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。     

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.     

吸附介导脑内靶向递药系统的研究进展

目的：综述吸附介导脑内靶向递药系统的研究进展。方法：查阅近年来有关文献，进行归纳总结。结果：吸附介导促进脑转运主要是利用递药系统表面的正电荷与血脑屏障（BBB）膜上阴离子（包括腔面侧的唾液酸和基膜侧的硫酸肝素）之间的静电作用完成的。常见的递释系统有碱性多肽、阳离子化蛋白、嵌和蛋白和阳离子蛋白结合载药系统等。结论：通过吸附介导能够有效地促进药物的脑内转运，该类递释系统对于脑部疾病的治疗具有较高的应用前景。     

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。一般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部位。简介angiopep-2的生物学性质及转运形式,重点介绍其穿透血脑屏障和靶向递药的治疗作用研究进展。     

脑靶向给药载体的研究进展

目的：介绍近年来国内外脑靶向给药载体的研究进展及应用。方法：查阅近年的国内外文献，进行分析和整理。结果：综述了目前研究较多的受体介导转运载体、吸附介导转运载体、基因载体、内源性物质载体及药剂学修饰等载体的特点及应用。结论：新的脑靶向给药载体的研究将极大地促进脑部疾病治疗的发展。     

脑靶向给给药载体的研究进展

目的:介绍近年来国内外脑靶向给药栽体的研究进展及应用.方法:查阅近年的国内外文献,进行分析和整理.结果:综述了目前研究较多的受体介导转运载体、吸附介导转运载体、基因载体、内源性物质栽体及药剂学修饰等载体的特点及应用.结论:新的脑靶向给药载体的研究将极大地促进脑部疾病治疗的发展.     

诊断兼治疗的多功能肿瘤靶向纳米递释系统

肿瘤靶向纳米递释系统可特异性转运抗肿瘤药物至肿瘤部位发挥疗效,已成为国内外研究热点。兼具诊断与治疗的多功能肿瘤靶向纳米递释系统是近年来出现的一类新型纳米递释系统,可同时实现分子诊断试剂、抗肿瘤药物的肿瘤靶向递释,同步进行对肿瘤的诊断与治疗。本文综述了纳米递释系统的肿瘤靶向机制,以及诊断与治疗双功能系统的构建。     

受体介导的肝靶向载药系统研究进展

介绍近几年已报道的有关受体介导的肝靶向载药系统的研究情况。近年来受体介导的肝靶向载药系统的研究取得了一些可喜进展,相关配体-受体可与药物、脂质体、纳米粒、基因、偶联物等相连,提高药物或载体的肝靶向能力。受体介导机制在肝靶向载药系统的研究领域具有广阔的应用前景,尤其是肝脏特异性受体的不断发掘,丰富了肝主动靶向的理论体系,展示了肝脏疾病治疗的美好未来。     

叶酸受体介导的肿瘤靶向纳米递药系统

叶酸受体在上皮源性的恶性肿瘤细胞膜表面高度表达。叶酸靶向纳米递药系统具有叶酸-叶酸受体主动靶向和纳米递药系统被动靶向的双重优势,可实现化疗药物对肿瘤组织的靶向递送,有效提高药物疗效,减少毒副作用。本文就近年来研究较多的叶酸-脂质体、叶酸-树枝状聚合物、叶酸-聚合物胶束、叶酸-纳米球等叶酸受体介导的肿瘤靶向递药系统进行综述。     

经鼻脑靶向递药系统的研究进展

鼻腔与脑在解剖生理上的独特联系使得鼻腔给药作为脑内递药途径成为可能.鼻腔给药作为脑靶向的途径之一,可有效地使通过其他给药途径不易透过血脑屏障的药物绕过血脑屏障到达脑部,为中枢神经系统疾病的治疗提供了一种极有发展前景的脑内递药途径.就鼻腔给药脑靶向的依据、影响因素、评价方法、剂型等方面对经鼻脑靶向递药系统的研究现状进行总结.     

