prior to encapsulation of the drug into liposomes. Insulin was chosen as a model protein drug and encapsulation efficiency was evaluated in various liposomes with and without DSPE-PEG. Scanning electron microscopy was used to examine the insulin-loaded cationic liposomes. Structural analysis was performed using spectropolarimetry. Additionally, the stability and cytotoxicity of insulin-loaded cationic liposomes were evaluated. Liposomes coated with DSPE-PEG showed higher insulin encapsulation efficiency than did those without DSPE-PEG, but not significantly. Moreover, among the liposomes coated with DSPE-PEG, those hydrated with 10% sucrose showed higher encapsulation efficiency than did liposomes hydrated in either phosphate-buffered saline or 5% dextrose. In vitro release of insulin was prolonged by cationic liposomes. Our findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of protein and peptide drugs to prolong efficacy and improve bioavailability.