微粒给药系统实现细胞表面受体靶向给药的研究进展

伴随着对疾病在分子水平上的认识以及对材料处理可控制在纳米级的范围内,纳米技术在疾病的预防、诊断及治疗等方面得到了广泛的应用.在各种各样的应用途径发展过程中,纳米技术在生物医学、纳米粒子载体等方面的应用表现出一些很独特的优势,如在传输上、传感上及靶向上等.     

基于超声靶向微泡破坏技术的纳米给药系统的研究进展

纳米给药系统是治疗多种疾病,尤其是肿瘤的一种极具应用潜力的方法。然而,目前其药物输送效率仍难以满足靶向治疗的需要。超声靶向微泡破坏(UTMD)技术作为一种安全的物理靶向方法,可以增强组织渗透性和细胞膜通透性,进而提高纳米给药系统的药物递送效率。本文就UTMD介导的纳米给药系统的研究进行综述。     

纳米给药系统在肿瘤靶向治疗中的应用

背景:纳米材料是抗肿瘤药物的理想载体,具有重要的科学价值和应用价值,为临床抗肿瘤提供了新的有效手段.目的:系统评价纳米给药系统在肿瘤靶向治疗的基础研究及临床应用.方法:以“nanoparticle, cancer, drug delivery system, nanotube, nanosphere”为关键词,计算机检索北美临床试验注册中心及Web of Science数据库2000-01-01/2012-12-31发表的纳米给药系统在肿瘤靶向治疗相关临床试验注册项目及文献.根据纳入与排除标准筛选文献,将检索结果以注册号、注册题目、项目状态、干预措施、试验的申办者、试验的疾病种类导出进行评价质量及文献分析.结果与结论:①北美临床试验注册中心关于纳米给药系统在肿瘤靶向治疗的相关临床试验研究开始于1999年,共检索到注册项目489项,经查阅后,共有429项纳入了分析.美国注册的纳米载体肿瘤靶向给药临床试验项目最多,共112项,其次为加拿大24项.中国注册的临床试验有22项,其中大陆注册8项,香港地区注册4项,台湾地区注册10项.研究的注册数量2003年跌至谷底,只有5项注册项目,之后数量大幅度升高,在2008年注册项目数量达到顶峰,为56项.2008年后,注册的项目数量处于波动状态.②北美临床试验注册中心纳米给药系统在肿瘤靶向治疗的相关临床试验项目样本量在1-2000之间,以50人以下的小样本研究为主.研究的肿瘤类型以乳腺癌为主,其次为内分泌腺瘤及淋巴瘤.③2000-01-01/2012-12-31在Web of Science数据库发表的纳米载体肿瘤靶向给药相关文章4497篇,其中,美国发文量占总数比重最大(66.42%),发表文章2987篇.高被引文章主要发表在Proceedings of the National Academy of Sciences of the United States of America (《美国科学院院刊》).     

本期专题：药物载体材料与载药人工骨给药系统

1 长效缓释双药物人工骨的制备及释放特性,见2012年38期7126—7130页。 2 成骨生长肽壳聚糖海藻酸钠微球的制备及体外检测,见2012年25期4663-4666页。     

肾脏靶向治疗研究进展

靶向治疗就是把治疗作用或药物效应尽量限定在特定的靶细胞、组织或器官内,而不影响正常细胞、组织或器官的功能,从而提高疗效、减少毒副作用的一种方法。靶向治疗分为3个层次：一是针对某个器官,叫器官靶向;二是细胞靶向,针对某种类别的细胞;三是分子靶向,是选择细胞特异的靶点,应用针对该靶点的药物进行治疗。     

药物载体材料与载药人工骨给药系统

目前,全世界每年进行骨移植的患者数量仅次于输血,居同种异体组织移植第2位。每年全球有超过200万例骨移植应用于骨缺损修复。随着骨组织工程研究的进展,这一医学难题有望得到解决。然而人工骨移植后     

