功能基修饰的脑靶向递药系统的研究概况

目的:研究功能基修饰的脑靶向递药系统,为提高脑靶向递药系统的靶向效率提供参考。方法:以"功能基""修饰""脑靶向""Functional group""Modified""Brain-targeting"等为关键词,组合查询2001年1月-2018年12月在中国知网、万方数据、维普网、PubMed、Elsevier、Springer Link等数据库中的相关文献,对功能基修饰的脑靶向递药系统进行综述。结果与结论:共检索到相关文献394篇,其中有效文献41篇。脑靶向包括受体介导(介导的受体如转铁蛋白受体、低密度脂蛋白受体、N-乙酰胆碱受体等)、转运体介导(介导的转运体如葡萄糖转运体、谷胱甘肽转运体等)、吸附介导。以上述受体、转运体的配体作为功能基,采用共价键结合或非共价键连接方法进行修饰,构建脑靶向递药系统;功能基通过与相应受体或转运体特异性结合,使药物跨越血脑屏障(BBB)并且在脑内病灶部位释药;除此之外,还可通过功能基带有的正电荷与BBB膜上的负电荷发生静电吸附作用产生非特异性的吸附,介导药物进入脑内。基于受体介导、转运体介导、吸附介导的靶向方式,有望提高脑组织中的药物浓度,提高中枢神经系统疾病的治疗效果,降低毒副作用及不良反应。与受体介导、转运体介导、吸附介导相比较,双级靶向可同时修饰两种靶向分子(一种靶向分子靶向于BBB,另一种靶向分子靶向于病灶),有望提高脑部疾病的治疗效果并降低药物在非病灶部位的蓄积,是一种更为理想的手段。在后续相关研究中建议开发新靶点和新型靶向分子,进一步提高脑靶向递药系统的靶向效率,为开发操作简单、成本低廉的脑靶向递药系统提供参考。     

大分子药物的脑靶向给药研究进展

介绍了几种脑靶向给药载体,如胰岛素受体单抗、转铁蛋白受体单抗、低密度脂蛋白受体单抗、与低密度脂蛋白受体相关的合成肽Angiopep-2、膜穿透肽以及来源于病毒衣壳糖蛋白中的肽段在外源性大分子物质尤其是蛋白质的脑靶向给药中的作用及研究进展。许多对中枢神经系统疾病具有潜在治疗作用的活性物质因其分子质量较大,脂溶性不佳而难以穿过血脑屏障发挥药效。血脑屏障中存在多种分子的受体,若以这些受体的抗体或配体为载体,则有可能实现外源性蛋白质的脑靶向转运。     

脑靶向非病毒基因递释系统的研究进展

脑靶向非病毒基因递释系统可有效介导基因药物跨越血脑屏障,到达病变部位发挥疗效,已成为研究热点之一。多项研究结果显示,通过适当机制如配体-受体特异性结合作用可显著提高非病毒基因递释系统在脑部的蓄积量,从而提高所携带外源基因在脑部的表达量。本文主要从受体介导和吸附介导两种机制入手,综述脑靶向非病毒基因递释系统的最新研究进展。     

长托宁

本品系新型选择性胆碱药，能通过血-脑屏障进入脑内。它能阻断乙酰胆碱对脑内毒蕈碱受体(M受体)和烟碱受体(N受体)的激动作用；因此，能较好地拮抗有机磷毒物(农药)中毒引起的中枢中毒症状，如惊厥，中枢呼吸、循环衰竭和烦躁不安等。     

RGD肽介导的脑胶质瘤靶向治疗和显像的研究进展

RGD肽是含有精氨酸-甘氨酸-门冬氨酸(Arg-Gly-Asp)序列的一类短肽,能和细胞表面的整合素受体特异性结合.整合素受体,尤其是αvβ3高表达于脑胶质瘤等肿瘤细胞表面,而在成熟血管内皮细胞呈低表达.因此,在脑胶质瘤的靶向治疗和显像研究中外源性RGD肽与肿瘤细胞表面的整合素受体的竞争性结合得到广泛研究.本文综述了RGD肽介导的脑胶质瘤靶向治疗及显像的典型方法及近年来的研究进展.     

