血脑屏障上的P—糖蛋白

Ｐ－糖蛋白是由多药耐药性基因编码的一个ＡＴＰ依赖性的药物外排泵，首先在肿瘤细胞上发现，也存在于脑毛细血管内皮细胞的腔面，使用体外培养的脑毛细血管内皮细胞、体内脑灌流技术、脑微透析技术和ｍｄｒ１ａ基因缺失鼠模型研究表明，Ｐ－糖蛋白主动排出许多化合物，如长春新碱、环孢素Ａ、秋水仙碱等，使它们的脑通透性降低，给予Ｐ－糖蛋白逆转剂可增加它们的脑浓度。因此，详细了解这个外排泵的作用机制，对研究靶药到脑或减少     

纳米粒穿透血脑屏障机制的研究进展

血脑屏障(blood-brain barrier,BBB)的存在使98%的药物无法进入脑组织,是制约神经系统药物发展的重要因素.纳米粒载药系统能够透过BBB,并提高脑内药物浓度,是实现脑内靶向给药的良好载体,但其透过BBB的机制至今尚未完全明白.自从2001年Kreuter提出关于纳米粒(nanoparticles,NP)透过BBB的6点可能机制后,针对此机制并进而提高载药NP入脑效率的探讨已成为热点之一,文中就目前NP穿透BBB机制研究进展做一综述.     

血脑屏障上的P-糖蛋白与药物转运功能

目的 :综述脑毛细血管内皮细胞上的P -糖蛋白药物外排功能。方法 :根据对有关的资料的分析、归纳、总结得出P -糖蛋白与脑内药物转运的关系。结果 :血脑屏障上的P -糖蛋白具有ATP依赖性的药物外排泵的功能 ,能降低脑内药物的浓度。结论 :利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应     

血脑屏障上的P-糖蛋白与药物转运功能

目的:综述脑毛细血管内皮细胞上的P -糖蛋白药物外排功能。方法:根据对有关的资料的分析、归纳、总结得出P -糖蛋白与脑内药物转运的关系。结果:血脑屏障上的P -糖蛋白具有ATP依赖性的药物外排泵的功能,能降低脑内药物的浓度。结论:利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应     

树枝状聚合物聚酰胺-胺作为药物载体应用研究进展

树枝状聚合物聚酰胺-胺(PAMAM)是一种三维的、高度枝化的树枝状高分子,具有单一分散性、无免疫原性、细胞毒性较低、生物可降解等特性,目前作为药物载体在药学领域引起了高度关注。文中分别综述了其载药机制及其在静脉、口服、经皮、眼部等不同给药途径的应用研究进展。研究发现其载药机制主要为物理包埋载药与静电、共价结合载药。PAMAM作为药物载体能够增加药物的溶解度,不同途径给药后能延缓药物的释放,增加药物皮肤渗透系数,延长角膜滞留时间,从而增加药物的生物利用度,是一种颇具发展潜力的新型药物载体。     

血脑屏障上的P-糖蛋白与药物转运功能

目的：综述脑毛细血管内皮细胞上的Ｐ－糖蛋白药物外排功能。方法：根据对有关的资料的分析,归纳,总结得出Ｐ－糖蛋白与脑内药物转运的关系。结果：血脑屏幕上的Ｐ－糖蛋白具有ＡＴＰ依赖性的药物外排泵的功能,能降低脑内药物的浓度。结论：利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应。     

肽类药物脑摄取特性的评价方法

肽类药物越来越多地用于疾病的治疗,中枢神经系统疾病的治疗也不例外.由于血脑屏障(BBB)的存在,向中枢神经系统转运肽类药物存在着许多问题,例如药物如何富集于脑、如何跨过BBB、如何进入神经元或神经胶质细胞等,均制约了肽类药物的开发与利用.为此,国内、外学者设计了许多方法,如嵌合肽等,使其先与脑毛细血管内皮细胞表面上的特异性受体或者与其表面含量丰富的转运蛋白结合,这些蛋白包括转铁蛋白受体、葡萄糖转运体-1.在受体等的介导下,这类药物先被内皮细胞内吞,然后以外吐的方式排泌到脑组织细胞间液,再作用于神经元、神经胶质细胞等的表面或进入其内部,发挥相应的药理作用.因此,这类药物在脑组织中的分布主要集中于4个区域:毛细血管内、脑毛细血管内皮细胞表面、脑毛细血管内皮细胞或周细胞内、脑实质细胞间液或细胞内.     