抗肿瘤纳米药物载体材料的安全性

目的:介绍抗肿瘤纳米药物载体材料在延长肿瘤内药物存留时间,减慢肿瘤生长,降低毒副作用中的优势,探讨抗肿瘤纳米药物载体材料的安全性.方法:以 "肿瘤,药物载体,载体材料,纳米技术,靶向" 为中文关键词,"cancer,drug carrier,carrier material,nanotechnology,targeting"为英文关键词,采用计算机检索1990-01/2009-12相关文章.结果:用于运载抗肿瘤药物的纳米材料有人工合成的有机高分子材料、天然生物大分子材料等,用其作为药物的载体可以有效降低抗肿瘤药物的不良反应并提高其疗效.人工合成的有机高分子材料纯度高,性能容易控制,并且具有良好的生物降解性能,已经成为世界范围内的开发热点.研究较多的有聚氰基丙烯酸烷基酯、聚乳酸、聚乳酸聚乙醇酸共聚物、聚酰胺-胺型树枝状高聚物等.天然生物大分子壳聚糖、白蛋白、明胶、淀粉等可作为纳米粒载体材料,具有良好的生物相容性、可降解性以及低毒性的特点.结论:纳米材料是抗肿瘤药物的理想载体,具有重要的科学价值和应用价值,为临床抗肿瘤提供了新的有效手段.     

靶向给药在慢性盆腔炎综合治疗中的应用及护理

慢性盆腔炎是妇科常见疾病之一,由于病程长,易反复发作,常规抗生素治疗效果欠佳或无效。因此,我科2002年12月-2004年5月采用抗生素结合靶向给药应用于慢性盆腔炎的综合治疗,效果满意,副作用小,病人易于接受,无痛苦,无不良反应,现报告如下。     

肿瘤靶向药物静脉给药流程优化的方法与效果

目的：探讨应用优化流程在肿瘤靶向药物静脉给药过程中的管理效果。方法依据《静脉输液护理实践指南》对传统的经验式靶向药物静脉给药流程进行优化,为靶向药物治疗的患者提供个体化、标准化、全程监控的静脉给药流程。比较流程优化前后给药错误发生率、患者满意度。结果流程优化前静脉给药的错误发生率为3．6％,优化流程后无一例给药错误,差异有统计学意义（χ2＝4．903, P＝0．027）;患者对护理工作的满意度从94．4％升高至97．8％,差异有统计学意义（χ2＝4．745, P＝0.029）。结论优化靶向药物静脉给药的护理流程,进一步确保了护理用药安全,增加了患者的满意度,有效提高了护士专业水平。     

Block copolymeric biotransport carriers as versatile vehicles for drug delivery

This review describes block copolymer-based systems that are used in drug formulation development. The use of amphiphilic block copolymers to modify pharmacological performance of various classes of drugs attracts more and more attention. This is largely attributable to the high tendency of block copolymer-based drug formulations to self-assemble, as well as flexibility of block copolymer chemistry, which allows precise tailoring of the carrier to virtually any chemical entity. Combination of these features allows adjustment of block copolymer-based drug formulations to achieve the most beneficial balance in drug biological interactions with the systems that control its circulation in and removal from the body and its therapeutic activity. The following major aspects are considered: 1) physical properties of formulations and the methods used to adjust these properties towards the highest pharmacological performance of the product; 2) combinatorial methods for optimisation of block copolymer-based formulations; 3) biological response modifying properties of block copolymer-based formulations.     

In situ-gelling gellan formulations as vehicles for oral drug delivery

Gels formed in situ following oral administration of 1% (w/v) aqueous solutions of gellan to rats and rabbits were evaluated as sustained-release vehicles. The formulation contained calcium ions in complexed form, the release of which in the acidic environment of the stomach caused gelation of the gellan gum. The in vitro release of theophylline from the rigid gellan gels followed root-time kinetics over a period of 6 h. Plasma levels of theophylline after oral administration of gellan solutions and a commercial oral sustained-release liquid dosage form containing an identical drug concentration were compared in both rats and rabbits. Bioavailability of theophylline from gellan gels formed by in situ gelation in the animal stomach was increased by four–fivefold in rats and threefold in rabbits compared with that from the commercial oral formulation. There was no significant difference in the mean residence times of theophylline when administered by these two vehicles.     

