含环丙基结构的药物研究进展

环丙基的化学结构不同于直链脂肪烃和其他多元脂肪环,在药物分子的设计中经常被使用,具有增强药物的药效、增强代谢稳定性、降低脱靶作用、增强对受体的亲和力、限制多肽的水解作用、增加血脑屏障渗透率、降低血浆清除率以及改善药物的解离度(pK_a)等功效。含有环丙基结构的药物被开发用于治疗呼吸系统疾病、精神障碍类疾病、内分泌和代谢系统疾病、感染性疾病、神经系统疾病、心脑血管疾病以及肿瘤等。本文将对含有环丙基结构药物的研究进展进行综述。     

多功能Aβ有机小分子探针的构建及诊疗应用进展

阿尔茨海默症(AD)是最主要的进行性神经类疾病之一. β-淀粉样蛋白(Aβ)的形成、 错误折叠和聚集沉积被认为是该类疾病的重要病理学标志. 近年来, 研究人员基于荧光成像灵敏度高、 操作简便及副作用小的优点, 围绕脑部特殊的血脑屏障(BBB)系统和Aβ蛋白结构, 开发了一系列多功能Aβ探针应用于AD的诊疗研究. 本文分别从检测和治疗两个角度出发, 综合评述了Aβ诊疗探针的脑靶向设计、 波长调控和诊疗一体化的化学调控策略, 并展望了功能性荧光探针在该领域的应用前景.     

苯硼酸功能化聚合物纳米载体用于蛋白质药物胞内递送

蛋白质药物在疾病治疗方面具有广泛应用,但它们的低细胞膜穿透性往往导致生物利用度较低.近年来,人们开发了一系列纳米载体用于提高蛋白质药物的胞内递送效率,其中基于苯硼酸及其衍生物的聚合物纳米载体显示出良好的应用前景.本文综述了苯硼酸功能化聚合物纳米载体在蛋白质药物胞内递送方面的最新研究进展.首先,简要介绍了苯硼酸的化学性质及其二醇、pH和活性氧(ROS)响应性.其次,从苯硼酸与蛋白质药物的结合方式不同出发,重点综述了通过动态共价作用和N→B配位等非共价作用构筑的苯硼酸功能化聚合物纳米载体在蛋白质药物胞内递送方面的典型研究实例,并对这些载体的组成、构筑方式和响应性释放机制进行了分析、总结.最后,介绍了利用苯硼酸增强细胞摄取和促进药物透过血脑屏障方面的研究进展.希望能为设计制备基于苯硼酸的新型蛋白质药物胞内递送体系提供借鉴.     

一类全新阿片样二肽的设计合成及镇痛活性研究

阿片系统是疼痛研究的重要靶点, 阿片肽作为一类内源性的神经递质参与诸多生理调节尤其是在痛觉方面的调节, 被视为潜在的可以替代吗啡的深层次痛觉调节药物. 然而由于其固有的酶解稳定性差、镇痛作用不持久、难以透过血脑屏障等缺陷, 从而限制了其在临床方面的应用. 我们从阿片肽构效关系的角度出发, 设计并合成了4个新型二肽化合物, 在多种疼痛模型中显示, 中枢系统注射这类化合物能够表现出明显的镇痛活性, 外周系统注射发现这类化合物可以通过血脑屏障在中枢神经系统发挥有效的镇痛作用. 这一类二肽阿片化合物在多种实验模型中都表现出较好的药理学活性, 有可能发展为一类新型具有临床应用潜力的镇痛药物先导化合物.     

聚合物纳米药物载体的研究进展

近年来, 大量研究结果表明纳米技术可显著提高传统药物的疾病治疗效果, 并在生物医学领域引起了广泛关注. 迄今, 多种聚合物纳米体系已被研发并用于药物的靶向递送. 随着纳米技术的不断发展, 各类生物微环境响应的功能基团也被应用于构筑新型药物载体, 以提高患病部位的药物富集及减少药物的毒副作用. 聚合物纳米药物载体在癌症治疗、 代谢类疾病治疗及抗菌等方面展现出巨大潜力. 本文系统评述了聚合物纳米药物载体的最新研究进展及在生物医药方面的应用.     

