超声微泡用于脑胶质瘤靶向药物递送

本文用超声微泡可逆地有限开放血脑屏障(blood-brain barrier,BBB),为抗肿瘤药物的脑内靶向递送打下基础。建立脑胶质瘤大鼠模型,探索低频超声(1 MHz)结合微泡对脑胶质瘤部位BBB开放的影响,并与非超声条件下伊文思蓝(Evans blue,EB)渗透BBB对比。考察超声的时机和时长对BBB渗透和脑组织的损伤作用。考察脑胶质瘤生长期对BBB渗透性的影响。结果表明,脑胶质瘤对BBB渗透性影响非常有限;而超声微泡可短暂有限开放BBB,并具有可逆性,可促进EB和核磁增强造影剂渗透BBB。超声时长30 s最合适,可开放BBB,并且对脑组织不会造成明显损伤。药物需在超声前注射才能借助BBB开放进入脑。超声微泡可安全有效开放BBB,控制时机和时长,能促进药物进入脑胶质瘤和脑组织。     

外泌体在脑靶向递送中的应用

血脑屏障(blood brain barrier, BBB)限制了大部分药物的脑靶向递送,进而影响神经系统疾病有效治疗。外泌体作为细胞衍生的纳米囊泡,可参与物质的细胞间运输、介导细胞间通讯和调节机体生物功能等,具有低免疫原性、低毒性及可天然跨越BBB的优点,在脑靶向递送中发挥重要作用。本文概括了外泌体分类、来源、脑靶向递送机制及其在脑部疾病中发挥的作用,为其临床应用提供参考。     

超声微泡介导的基因递送系统应用进展

超声波可聚焦于体内的特定部位。含气体微泡既可以作为医学超声显像的造影剂，又可以作为药物或基因载体。超声微泡有望实现基因的靶向递送，因此成为药物递送系统研究的热门领域。本文阐述了超声微泡介导的基因递送系统在心肌、血管、骨骼肌和肿瘤组织等方面的研究进展，讨论其在未来应用中面临的问题。     

超声诊断或治疗用微/纳泡的研究进展

过去几十年中,微泡作为超声造影剂广泛应用于肿瘤成像领域,随着研究的逐渐深入,超声靶向微泡破坏技术结合载药微泡能够实现药物的精准释放,发挥治疗作用。微泡作为微米级载体难以透过肿瘤内皮细胞间隙,纳米级递药系统——纳泡应运而生,两者结构特征相似,但尺寸上的差异突显出纳泡在药物递送方面独特的优势。本综述以外壳材料为分类原则,对用作超声诊断或治疗的微/纳泡进行归纳总结,并探讨其未来可能的发展方向,为微/纳泡的后续开发提供参考。     

一种新的药物传递系统——超声微泡剂

目的：探讨超声微泡剂作为药物载体传输药物的机制及临床应用前景。方法：查阅国内外文献，进行归纳总结，分析其作用机制及应用前景。结果：超声微泡剂可作为药物载体，可传输基因和药物，能提高基因的转染率和表达，配合超声处理产生的空化效应可提高细胞膜的通透性，利于药物穿透；并且具有靶向性。因此在基因治疗和抗肿瘤治疗方面有很好的应用前景。结论：随着超声技术和微泡剂制备技术的发展，超声微泡剂必将为临床治疗提供一种安全、高效、无创的超声介导靶向传输及治疗系统。     

超声微泡造影剂在肿瘤治疗方面的研究进展

微泡载体技术是应用一定的技术手段将微泡与基因或药物结合在一起的一种新方法.超声造影剂结合超声技术可实现药物局部靶向释药.微泡载体技术和超声造影剂的联合使用在肿瘤诊断和治疗中发挥作用,尤其是在治疗肿瘤方面具有巨大的潜力.现简单介绍了超声造影剂和微泡载体技术,以及在肿瘤治疗中作为基因、药物的载体和在栓塞治疗中的研究进展.     

iRGD靶向载药脂质体-微泡复合物的制备及其靶向性研究

目的:制备iRGD靶向载药脂质体-微泡复合物,研究其靶向性。方法:采用薄膜-超声分散法制备生物素化的iRGD靶向载药脂质体和生物素化的超声微泡。利用生物素-亲和素系统(Biotin-avidin-system, BAS)连接脂质体与微泡,构建并表征iRGD靶向载药脂质体-微泡复合物。细胞黏附实验验证复合物的体外靶向结合性能;构建小鼠乳腺癌移植瘤模型,通过靶组织的药物荧光强度验证复合物的体内靶向性。结果:iRGD靶向载药脂质体的粒径为(165.07±4.01)nm,电位为(-12.92±0.26)mv,复合物的载药量为每10⁸个复合物载紫杉醇(46.22±1.95) μg;黏附实验表明靶向组复合物与血管内皮细胞结合数量明显多于非靶向组复合物(7.8±1.1,0.2±0.45,P<0.01);荷瘤小鼠活体成像实验显示靶向组复合物的肿瘤组织荧光明显强于非靶向组复合物。结论:iRGD靶向载药脂质体-微泡复合物,作为一种靶向给药系统,可以实现超声分子成像与超声给药的有机结合,显著提高药物靶向递送的效率。     