Designing peptide-based scaffolds as drug delivery vehicles.

Methods for delivering drugs into cells remain an important part of the process of designing drugs. One promising approach is the concept of loligomers, synthetic peptides composed of a branched polylysine core harboring identical arms. Loligomers are typically synthesized with eight arms, each carrying peptide signals guiding their import and localization into cells. The most important advantage of loligomers is the multivalent presentation of targeting signals resulting from a tentacular arrangement. Multivalency increases the efficiency of import and intracellular routing signals as compared to similar linear peptides. Secondly, it reduces and delays the impact of peptide degradation in terms of cellular processing and compartmentalization. The vectorial delivery of nucleus-directed loligomers into cells has recently been confirmed by microscopy and flow cytometry studies. Practical uses of loligomers as intracellular vehicles include the import of plasmid DNA into cells, the conjugation of chemical groups, such as photosensitizers for use in photodynamic therapy, and the incorporation of cytotoxic T-lymphocyte (CTL) epitopes with a view to creating synthetic vaccines. Branched peptides such as loligomers represent simple and versatile molecular vehicles with potential applications in a wide variety of drug design approaches.     

E-selectin as a target for drug delivery and molecular imaging

E-selectin, also known as CD62E, is a cell adhesion molecule expressed on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation and in the adhesion of metastatic cancer cells to the endothelium. E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. E-selectin has been chosen as a target for several therapeutic and medical imaging applications, based on its expression in the vicinity of inflammation, infection or cancer. These systems for drug delivery and molecular imaging include immunoconjugates, liposomes, nanoparticles, and microparticles prepared from a wide range of starting materials including lipids, synthetic polymers, polypeptides and organo-metallic structures. After a brief introduction presenting the selectin family and their implication in physiology and pathology, this review focuses on the formulation of these new delivery systems targeting E-selectin at a molecular level.     

Evaluation of polyanion-coated biodegradable polymeric micelles as drug delivery vehicles

Polymeric micelles, as drug delivery vehicles, must achieve specific targeting and high stability in the body for efficient drug delivery. We recently reported the preparation of polyanion-coated biodegradable polymeric micelles by coating positively charged polymeric micelles consisting of poly(l-lysine)-block-poly(l-lactide) (PLys-b-PLLA) AB diblock copolymers with anionic hyaluronic acid (HA) by polyion complex (PIC) formation. The obtained HA-coated micelles showed significantly higher stability in aqueous solution. In this study, to evaluate the HA-coated polymeric micelles as a drug carrier, model drug release from the micelles and cytotoxicity of the micelles were investigated. The HA-coated micelles showed sustained release of model drugs and low cytotoxicity. It is known that there are receptors for HA on liver sinusoidal endothelial cells (LSEC). Specific interactions of HA-coated micelles with LSECs and Kupffer cells were investigated and compared with polymeric micelles coated with other polyanionic polysaccharides, i.e., heparin (Hep) and carboxymethyl-dextran (CMDex). Although Hep-coated micelles and CMDex-coated micelles were incorporated into both Kupffer cells and LSECs, HA-coated micelles were taken up only into LSECs. These results suggest HA-coated micelles have potential utility as drug delivery vehicles exhibiting specific accumulation into LSECs.     

Novel periodontal drug delivery system for treatment of periodontitis.

A conceptually novel periodontal drug delivery system (DDS) is described that is intended for treatment of microbial infections associated with periodontitis. The DDS is a composite wafer with surface layers possessing adhesive properties, while the bulk layer consists of antimicrobial agents, biodegradable polymers, and matrix polymers. The wafers contain poly(lactic-co-glycolic acid) as the main bioerodible component used in the bulk layer and ethyl cellulose applied as a matrix polymer enabling diffusion-controlled release. Starch and other polymers in combination with AgNO(3) serve as coatings adhesive to the teeth. In vitro experiments demonstrate that the wafers are capable of zero-order release of antimicrobial agents such as silver nitrate, benzylpenicillin, and tetracycline, for over 4 weeks.     

Novel biomimetic polymersomes as polymer therapeutics for drug delivery.