Strategies on the nuclear-targeted delivery of genes

Abstract

To improve the nuclear-targeted delivery of non-viral vectors, extensive effort has been carried out on the development of smart vectors which could overcome multiple barriers. The nuclear envelope presents a major barrier to transgene delivery. Viruses are capable of crossing the nuclear envelope to efficiently deliver their genome into the nucleus through the specialized protein components. However, non-viral vectors are preferred over viral ones because of the safety concerns associated with the latter. Non-viral delivery systems have been designed to include various types of components to enable nuclear translocation at the periphery of the nucleus. This review summarizes the progress of research regarding nuclear transport mechanisms. “Smart” non-viral vectors that have been modified by peptides and other small molecules are able to facilitate the nuclear translocation and enhance the efficacy of gene expression. The resulting technology may also enhance delivery of other macromolecules to the nucleus.     

Gene medicine: A new field of molecular medicine

Gene therapy has emerged as a new concept of therapeutic strategies to treat diseases which do not respond to the conventional therapies. The principle of gene therapy is to introduce genetic materials into patient cells to produce therapeutic proteins in these cells. Gene therapy is now at the stage where a number of dinical trials have been carried out to patients with gene-deficiency disease or cancer. Genetic materials for gene therapy are generally composed of gene expression system and gene delivery system. For the dinical application of gene therapy in a way which conventional drugs are used, researches have been focused on the design of gene delivery system which can offer high transfection efficiency with minimal toxicity. Currently, viral delivery systems generally provide higher transfection efficiency compared with non-viral delivery systems while non-viral delivery systems are less toxic, less immunogenic and manufacturable in large scale compared with viral systems. Recently, novel strategies towards the design of new non-viral delivery system, combination of viral and non-viral delivery systems and targeted delivery system have been extensively studied. The continued effort in this area will lead us to develop gene medicine as 'gene as a drug' in the near future.     

Effective gene delivery with novel liposomal bubbles and ultrasonic destruction technology

From the viewpoint of safety, non-viral vector systems represent an attractive gene delivery system for gene therapy. However, the transfection efficiency of non-viral vectors in vivo is generally very low. Previously, it was reported that microbubbles, utilized as imaging agents for diagnostic echocardiography, could promote gene delivery into cells when combined with ultrasound exposure. We therefore developed novel liposomal bubbles (Bubble liposomes) containing the lipid nanobubbles of perfluoropropane which is used as ultrasound imaging agent. These Bubble liposomes were smaller in diameter than conventional microbubbles and induced cavitation upon exposure to ultrasound. These results suggested that cavitation of these Bubble liposomes could be an efficient approach for delivering plasmid DNA into cells. In addition, in in vivo gene delivery, the combination of Bubble liposomes and ultrasound provided more effective gene delivery than conventional lipofection methods, further suggesting that Bubble liposomes could be effective as a non-viral vector system in in vivo gene delivery. In this review, we discuss the characteristics of Bubble liposomes and their potential utility as a gene delivery tool in vitro and in vivo.     

Nuclear targeting of viral and non-viral DNA

The nuclear envelope presents a major barrier to transgene delivery and expression using a non-viral vector. Virus is capable of overcoming the barrier to deliver their genetic materials efficiently into the nucleus by virtue of the specialized protein components with the unique amino acid sequences recognizing cellular nuclear transport machinery. However, considering the safety issues in the clinical gene therapy for treating critical human diseases, non-viral systems are highly promising compared with their viral counterparts. This review summarizes the progress on exploring the nuclear traffic mechanisms for the prominent viral vectors and the technological innovations for the nuclear delivery of non-viral DNA by mimicking those natural processes evolved for the viruses as well as for many cellular proteins.     

The features and shortcomings for gene delivery of current non-viral carriers

Since the viral vector for gene therapy has serious problems, including oncogenesity and other adverse effects, non-viral carriers have attracted a great deal of attention. Non-viral carriers are expected to achieve gene therapy without serious side effects. However, the most critical issue of gene delivery by non-viral carriers is the low-expression efficiencies of the desired gene. In order to apply non-viral carriers for gene therapy in practical clinical usage, further understanding of the cellular barriers against gene delivery is a prerequisite. Moreover, additional intelligent concepts for gene delivery are also needed. We will summarize the features and shortcomings of currently developed non-viral delivery systems. Especially, we will address the current progress of cationic lipids (lipoplex) and cationic polymers (polyplex) in terms of transfection efficiency. Furthermore, our group has developed a system that responds to the particular intracellular signals of target disease cells. We have named this gene delivery system a drug delivery system based on responses cellular signal (D-RECS). We will introduce this new concept of intelligent non-viral delivery system that our group recently developed.     