脑靶向给药方式及研究进展

血脑屏障（BBB）是一层连续的、覆盖在99％脑毛细血管表面的内皮细胞膜,由三部分组成：最内层是脑毛细血管内皮细胞及其之间的紧密连接,中间层为基质和周细胞,最外层是星形胶质细胞和细胞外基质。脑毛细血管内皮细胞间的紧密连接和彼此间的互相重叠（物理性）、     

抗感染药物对脑脊液的透过性

药物对中枢神经系统(CNS)的活性作用直接取决于其透过血脑屏障。这一屏障是由含有一种连续的内皮基底膜与邻近紧密相连的内皮细胞层的选择性可透过的毛细血管所组成。脑毛细血管缺乏基底膜毛孔和存在于全身的细胞间裂缝,但CNS外的毛细血管管壁可转运直径     

蛋白多肽类药物鼻黏膜给药直接入脑途径的研究进展

随着生物技术的发展,生物大分子在药学领域中的应用越来越广泛.大量的蛋白多肽类药物用于临床,给药剂学研究带来了新的机遇和挑战.许多蛋白质和多肽类药物均有中枢神经活性,而血脑屏障(blood brain barrier,BBB)的存在,阻碍了这些物质进入中枢神经系统(central nerves system,CNS)和发挥疗效.鼻黏膜给药后药物通过鼻黏膜直接入脑途径,可避开BBB而直接入脑,为蛋白多肽类药物进入脑中发挥疗效提供了一种有效的途径.     

A review of nanocarrier-based CNS delivery systems

Drug delivery to the central nervous system (CNS) is one of the most challenging fields of research and development for pharmaceutical and biotechnology products. A number of hydrophilic therapeutic agents, such as antibiotics, anticancer agents, or newly developed neuropeptides do not cross the blood brain barrier (BBB) after systemic administration. The BBB is formed by the tight junctions at the brain capillary endothelial cells, which strictly control drug transfer from blood to brain. Drug modification, osmotic opening of cerebral capillary endothelium, and alternative routes for administration (e.g., intracerebral delivery) have been successfully used to enhance drug transport to the CNS. The use of nanocarriers, such as liposomes and solid polymeric or lipid nanoparticles may be advantageous over the current strategies. These nanocarriers can not only mask the BBB limiting characteristics of the therapeutic drug molecule, but may also protect the drug from chemical/enzymatic degradation, and additionally provide the opportunity for sustained release characteristics. Reduction of toxicity to peripheral organs can also be achieved with these nanocarriers. This review article discusses the various barriers for drug delivery to the CNS and reviews the current state of nanocarriers for enhancing drug transport into the CNS.     

Blood-brain barrier genomics and the use of endogenous transporters to cause drug penetration into the brain

Blood-brain barrier (BBB) genomics enables the rapid discovery of novel transporters that are expressed at the brain capillary endothelium. The BBB transporters are potential conduits to the brain that therapeutic drugs may use to gain passage across the BBB. Due to the small volume of brain occupied by the endothelium (10(-3) parts of the brain), it is necessary to build a BBB genomics program that is separate from a whole-brain genomics analysis. It is estimated that approximately 15% of all genes selectively expressed at the BBB encode for transporter proteins, and that only approximately 50% of BBB transporters are currently known. The development of a BBB genomics program and the discovery of novel BBB transporters could lead to the invention of new approaches to solving the BBB drug delivery problem.     

Passage into the rat brain of dopa and dopamine injected into the lateral ventricle

1. The green fluorescence of catechols of the brain was studied in rats after intraventricular injection of L-dopa or dopamine in untreated rats as well as in rats in which dopa decarboxylase (DC) was inhibited by Ro 4602, or the monoamine oxidase by nialamide.2. From the patterns of fluorescence obtained in these conditions, it is concluded that in the areas close to the liquor space dopa is rapidly taken up by the endothelium of the brain capillaries and then converted into dopamine; when the DC is inhibited the dopa passes freely from the endothelium into the brain tissue.3. On the other hand, dopamine passes from the liquor space via the ependyma directly into the brain tissue and from there into the capillary endothelium which is thus permeable to the amine in the direction from the brain tissue, in contrast to the impermeability in the direction from the capillary lumen.     

Drug Targeting to the Brain

The goal of brain drug targeting technology is the delivery of therapeutics across the blood–brain barrier (BBB), including the human BBB. This is accomplished by re-engineering pharmaceuticals to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Certain endogenous peptides, such as insulin or transferrin, undergo receptor-mediated transport (RMT) across the BBB in vivo. In addition, peptidomimetic monoclonal antibodies (MAb) may also cross the BBB via RMT on the endogenous transporters. The MAb may be used as a molecular Trojan horse to ferry across the BBB large molecule pharmaceuticals, including recombinant proteins, antibodies, RNA interference drugs, or non-viral gene medicines. Fusion proteins of the molecular Trojan horse and either neurotrophins or single chain Fv antibodies have been genetically engineered. The fusion proteins retain bi-functional properties, and both bind the BBB receptor, to trigger transport into brain, and bind the cognate receptor inside brain to induce the pharmacologic effect. Trojan horse liposome technology enables the brain targeting of non-viral plasmid DNA. Molecular Trojan horses may be formulated with fusion protein technology, avidin–biotin technology, or Trojan horse liposomes to target to brain virtually any large molecule pharmaceutical.     

Exploiting the properties of biomolecules for brain targeting of nanoparticulate systems

The main obstacle in the treatment of central nervous system diseases is represented by a limited passage of diagnostic and therapeutic agents across the blood-brain barrier, which separates the blood stream from the cerebral parenchyma and maintains the homeostasis of the brain. The growing knowledge about the brain capillary endothelium and the discovery of specific mechanisms for the uptake of substances enables the development of various strategies to enhance the drug delivery rate into the brain. Among the different strategies, nanoparticles are promising candidates for drug delivery to the brain due to their potential in encapsulating drugs and thereby disguising their permeation limiting characteristics. Furthermore a surface functionalization of many nanoparticles can easily be achieved allowing the active targeting of nanoparticles to the brain. For this non-invasive approach, the surface functionalization of nanoparticles with biomolecules has shown promising potential for effective drug delivery to the brain. This review indexes the main classes of biomolecules used for the surface functionalization of nanoparticles and discusses their potential as drug delivery systems for an enhanced passage of diagnostic and therapeutic agents into the brain parenchyma.     

CSF,blood-brain barrier,and brain drug delivery

ABSTRACT

Introduction: There are 2 misconceptions about the cerebrospinal fluid (CSF), the blood-brain barrier (BBB), and brain drug delivery, which date back to the discovery of a barrier between blood and brain over 100 years ago. Misconception 1 is that drug distribution into CSF is a measure of BBB transport. Misconception 2 is that drug injected into the CSF compartment distributes to the inner parenchyma of brain.

Areas Covered: Drug distribution into the CSF is a function of drug transport across the choroid plexus, which forms the blood-CSF barrier, and not drug transport across the BBB, which is situated at the microvascular endothelium of brain. Drug injected into CSF undergoes rapid efflux to the blood compartment via bulk flow. Drug penetration into brain parenchyma from the CSF is limited by diffusion and drug concentrations in brain decrease exponentially relative to the CSF concentration.

Expert Opinion: The barrier between blood and brain was discovered in 1913, when it was believed that the BBB was localized to the choroid plexus, and that nutrient flow from blood passed through the CSF en route to brain. These misconceptions are still widely held, and hinder progress in the development of technology for BBB drug delivery.     

Transport of drugs across the blood-brain barrier in Alzheimer's disease

Alzheimer's disease, a neurodegenerative disorder, is associated with various pathological alterations to the blood-brain barrier, including disruption to the inter-endothelial tight junction proteins, altered expression of transport proteins involved in drug efflux, a reduction in cerebral blood flow and a thickening of the brain capillary basement membrane. There are many conflicting reports on whether such changes alter the ability of endogenous proteins to extravasate into the brain parenchyma, and there are even fewer reports focusing on the potential impact of these changes on drug transport into the CNS. The purpose of this review is to critically evaluate how the reported changes to the blood-brain barrier in Alzheimer's disease have (or have not) resulted in altered CNS drug delivery, and to highlight the requirement for more rigorous and systematic studies in this field for the benefit of drug discovery and delivery scientists.     

Uptake of Cationized Albumin Coupled Liposomes by Cultured Porcine Brain Microvessel Endothelial Cells and Intact Brain Capillaries

The suitability of protein-coupled liposomes as drug carriers for brain specific targeting was investigated using albumin (BSA) and cationized albumin (CBSA), respectively, as model proteins. Liposomes coated with polyethylene glycol (sterically stabilized, PEG-liposomes) were prepared from phosphatidylcholine, cholesterol, and a PEG-derivatized phospholipid and covalently coupled to thiolated BSA or CBSA. Liposomes were loaded with carboxy-fluorescein and rhodamine-labeled dipalmitoyl-phosphatidylethanolamine as hydrophilic and lipophilic marker compounds, respectively. The interaction of these constructs with monolayers of porcine brain capillary endothelial cells (BCEC) and freshly isolated porcine brain capillaries was studied by means of fluorescence assays and confocal laser scanning fluorescence microscopy (CLSFM). In contrast to BSA, CBSA was rapidly taken up by cultured BCECs. BSA-coupled liposomes did not interact with endothelial cells, whereas CBSA-coupled liposomes bound to cellular surfaces and exhibited time dependently a high intracellular accumulation. CBSA-conjugated liposomes were also taken up by intact brain capillaries. Cellular uptake could be inhibited by free cationized albumin, phenylarsineoxide, nocodazole, and filipin, but not by dansylcadaverine, suggesting a caveolae-mediated incorporation process. Immunostaining demonstrated a high expression of caveolin in the capillary endothelium. In conclusion, liposomes coupled to CBSA are taken up into brain endothelium via an endocytotic pathway and may therefore be a suitable carrier for drug delivery to the brain.     

Uptake of cationzied albumin coupled liposomes by cultured porcine brain microvessel endothelial cells and intact brain capillaries

The suitability of protein-coupled liposomes as drug carriers for brain specific targeting was investigated using albumin (BSA) and cationized albumin (CBSA), respectively, as model proteins. Liposomes coated with polyethylene glycol (sterically stabilized, PEG-liposomes) were prepared from phosphatidylcholine, cholesterol, and a PEG-derivatized phospholipid and covalently coupled to thiolated BSA or CBSA. Liposomes were loaded with carboxy-fluorescein and rhodamine-labeled dipalmitoyl-phosphatidylethanolamine as hydrophilic and lipophilic marker compounds, respectively. The interaction of these constructs with monolayers of porcine brain capillary endothelial cells (BCEC) and freshly isolated porcine brain capillaries was studied by means of fluorescence assays and confocal laser scanning fluorescence microscopy (CLSFM). In contrast to BSA, CBSA was rapidly taken up by cultured BCECs. BSA-coupled liposomes did not interact with endothelial cells, whereas CBSA-coupled liposomes bound to cellular surfaces and exhibited time dependently a high intracellular accumulation. CBSA-conjugated liposomes were also taken up by intact brain capillaries. Cellular uptake could be inhibited by free cationized albumin, phenylarsineoxide, nocodazole, and filipin, but not by dansylcadaverine, suggesting a caveolae-mediated incorporation process. Immunostaining demonstrated a high expression of caveolin in the capillary endothelium. In conclusion, liposomes coupled to CBSA are taken up into brain endothelium via an endocytotic pathway and may therefore be a suitable carrier for drug delivery to the brain.