Novel amphiphilic diblock copolymers, cholesterol-end-capped poly(2-methacryloyloxyethyl phosphorylcholine) (CMPC), which have poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) as hydrophilic segment and cholesterol as hydrophobic segment, was specially designed as drug delivery systems. Fluorescence probe technique and transmission electron microscope (TEM) characterizations indicated that this novel amphiphilic copolymer formed micelles structure in water and the critical micelle concentration (CMC) was determined to be 1.57 x 10(-7) mol/l. A commercial obtained polymeric amphiphiles, Cholesterol end capped PEO (CPEO), which had a similar structure with CMPC, was used as a control in the cytotoxicity test. While CPEO showed obvious cytotoxicity, cytotoxicity of this novel amphiphiles was not observed as indicated by cell culture. Anti-cancer drug adriamycin (ADR) was incorporated into the micelles by oil-in-water method. The size of the drug-containing micelles was less than 200 nm, and the size distribution of the drug-containing micelles showed a narrow and monodisperse unimodal pattern. The release rate of ADR from the nanosphere was slow and the release continued over 7 days and the release rate decreased with the increase of molecular weights of the copolymer and the amount of the drug entrapped. These experimental results suggested that the nanoparticles prepared from CMPC block copolymers could be a good candidate for injectable drug delivery carrier.     

Lipid-based microtubular drug delivery vehicles.

Lipid microtubules that self-assemble from a diacetylenic lipid are suitable structures for the sustained release of bioactive agents. Microtubules were loaded with agents under aqueous conditions and embedded in an agarose hydrogel for localization at areas of interest. Protein release from our microtubule-hydrogel delivery system was characterized in vitro, and in vivo biocompatibility was examined. The influences of protein molecular weight and initial loading concentration on release profile were evaluated by releasing test proteins myoglobin, albumin, and thyroglobulin. Protein molecular weight inversely affected the release rate, and loading with a higher protein concentration increased the mass but not the percent of initially loaded protein released daily. Preservation of protein activity was demonstrated by the ability of a neurotrophic factor released from the delivery system to induce neurite extension in PC12 cells. Bovine aortic smooth muscle cells co-cultured with the microtubule-hydrogel system showed no evidence of cytotoxicity and proliferated in the presence of the microtubules. Subcutaneous implantation of microtubules in rodents revealed no significant inflammatory response after 10 days. Our microtubule-hydrogel system is useful for applications where sustained release without contact between agent and organic solvents is desired.     

Responsive layer-by-layer materials for drug delivery

Due to its versatility and ease of use the layer-by-layer (LbL) assembly technique has been under intensive investigation for drug and gene delivery applications. Especially the development of responsive LbL materials has advanced significantly in recent years. Responsiveness plays an important role in many delivery applications, either for loading of therapeutics or controlled and triggered release. In general four basic mechanisms within responsive LbL films have been identified: disruption of layer interactions, degradation of the LbL film, multilayer destruction via physical stimuli, and phase transitions or polymer rearrangements within the LbL film. This review will outline these different mechanisms and highlight recent advances in these fields.     

Nanobiohybrids as delivery vehicles for camptothecin.

A novel method of delivering non-ionic, poorly water-soluble drugs such as campthothecin was developed. Camptothecin was first incorporated into micelles derived from negatively charged surfactants. The negatively charged micelles were then encapsulated in nanoparticles of magnesium-aluminum layered double hydroxides (LDHs) by an ion exchange process. The resulting nanobiohybrids released camptothecin rapidly with complete release within 10 min at both pH 4.8 and 7.2. The LDH complex with carmine released carmine within 30 min at pH 4.8, but took over 70 days at pH 7.2. When administered to Glioma cells in vitro, the nanobiohybrid containing camptothecin resulted in significantly lower survival times compared to untreated cells, or to cells incubated with the surfactant, the pristine LDH, or water (delivery medium). The encapsulation method allowed for an approximately threefold increase in solubility of camptothecin. In addition, the modification of the surface of the LDH provided potential site-directing of the nanohybrids. These enhancements to the delivery scheme suggest the potential use of these hybrids for a variety of drug therapies.