基于环糊精的抗肿瘤药物主客体递送系统研究进展北大核心CSCD

恶性肿瘤是威胁人类健康的重大疾病。开发安全高效的抗肿瘤药物及其递送系统是改善抗肿瘤药物疗效的重要保证。近年来,基于环糊精的抗肿瘤药物主客体递送系统受到了广泛关注。环糊精是通过淀粉酶解获得的环状低聚糖,具有外部亲水内部疏水的特殊结构,在基因治疗、免疫细胞治疗、免疫靶向治疗和化疗中均得到了广泛的应用。本综述主要总结了环糊精作为抗癌药物递送载体近10年的相关进展,同时对主客体递送系统在癌症治疗方面的机遇和挑战进行了展望和讨论。     

甲状腺结合前清蛋白的理论研究

甲状腺结合前清蛋白TTR是一种具有重要生理功能的蛋白质,它是约30种与淀粉样疾病相关的非同源蛋白中的一种。与TTR相关的淀粉样疾病主要有：家族淀粉化心肌疾病,家族淀粉化神经系统疾病,老年系统性淀粉样病变,以及中枢神经系统选择性淀粉化疾病等。这些疾病是由TTR四聚体解聚过程中错误折叠形成cross-β-sheet结构形态的淀粉样纤维所导致。本文介绍了TTR的生理功能及结构特征,并综述了到目前为止用分子动力学模拟、分子对接和定量构效关系等方法在研究TTR淀粉样机理及TTR和小分子相互作用过程中的计算化学研究成果,为基于TTR结构的TTR淀粉样抑制剂药物分子的设计和筛选提供有力参考。     

肝靶向纳米给药系统的最新研究进展

肝脏疾病是威胁人类生命健康的重要疾病之一,对肝脏疾病检测及治疗方法的研究也引起人们的极大重视。靶向药物递送系统(TDDS)可将药物选择性地输送到靶点组织,从而提高药物的生物利用率并降低毒副作用,已引起了研究者的广泛关注。近年来,越来越多的研究尝试将靶向药物递送系统应用于肝脏疾病的显像检测以及药物/基因治疗,并取得了十分显著的成绩。本文将对近年来开发的新型纳米肝靶向给药系统,尤其是配体-受体介导的主动肝靶向给药系统在药物/基因递送以及显影检测方面的最新进展做一个综述,对各靶向给药系统的肝靶向能力进行了总结对比,并对肝靶向给药系统的发展方向进行了预测。     

生物分配色谱:高通量筛选药物膜通透性和活性

生物分配色谱是指在色谱系统中引入类生物膜结构,以色谱学方法仿真药物与生物膜的相互作用,现已成为评估药物膜通透性和活性的高通量筛选模型。根据最新进展并结合课题组研究内容,对其理论基础、分类及应用进行了评述,并对这一领域的发展和前景进行了展望。     

纳米高分子材料在医用载体方面的应用

医用纳米高分子作为药物、基因传递和控释的载体,是一种新型的控释体系,它与微米粒子载体的主要区别是超微小体积,它能穿过组织间隙并被细胞吸收,可通过人体最小的毛细血管,还可通过血脑屏障,因而作为新的控释体系而被广泛研究,具有广阔的发展前景,重点论述了纳米高分子控释系统在药物和基因载体方面的最新研究进展,并对其发展前景提出了展望。     

Nano Carrier Drug Delivery Systems for the Treatment of Neuropsychiatric Disorders: Advantages and Limitations

Neuropsychiatric diseases are one of the main causes of disability, affecting millions of people. Various drugs are used for its treatment, although no effective therapy has been found yet. The blood brain barrier (BBB) significantly complicates drugs delivery to the target cells in the brain tissues. One of the problem-solving methods is the usage of nanocontainer systems. In this review we summarized the data about nanoparticles drug delivery systems and their application for the treatment of neuropsychiatric disorders. Firstly, we described and characterized types of nanocarriers: inorganic nanoparticles, polymeric and lipid nanocarriers, their advantages and disadvantages. We discussed ways to interact with nerve tissue and methods of BBB penetration. We provided a summary of nanotechnology-based pharmacotherapy of schizophrenia, bipolar disorder, depression, anxiety disorder and Alzheimer’s disease, where development of nanocontainer drugs derives the most active. We described various experimental drugs for the treatment of Alzheimer’s disease that include vector nanocontainers targeted on β-amyloid or tau-protein. Integrally, nanoparticles can substantially improve the drug delivery as its implication can increase BBB permeability, the pharmacodynamics and bioavailability of applied drugs. Thus, nanotechnology is anticipated to overcome the limitations of existing pharmacotherapy of psychiatric disorders and to effectively combine various treatment modalities in that direction.     

Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening

Since most of the central nervous system (CNS) drug candidates show poor permeability across the blood-brain barrier (BBB), development of a reliable platform for permeability assay will greatly accelerate drug discovery. Herein, we constructed a microfluidic BBB model to mimic drug delivery into the brain to induce cytotoxicity at target cells. To reconstitute the in vivo BBB properties, human cerebral microvessel endothelial cells (hCMEC/D3) were dynamically cultured in a membrane-based microchannel. Sunitinib, a model drug, was then delivered into the microchannel and forced to permeate through the BBB model. The permeated amount was directly quantified by an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF MS) after on-chip SPE (μSPE) pretreatment. Moreover, the permeated drug was incubated with glioma cells (U251) cultured inside agarose gel in the downstream to investigate drug-induced cytotoxicity. The resultant permeability of sunitinib was highly correlated with literature reported value, and it only required 30 min and 5 μL of sample solution for each permeation experiment. Moreover, after 48 h of treatment, the survival rate of U251 cells cultured in 3D scaffolds was nearly 6% higher than that in 2D, which was in accordance with the previously reported results. These results demonstrate that this platform provides a valid tool for drug permeability and cytotoxicity assays which have great value for the research and development of CNS drugs.     

A Recurrent Neural Network model to predict blood–brain barrier permeability

The rapid development of computational methods and the increasing volume of chemical and biological data have contributed to an immense growth in chemical research. This field of study is known as “chemoinformatics,” which is a discipline that uses machine-learning techniques to extract, process, and extrapolate data from chemical structures. One of the significant lines of research in chemoinformatics is the study of blood–brain barrier (BBB) permeability, which aims to identify drug penetration into the central nervous system (CNS). In this research, we attempt to solve the problem of BBB permeability by predicting compounds penetration to the CNS. To accomplish this goal: (i) First, an overview is provided to the field of chemoinformatics, its definition, applications, and challenges, (ii) Second, a broad view is taken to investigate previous machine-learning and deep-learning computational models to solve BBB permeability. Based on the analysis of previous models, three main challenges that collectively affect the classifier performance are identified, which we define as “the triple constraints”; subsequently, we map each constraint to a proposed solution, (iii) Finally, we conclude this endeavor by proposing a deep learning based Recurrent Neural Network model, to predict BBB permeability (RNN-BBB model). Our model outperformed other studies from the literature by scoring an overall accuracy of 96.53%, and a specificity score of 98.08%. The obtained results confirm that addressing the triple constraints substantially improves the classification model capability specifically when predicting compounds with low penetration.     

Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB)

The blood-brain barrier (BBB), a unique selective barrier for the central nervous system (CNS), hinders the passage of most compounds to the CNS, complicating drug development. Innovative in vitro models of the BBB can provide useful insights into its role in CNS disease progression and drug delivery. Static transwell models lack fluidic shear stress, while the conventional dynamic in vitro BBB lacks a thin dual cell layer interface. To address both limitations, we developed a microfluidic blood-brain barrier (μBBB) which closely mimics the in vivo BBB with a dynamic environment and a comparatively thin culture membrane (10 μm). To test validity of the fabricated BBB model, μBBBs were cultured with b.End3 endothelial cells, both with and without co-cultured C8-D1A astrocytes, and their key properties were tested with optical imaging, trans-endothelial electrical resistance (TEER), and permeability assays. The resultant imaging of ZO-1 revealed clearly expressed tight junctions in b.End3 cells, Live/Dead assays indicated high cell viability, and astrocytic morphology of C8-D1A cells were confirmed by ESEM and GFAP immunostains. By day 3 of endothelial culture, TEER levels typically exceeded 250 Ω cm(2) in μBBB co-cultures, and 25 Ω cm(2) for transwell co-cultures. Instantaneous transient drop in TEER in response to histamine exposure was observed in real-time, followed by recovery, implying stability of the fabricated μBBB model. Resultant permeability coefficients were comparable to previous BBB models, and were significantly increased at higher pH (>10). These results demonstrate that the developed μBBB system is a valid model for some studies of BBB function and drug delivery.     

Oral delivery of polyester nanoparticles for brain-targeting: Challenges and opportunities

Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including:(1)instability in the gastrointestinal tract;(2) poor penetration of the intestinal mucosa and epithelium;(3)blood clearance; and(4) restriction by the BBB. Then the key factors infl...     