Targeted delivery to the nucleus

Macromolecules and supramolecular complexes are frequently required to enter and exit the nucleus during normal cell function, but access is restricted and exchange to and from the nucleus is tightly controlled. We describe the mechanisms which regulate nuclear import of endogenous molecules and indicate how viruses exploit these mechanisms during their life cycle. Opportunities exist to make use of natural pathways for delivery of therapeutic entities, in particular to develop safe and effective methods for gene therapy, although past attempts to design non-viral nuclear delivery systems have met with limited success. To increase the likelihood of success scientists will need an appreciation of the mechanisms by which viruses deliver their genomes to the nucleus, and will need a commitment to control the architecture of non-viral delivery systems at the molecular level. Effective delivery systems will require several attributes to facilitate endosomal escape, microtubular transport and uptake through the nuclear pore complex. The published literature provides a strong foundation for design of nuclear targeting systems. The challenge faced by delivery scientists is to assemble a system which is as effective as, for example, the adenovirus but which lacks its immunogenicity. This article reviews the relevant literature and indicates key areas for future research.     

Poly(amidoamine) dendrimer complexes as a platform for gene delivery

Introduction: Gene therapy is one of the most effective ways to treat major infectious diseases, cancer and genetic disorders. It is based on several viral and non-viral systems for nucleic acid delivery. The number of clinical trials based on application of non-viral drug and gene delivery systems is rapidly increasing.

Areas covered: This review discusses and summarizes recent advances in poly(amidoamine) dendrimers as effective gene carriers in vitro and in vivo, and their advantages and disadvantages relative to viral vectors and other non-viral systems (liposomes, linear polymers) are considered.

Expert opinion: In this regard, dendrimers are non-immunogenic and have the highest efficiency of transfection among other non-viral systems, and none of the drawbacks characteristic for viral systems. The toxicity of dendrimers both in vitro and in vivo is an important question that has been addressed on many occasions. Several non-toxic and efficient multifunctional dendrimer-based conjugates for gene delivery, along with modifications to improve transfection efficiency while decreasing cytotoxicity, are discussed. Twelve paradigms that affected the development of dendrimer-based gene delivery are described. The conclusion is that dendrimers are promising candidates for gene delivery, but this is just the beginning and further studies are required before using them in human gene therapy.     

Current status of polymeric gene delivery systems

Gene therapy provides great opportunities for treating diseases from genetic disorders, infections and cancer. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several non-viral gene transfer methods have been developed to overcome the safety problems of their viral counterpart. Polymer-based non-viral gene carriers have been used due to their merits in safety including the avoidance of potential immunogenecity and toxicity, the possibility of repeated administration, and the ease of the establishment of good manufacturing practice (GMP). A wide range of polymeric vectors have been utilized to deliver therapeutic genes in vivo. The modification of polymeric vectors has also shown successful improvements in achieving target-specific delivery and in promoting intracellular gene transfer efficiency. Various systemic and cellular barriers, including serum proteins in blood stream, cell membrane, endosomal compartment and nuclear membrane, were successfully circumvented by designing polymer carriers having a smart molecular structure. This review explores the recent development of polymeric gene carriers and presents the future directions for the application of the polymer-based gene delivery systems in gene therapy.     

Physical stabilization of DNA-based therapeutics

The development of non-viral vectors for gene delivery has primarily focused on improving the efficiency of gene transfer in vivo. Although there is clearly a need to improve delivery efficiency, studies also indicate that the physical stability of non-viral vectors is not nearly adequate for a marketable pharmaceutical product. Here, we describe the different strategies that have been used to enhance stability and discuss the mechanisms by which prolonged stabilization (>2 years) might be achieved.