含气微泡介导反义寡核苷酸转染实验的参数优化

近年的研究表明，含气微泡在超声作用下的声孔效应（sonorporation）可明显增加基因的转染率，不仅安全性高，而且针对不同的基因具有定位和时空可控性。利用含气微泡作为基因与药物的超声靶向递送的载体，要求微泡的包膜材料在包裹气体的同时还必须具有足够的韧性和强度，使其在体内外都能保持一定的稳定性，特别是能克服体内动脉压力的影响。     

超声微泡靶向治疗急性心肌梗死的研究进展

随着人们生活习惯和饮食结构的改变，急性心肌梗死（acute myocardial infarction ，AMI）发病率逐年递增。如何有效减少心肌坏死并挽救缺血心肌是临床研究的重要目标，然而临床上常规应用的手术和药物治疗难以有效地挽救心肌细胞，避免不良事件发生。随着微泡技术的发展，超声靶向微泡破坏（ultrasound-targeted microbubble destruction ，UTMD）作为一种安全有效的靶向递送系统在未来有望成为急性心肌梗死治疗的一种有效手段。本文就UTMD在AMI治疗中的作用机制及应用进展做一综述。     

超声靶向微泡破裂增强恩度凝胶抑制裸鼠乳腺癌移植瘤血管生成作用

目的:探讨超声靶向微泡破裂对恩度凝胶瘤体内注射抑制裸鼠乳腺癌移植瘤血管生成作用的影响。方法:制备载恩度的PLGA-PEG-PLGA温度敏感型凝胶,检测恩度凝胶体外释放及超声辐照对药物释放的影响;建立荷人乳腺癌裸鼠移植瘤模型,分为模型组、恩度凝胶瘤体内注射组、恩度凝胶联合超声靶向微泡破裂组,每周治疗1次,连续3次后行肿瘤超声造影,测定肿瘤组织微血管密度,评价各种处理对肿瘤血管生成的抑制作用。结果:恩度凝胶在体外平稳释放约1周时间,超声辐照可提高恩度凝胶的释放速率;恩度凝胶瘤体内注射联合超声靶向微泡破裂处理具有明显的抑制肿瘤血管生成作用,肿瘤超声造影峰值强度及微血管密度均明显低于对照组及单纯恩度凝胶治疗组(P0.05)。结论:恩度凝胶联合超声靶向微泡破裂可阻断肿瘤微循环,并有效控制缓释载体的药物释放速率,使更多释放药物作用于血管内皮细胞,具有明显的抑制肿瘤血管生成作用。     

Drug delivery across the blood–brain barrier using focused ultrasound

Introduction: The presence of the blood–brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain.

Areas covered: The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed.

Expert opinion: The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.     

Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

The physiology of the vasculature in the central nervous system (CNS), which includes the blood–brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB.     

Ultrasound-induced blood-brain barrier opening

Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.     

泊洛沙姆在药物穿越血脑屏障中的重要作用

泊洛沙姆是一种具有药理活性的多功能药用辅料，在药剂学中应用广泛。近年来，研究发现泊洛沙姆可以通过多种作用机制帮助药物穿越血脑屏障，抑制血脑屏障上的P-糖蛋白、多药耐药相关蛋白等外排泵系统；吸附血浆中的不同载脂蛋白后，通过与血脑屏障上相应受体的结合，使泊洛沙姆包被的纳米粒主动转运入脑；连接各种配体及单克隆抗体等导向性分子，使其通过受体介导的转运进入脑部。本文综述了泊洛沙姆在促进药物穿越血脑屏障的重要作用，对设计脑靶向药物传递系统具有重要意义。     

Preparation,transportation mechanisms and brain-targeting evaluation in vivo of a chemical delivery system exploiting the blood–cerebrospinal fluid barrier