Insights into Multifunctional Nanoparticle-Based Drug Delivery Systems for Glioblastoma Treatment

Glioblastoma (GB) is an aggressive cancer with high microvascular proliferation, resulting in accelerated invasion and diffused infiltration into the surrounding brain tissues with very low survival rates. Treatment options are often multimodal, such as surgical resection with concurrent radiotherapy and chemotherapy. The development of resistance of tumor cells to radiation in the areas of hypoxia decreases the efficiency of such treatments. Additionally, the difficulty of ensuring drugs effectively cross the natural blood–brain barrier (BBB) substantially reduces treatment efficiency. These conditions concomitantly limit the efficacy of standard chemotherapeutic agents available for GB. Indeed, there is an urgent need of a multifunctional drug vehicle system that has potential to transport anticancer drugs efficiently to the target and can successfully cross the BBB. In this review, we summarize some nanoparticle (NP)-based therapeutics attached to GB cells with antigens and membrane receptors for site-directed drug targeting. Such multicore drug delivery systems are potentially biodegradable, site-directed, nontoxic to normal cells and offer long-lasting therapeutic effects against brain cancer. These models could have better therapeutic potential for GB as well as efficient drug delivery reaching the tumor milieu. The goal of this article is to provide key considerations and a better understanding of the development of nanotherapeutics with good targetability and better tolerability in the fight against GB.     

Shuttle-mediated drug delivery to the brain

Advances in the field of shuttle-mediated drug delivery have been made in the last decade; however, the treatment of brain disorders still remains a great challenge because of the presence of the blood-brain barrier (BBB), a structure that limits the access of drugs to their site of action in the central nervous system. Several strategies have been proposed to enhance the transport of drugs across the BBB. In this Review, we focus on the vector-mediated approach, in which a drug is coupled to a molecule (shuttle) that has the ability to cross the BBB and deliver the drug to the brain.     

Efficient Cholera Toxin B Subunit‐Based Nanoparticles with MRI Capability for Drug Delivery to the Brain Following Intranasal Administration

Alzheimer's disease (AD) is an incurable neurodegenerative brain disorder that exhibits clear pathologic changes in the hippocampus. Traditional drug delivery systems are ineffective due to the existence of the blood–brain barrier (BBB). In this study, an efficient, stable, and easily constructed nanosystem (CB‐Gd‐Cy5.5) based on the cholera toxin B subunit (CB) is designed to improve the efficiency of drug delivery to the brain, especially the hippocampus. Through intranasal administration, CB‐Gd‐Cy5.5 is easily delivered to the brain without intervention by the BBB. The CB in CB‐Gd‐Cy5.5 is used for specifically combining with the monosialoganglioside GM1, which is widely found in the hippocampus. This nanosystem exhibits impressive performance in accumulating in the hippocampus. In addition, the good magnetic resonance imaging (MRI) capability of CB‐Gd‐Cy5.5 can satisfy the monitoring of AD in the different stages.     

Progress in the Application of Nanoparticles and Graphene as Drug Carriers and on the Diagnosis of Brain Infections

The blood–brain barrier (BBB) is the protective sheath around the brain that protects the sensitive microenvironments of the brain. However, certain pathogens, viruses, and bacteria disrupt the endothelial barrier and cause infection and hence inflammation in meninges. Macromolecular therapeutics are unable to cross the tight junctions, thereby limiting their bioavailability in the brain. Recently, nanotechnology has brought a revolution in the field of drug delivery in brain infections. The nanostructures have high targeting accuracy and specificity to the receptors in the case of active targeting, which have made them the ideal cargoes to permeate across the BBB. In addition, nanomaterials with biomimetic functions have been introduced to efficiently cross the BBB to be engulfed by the pathogens. This review focuses on the nanotechnology-based drug delivery approaches for exploration in brain infections, including meningitis. Viruses, bacteria, fungi, or, rarely, protozoa or parasites may be the cause of brain infections. Moreover, inflammation of the meninges, called meningitis, is presently diagnosed using laboratory and imaging tests. Despite attempts to improve diagnostic instruments for brain infections and meningitis, due to its complicated and multidimensional nature and lack of successful diagnosis, meningitis appears almost untreatable. Potential for overcoming the difficulties and limitations related to conventional diagnostics has been shown by nanoparticles (NPs). Nanomedicine now offers new methods and perspectives to improve our knowledge of meningitis and can potentially give meningitis patients new hope. Here, we review traditional diagnosis tools and key nanoparticles (Au-NPs, graphene, carbon nanotubes (CNTs), QDs, etc.) for early diagnosis of brain infections and meningitis.     

Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase

The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline.