细胞膜仿生纳米技术在肿瘤靶向递药系统中的研究进展

纳米技术的发展为构建安全高效、精准可控的药物递送系统(drug delivery system, DDS)提供了可能。其中,有机或无机合成纳米载体已被广泛报道并用于肿瘤治疗药物的递送,但部分载体存在易被机体内免疫系统清除、制备过程繁琐和体内安全性较差等问题。近年来,随着生物医学的发展,基于仿生技术的生物膜介导的纳米药物递送系统,因其有机整合了天然生物膜的低免疫原性、肿瘤靶向性和智能纳米载体设计的可调控性、多功能性,有望实现纳米技术在肿瘤靶向治疗上的新突破。本文基于细胞膜仿生技术和纳米医学在肿瘤治疗领域的最新进展,从细胞膜仿生纳米技术的实验基础、膜仿生纳米递药平台的分类和在肿瘤靶向治疗上的应用三方面进行阐述,旨在为仿生智能DDS的设计及其在肿瘤靶向治疗中的发展提供参考。     

基于组氨酸的肿瘤靶向药物递送系统研究进展

组氨酸作为一种碱性氨基酸, pK_a接近肿瘤弱酸微环境pH,其带电性和溶解性具有pH敏感性,在中性环境中,组氨酸不带电,表现为疏水特性,而在肿瘤酸性环境中,组氨酸可质子化带正电,同时转变为亲水特性,因此,组氨酸被广泛应用于靶向肿瘤弱酸性微环境的药物递送系统设计。本文全面综述了近年来基于组氨酸构建肿瘤靶向药物递送系统的研究进展,系统总结了利用组氨酸促进细胞摄取和调控药物释放的设计思路,并指出了相关研究工作的共性问题和未来发展方向。     

基于线粒体靶向纳米药物递送系统的设计及研究进展

线粒体参与能量提供、信号传导、细胞分化等诸多生理活动,在肿瘤的发生发展中起重要作用,以线粒体为靶标是一种癌症治疗新策略。利用纳米技术构建线粒体靶向纳米药物递送系统可改善传统药物溶解性,延长药物半衰期,提高其生物利用度及降低不良反应,有望解决肿瘤治疗中出现的耐药性问题。本综述着重于癌症治疗领域,介绍了线粒体靶向纳米药物递送系统用于癌症治疗的机制,并概述了近5年线粒体靶向纳米药物递送系统的设计思路、分类及应用研究,最后拓展分析了以线粒体为靶点的其他研究如仿生载体等,并讨论其存在的优势及不足,为未来纳米药物靶向线粒体的深入研究提供了依据。     

肿瘤微环境调节型细胞器靶向递药系统的研究进展

近年来,利用机体免疫系统进行抗肿瘤的免疫疗法受到了广泛关注。然而抑制性肿瘤微环境限制了免疫治疗的效果,因此克服肿瘤微环境及其中的免疫抑制性细胞的作用成为肿瘤免疫疗法的一大热点。纳米制剂具有重新编程免疫抑制性微环境的巨大潜力,为免疫治疗提供了有效策略。随着主动靶向性纳米载体技术的不断发展和对药物作用位点研究的不断深入,具有更精准主动靶向功能的亚细胞器靶向性纳米载体材料也受到越来越多的关注。本文简要介绍了各亚细胞器与肿瘤的关系,概述了基于酸碱性调节、活性氧含量、免疫原性及免疫抑制细胞的肿瘤微环境特点的纳米药物靶向递送系统的设计策略与研究进展,为亚细胞器途径靶向递药系统的构建及其在肿瘤免疫治疗方面的应用提供借鉴和参考。     

聚(β-氨基酯)肿瘤靶向给药系统的研究进展

聚(β-氨基酯)[poly(β-amino esters),PBAE]是一类p H敏感、低毒、合成方法简单且结构多样的药物载体,在肿瘤靶向给药系统中具有广阔的应用前景。本文主要总结了PBAE的结构特点和靶向递药特性,重点介绍PBAE作为靶向递药系统的应用形式和基于PBAE递送不同抗癌药物的肿瘤靶向给药系统。     

主动靶向肿瘤的纳米递药系统改善肿瘤免疫治疗研究进展

近年来,免疫疗法在肿瘤临床治疗方面已取得巨大进展,但在免疫治疗药物体内递送过程中仍存在肿瘤特异性差、肿瘤深部渗透率低和细胞摄取率低等问题,导致其疗效和安全性较差,严重限制了免疫疗法的临床效果。通过表面偶联的抗体或配体与靶细胞膜受体间的相互作用,设计构建主动靶向肿瘤的纳米递药系统(aNDDS)可提高药物在靶细胞内的浓度,为实现特异高效的药物递送提供了可行的策略。此外,一些特定类型的细胞膜因具有天然的靶向能力被用于仿生纳米载体的构建,进而提高药物的递送效率。基于主动靶向肿瘤纳米载体的诸多优势,科研人员也设计了一系列用于促进抗肿瘤免疫应答的aNDDS,并证明其可以提高免疫治疗的有效性和安全性。本文回顾了近年来aNDDS改善肿瘤免疫治疗的研究进展,并对该领域的主要挑战和未来的发展进行了展望。     

抗肿瘤药物靶向递送系统专刊评述

如果把原料药比作炸药,药物递送系统则像是大炮,可把炸药输送到靶标。杀伤力越大的炸药就越是需要精准输送,这就不难理解为什么抗肿瘤化疗药物特别需要靶向递送。理想的靶向递送系统可有效载带药物,克服生理病理屏障,实现靶组织/细胞的高效富集,发挥增效减毒的功效,在肿瘤治疗领域具有广阔应用前景,是递送系统研发的重要方向。     

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。     

口服多糖靶向药物递送体系在结肠疾病治疗中的应用研究进展

多糖(polysaccharide)作为常见的药物递送材料,具有来源广泛、生物安全性好及功能丰富等优点,在医药及食品领域应用广泛,特别是在结肠疾病的口服靶向药物递送中具有重要的研究和应用价值。利用多糖的结构与理化特性优势,目前研究已构建出基于pH响应、微生物酶响应、活性氧响应、肠黏膜吸附和受体分子靶向等递送策略的交联型纳米粒、自组装型纳米粒及水凝胶,并在结肠炎与结肠癌等消化道疾病治疗中展现出优异效果。本文综述了基于多糖的口服靶向型药物递送体系在结肠疾病治疗中的研究进展,并对其研究和应用前景进行深入讨论。     

肿瘤微环境响应型的RNA药物递送系统的研究进展

肿瘤作为全球危害人类健康的重大疾病之一,亟需寻找更加安全高效的治疗方案。核糖核酸(ribonucleic acid, RNA)药物的基因疗法可以调节肿瘤相关基因的表达,已在临床前和临床试验中展示出良好的抗肿瘤治疗潜力。基于肿瘤组织在pH、特异性酶浓度或氧化还原梯度变化等微环境信号特征与正常组织存在差异性,各类微环境响应型纳米载体正在被研究开发用于递送RNA药物,实现对肿瘤组织与细胞的靶向递送,提高RNA药物的抗肿瘤疗效并且降低不良反应。本文综述了肿瘤微环境的病生理特征以及各类肿瘤微环境响应型载体策略,旨在为设计安全高效的RNA药物肿瘤靶向递送系统提供参考。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.