Abstract

In recent years, specific transportation mechanisms on the blood–brain barrier (BBB) are extensively employed for brain-targeted drug delivery via colloidal nanocarriers. However, in this study, we purposed to exploit the sodium-dependent vitamin C transporter 2 (SVCT2)-mediated transportation on the blood–cerebrospinal fluid barrier to enhance central nervous system penetration of the highly hydrophilic ibuprofen (IBU) by synthesizing a SVCT2-targeted chemical delivery system (CDS), ibuprofen-C6-O-ascorbic acid (IAA). The physicochemical parameters of IAA were determined, and the transporter-mediated transportation mechanism of IAA was explored on a BBB monolayer mode. The overall brain targeting effect of IAA was assayed on mice by measuring the biodistribution of IBU after i.v. administration and calculating the pharmacokinetic parameters and targeting indexes. Results showed that lipophilicity and solubility of IAA was conspicuously improved compared with IBU. At the physiological pH, IAA was stable while in brain homogenates it was easily degraded. Transport studies on the BBB monolayer mode revealed that IAA displayed higher transepithelial permeability than IBU via SVCT2. The biodistribution study in vivo demonstrated that the overall targeting efficiency of IAA was 1.77-fold greater than that of the IBU. In conclusion, the synthetic IAA might be a promising brain-targeted CDS for smuggling small-molecule hydrophilic pharmaceuticals into the brain.     

脑靶向性鼻腔给药的研究进展

鼻腔给药作为脑靶向给药的途径之一,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,靶向递送到脑部,为中枢神经系统疾病的治疗提供一种极有发展前景的给药途径.现从药物由鼻腔到脑的转运方式、影响因素、剂型、评价方法以及增强脑靶向性的方法等方面,对近年来鼻腔给药脑靶向性的研究进展进行综述.     

Therapeutic applications of lipid-coated microbubbles

Lipid-coated microbubbles represent a new class of agents with both diagnostic and therapeutic applications. Microbubbles have low density. Stabilization of microbubbles by lipid coatings creates low-density particles with unusual properties for diagnostic imaging and drug delivery. Perfluorocarbon (PFC) gases entrapped within lipid coatings make microbubbles that are sufficiently stable for circulation in the vasculature as blood pool agents. Microbubbles can be cavitated with ultrasound energy for site-specific local delivery of bioactive materials and for treatment of vascular thrombosis. The blood-brain barrier (BBB) can be reversibly opened without damaging the neurons using ultrasound applied across the intact skull to cavitate microbubbles within the cerebral microvasculature for delivery of both low and high molecular weight therapeutic compounds to the brain. The first lipid-coated PFC microbubble product is currently marketed for diagnostic ultrasound imaging. Clinical trials are currently in process for treatment of vascular thrombosis with ultrasound and lipid-coated PFC microbubbles (SonoLysis Therapy). Targeted microbubbles and acoustically active PFC nanoemulsions with specific ligands can be developed for detecting disease at the molecular level and targeted drug and gene delivery. Bioactive compounds can be incorporated into these carriers for site-specific delivery. Our aim is to cover the therapeutic applications of lipid-coated microbubbles and PFC emulsions in this review.     

Targeted Delivery of Nano-Therapeutics for Major Disorders of the Central Nervous System

Major central nervous system (CNS) disorders, including brain tumors, Alzheimer’s disease, Parkinson’s disease, and stroke, are significant threats to human health. Although impressive advances in the treatment of CNS disorders have been made during the past few decades, the success rates are still moderate if not poor. The blood–brain barrier (BBB) hampers the access of systemically administered drugs to the brain. The development of nanotechnology provides powerful tools to deliver therapeutics to target sites. Anchoring them with specific ligands can endow the nano-therapeutics with the appropriate properties to circumvent the BBB. In this review, the potential nanotechnology-based targeted drug delivery strategies for different CNS disorders are described. The limitations and future directions of brain-targeted delivery systems are also discussed.     

Liposomes for brain delivery

Introduction: Development of drug delivery systems for brain delivery is one of the most challenging research topics in pharmaceutical areas, mainly due to the presence of the blood–brain barrier (BBB), which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the majority of therapeutic agents. Among the several carriers, which have been studied to overcome this problem, liposomes have gained increasing attention as promising strategies for brain-targeted drug delivery. The most advantageous features of liposomes are their ability to incorporate and deliver large amounts of drug and the possibility to decorate their surface with different ligands.

Areas covered: The purpose of this review is to explore the different approaches studied to transport and deliver therapeutics and imaging agents to the brain by using liposomes. In the first part of the review, particular attention is paid to describe the anatomy of the BBB and different physiological transport mechanisms available for drug permeation. In the second part, the different strategies for the delivery of a drug to the brain using liposomes are reviewed for each transport mechanism.

Expert opinion: Over the last decade, there have been significant developments concerning liposomal brain delivery systems conjugated with selected ligands with high specificity and low immunogenicity. An universally useful liposomal formulation for brain targeting does not exist but liposome design must be modulated by the appropriate choice of the specific homing device and transport mechanism.     

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.