非小细胞肺癌脑转移的靶向治疗进展

非小细胞肺癌(NSCLC)脑转移患者预后差,自然中位生存期短。靶向药物的应用可使NSCLC脑转移患者的生存期显著延长。目前已发现的驱动基因中,表皮生长因子受体(EGFR)基因突变的占比最大,间变性淋巴瘤激酶(ALK)融合基因重排的脑转移发生率最高。针对上述2种基因的靶向药物不断被研发,美国国立癌症综合网络(NCCN)指南也推荐了不同的靶向治疗方案。本文结合NCCN指南,综述靶点为EGFR突变和ALK重排的靶向药物研究现状,聚焦药物颅内效应,旨在为上述2种驱动基因阳性的NSCLC脑转移患者的靶向治疗提供用药参考。     

跨血脑屏障纳米递药系统的研究进展

血脑屏障是治疗多种中枢神经系统疾病的主要障碍.随着纳米技术的发展,新型脑靶向递药系统的研究取得了较大进展.该类递药系统可通过受体、转运体、吸附等介导的转胞吞作用,以及暂时破坏血脑屏障结构完整性等多种机制跨越血脑屏障并完成脑内药物递释,达到治疗中枢神经系统疾病的目的.本文综述了近年来跨血脑屏障纳米递药系统的研究进展.     

脑靶向给药的研究进展

通过查阅国内外相关文献,总结了近年来脑靶向给药的研究进展,为研制趋脑性给药系统及可透过血-脑屏障治疗中枢神经系统疾病的药物提供理论参考。初步探讨了脂质体、药质体、化学传递系统和磁性靶向给药的概念、应用与评价。     

纳米药物载体的脑靶向评价方法

利用纳米药物载体将难以透过血脑屏障的药物递送入脑是脑靶向治疗的策略之一,纳米药物载体脑靶向特性的评价是相关研究的重要环节。本文对体外细胞模型和体内光学成像、药代动力学、行为学检测等方法,以及脑摄取参数等体内外评价指标进行了综述,为系统评价纳米药物脑靶向特性提供方法学依据。     

Angiopep-2用于脑靶向递药系统的研究进展

随着社会的发展,脑部疾病已成为影响人类生活质量和健康的重要因素.一股给药系统很难穿透血脑屏障抵达病变部位,但靶向递药系统的出现,实现了药物在脑内递释,从而达到治疗的效果.Angiopep是一类能与低密度脂蛋白受体结合介导穿透血脑屏障的相关肽家族,其中angiopep-2可用于药物脑靶向递送,改善药物转运及精准作用于病变...     

The potential use of rabies virus glycoprotein-derived peptides to facilitate drug delivery into the central nervous system: a mini review

Rabies virus glycoprotein (RVG), a 505 amino acid type-1 glycoprotein, is responsible for the neurotrophic nature of the rabies virus infection. Despite varying reports in the literature as to which receptor is ultimately responsible for interaction of RVG with the nervous system, there is a strong argument for major nicotinic acetylcholine receptor (nAChR) involvement. Peptide derivatives of RVG, such as rabies virus-derived peptide (RDP) and RVG-29 are emerging as promising targeting ligands for the delivery of therapeutics to the central nervous system (CNS). The neurotrophic nature of RVG and indeed its derivatives may be due to interaction with ubiquitous nAChRs principally, but also association with other neural cell-specific molecules such as neural cell adhesion molecule (NCAM). It is possible that nAChR-mediated uptake of RVG-derived peptides may serve as an attractive new approach for targeting drug delivery to the brain. Potential application of this type of drug delivery system extends to many diseases affecting the CNS, where specific and effective drug delivery is normally a challenging process.     

Selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species-specific receptor-targeted antibodies

Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood–brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb–IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb–IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb–IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein.     

Selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species-specific receptor-targeted antibodies

Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood-brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb-IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb-IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb-IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein.     

A novel chemical delivery system for brain targeting

Two different chemical approaches for brain drug delivery and targeting are proposed in the present review. One is a chemical drug delivery using a ring-closure reaction to the hydrophilic quaternary thiazolium compound in the brain. The other is a chemical drug targeting utilizing the nutrient receptor (transporter) system on the blood-brain barrier. The brain delivery system has been optimized and it was demonstrated that the brain delivery of three drugs, a drug for Parkinson's disease, an excitatory amino acid antagonist and a free radical scavenger, were improved by the conjugation with cis-2-formylaminoethenylthio derivatives in vivo. As for the brain targeting system, it was demonstrated that the conjugation with L-Glu improved the drug's brain distribution via the L-Glu excitatory and/or transport receptors in vitro and in vivo. These findings suggest that the concepts of two chemical approaches will contribute to the development of new central nervous system drugs.     

Brain-Targeted Drug Delivery

Because the brain is tightly segregated from the circulating blood by a unique membranous barrier, the blood-brain barrier (BBB), many pharmaceuticals cannot be efficiently delivered to, or sustained within the brain; hence, they are ineffective in treating cerebral diseases. Therefore, drug delivery methods that can provide brain delivery, or eventually preferential brain delivery (i.e. brain targeting), are of particular interest. To achieve successful delivery, an understanding of the major structural, enzymatic, and active transport aspects related to the BBB, and of the issues related to lipophilicity and its role in CNS entry, is critical. During the last years, considerable effort was focused in the field of brain-targeted drug delivery. Various more or less sophisticated approaches, such as intracerebral delivery, intracerebroventricular delivery, intranasal delivery, BBB disruption, nanoparticles, receptor mediated transport (vector-mediated transport or ‘chimeric’ peptides), cell-penetrating peptides, prodrugs, and chemical delivery systems, have been attempted. These approaches may offer many intriguing possibilities for brain delivery and targeting, but only some have reached the phase where they can provide safe and effective human applications. Site-target indexing and the use of targeting enhancement factors can be used to quantitatively assess the site-targeting effectiveness from a pharmacokinetic perspective of chemical delivery systems.     

Effects of antisense oligonucleotides on brain delta-opioid receptor density and on SNC80-induced locomotor stimulation and colonic transit inhibition in rats

1. To reduce the density of delta-opioid receptor protein, five antisense phosphorothioate oligodeoxynucleotides (aODN), targeting the three exons of rat delta-opioid receptor mRNA (DOR), were injected twice daily for 4 days or continuously infused for 7 days into brain lateral ventricles (i.c.v.) of Sprague-Dawley rats. Rats acting as controls were infused or injected with a mismatch sequence (mODN) of each aODN. The density of opioid receptors in rat brain membranes was measured by saturation binding experiments using selective ligands for delta, mu and kappa opioid receptors. 2. aODNs injected twice a day for 4 days left rat brain delta-opioid receptor density unchanged. The ODN targeting the DOR nucleotide sequence 280 - 299 (aODN280 - 299, exon 2), decreased brain delta-opioid receptor density significantly more than aODNs targeting exon 1 (aODN239 - 258), exon 2 (aODN361 - 380), or exon 3 (aODN741 - 760) (to 52% vs 79, 72, and 68%). None of the aODNs to the DOR changed the brain density of mu- or k-opioid receptors. 3. When in a novel environment (but not when kept in their home cages), the locomotor activity of aODN280 - 299 treated rats was significantly lower than that of saline or mODN treated rats. The delta-opioid agonist SNC80 (5 mg kg-1, s.c.) significantly and potently stimulated locomotion and delayed colonic propulsion in saline- and mODN-infused rats, but left motor behaviour and colonic transit of delta-knockdown rats unchanged. 4. The baseline nociceptive threshold and the antinociceptive response to morphine were unchanged in delta-knockdown rats.     

T7 peptide-functionalized nanoparticles utilizing RNA interference for glioma dual targeting

Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood–brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors.     

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.     

NMDA receptors and schizophrenia

The pathophysiology of schizophrenia is poorly understood but is likely to involve alterations in excitatory glutamatergic signaling molecules in several areas of the brain. Clinical and experimental evidence has shown that expression of the N-methyl-D-aspartate (NMDA) receptor and intracellular NMDA receptor-interacting proteins of the glutaminergic synapse appear to be dysregulated in schizophrenia. It has been suggested that schizophrenia involves molecular changes in the glutamatergic pathways that mediate excitatory communication between multiple brain regions. Recent data also implicate abnormalities in cellular functions such as receptor trafficking and synaptic targeting.     

Development of radioligands for the imaging of α7 nicotinic acetylcholine receptors with positron emission tomography

Molecular imaging of brain structures by highly sensitive non-invasive techniques offers unique possibilities in the understanding of physiological and pathological processes in the central nervous system. In particular, the quantitative analysis by positron emission tomography (PET) of α7 nicotinic acetylcholine receptors (α7 nAChR), which are involved in different signalling pathways in the brain, is assumed to provide important information on the relation between receptor dysfunction and the pathogeneses of neuropsychiatric brain diseases, but the applicability of this imaging approach is still hampered due to insufficient imaging agents. This paper presents the recent efforts made to develop PET radiotracers targeting α7 nAChR as well as the current state of the evaluation of the most promising radiolabelled compounds in animal models and humans.