经鼻纳米递药系统在中枢神经系统疾病治疗中的研究进展

中枢神经系统疾病治疗药物的脑内递送通常受限于血脑屏障。经鼻给药作为脑靶向递药的一种无创给药方式，可绕开血脑屏障，实现药物至脑部的直接、高效靶向输送，在中枢神经系统疾病治疗中具有极大应用潜力。然而，鼻腔黏液纤毛清除力等屏障限制了经鼻给药递送效果。依托纳米递药技术的发展，经鼻纳米递药系统为中枢神经系统疾病的治疗带来了新的希望。本文综述了经鼻入脑递药通路、常见经鼻纳米递药系统及其特性和治疗应用进展，为基于中枢神经系统疾病治疗的经鼻纳米递药系统设计提供思路和方法。     

纳米结构脂质载体在脑靶向传递体系的研究进展

随着全球环境不断恶化以及社会老龄化程度不断加深,中枢神经系统疾病已经成为社会关注的热点话题,而血脑屏障是治疗多种中枢神经系统疾病的主要障碍。纳米技术已被证明有效用于脑靶向的治疗,而纳米结构脂质载体是一种极具发展前景的新型纳米载体给药系统。通过查阅近年来的相关文献,本文介绍了纳米结构脂质载体和血脑屏障的结构特点,总结了药物透过血脑屏障的评价方法,并对纳米结构脂质载体在治疗中枢神经系统疾病中的应用进行综述。笔者对近年来纳米结构脂质载体在脑靶向传递体系的研究进展进行归纳和总结,同时对其发展前景进行展望,以期为今后纳米结构脂质载体用于中枢神经系统疾病的临床治疗提供更理想的治疗方案,为更深层次的理论研究和机制探索开拓思路。     

Strategies for Enhanced Drug Delivery to the Central Nervous System

Treating central nervous system diseases is very challenging because of the presence of a variety of formidable obstacles that impede drug delivery. Physiological barriers like the blood-brain barrier and blood-cerebrospinal fluid barrier as well as various efflux transporter proteins make the entry of drugs into the central nervous system very difficult. The present review provides a brief account of the blood brain barrier, the P-glycoprotein efflux and various strategies for enhancing drug delivery to the central nervous system.     

Current advances in delivery of biotherapeutics across the blood-brain barrier

Significant efforts through genomic approaches have been dedicated toward the identification of novel protein-protein interactions as promising therapeutic targets for indications such as Alzheimer's disease, Parkinson's disease and neuropsychiatric disorders. Additionally, the number of biotherapeutic agents entering the Pharmaceutical sector continues to increase and according to EvaluatePharma's "World Preview 2014" report, "the compounded annual growth rate of biologics is expected to be 8.5 percent from 2008-2014, eight to 10 times greater than the growth rate of small molecules". However, there are limited examples of success in developing biotherapeutic modalities for central nervous system (CNS) diseases in the drug development pipeline. A primary reason for the lack of application of biotherapeutics to neuroscience targets, is that the blood-brain barrier (BBB) isolates and protects CNS structures creating a unique biochemically and immunologically privileged environment, therefore passage of macromolecules across this barrier has additional challenges. An understanding of the anatomical and physiological properties of this barrier with respect to penetration of biotherapeutics is presented in this review document. In this summary, recent advances in biotherapeutic delivery mechanisms across the BBB including transcranial brain drug delivery, focused ultrasound technology, nasal delivery, absorptive endocytosis, and receptor mediated endocytosis are evaluated using an industrial perspective. With acknowledgement that each approach has advantages and disadvantages, this review discusses the opportunities and challenges that are encountered during application of these methods across a variety of therapeutic areas such as, pain, obesity, neuroscience, and oncology. Utilizing an industrial perspective, including consideration of cost of goods and commercial feasibility for these approaches, this review highlights technology features which would enable industry investments toward novel BBB delivery technologies for biologics. Through continued development and improvement of such technology, new therapeutic options to treat and potentially cure central nervous system diseases could eventually evolve.     

Drug delivery across the blood-brain barrier

The brain is protected and isolated from the general circulation by a highly efficient blood-brain barrier. This is characterised by relatively impermeable endothelial cells with tight junctions, enzymatic activity and active efflux transport systems. Consequently the blood-brain barrier is designed to permit selective transport of molecules that are essential for brain function. This creates a considerable challenge for the treatment of central nervous system diseases requiring therapeutic levels of drug to enter the brain. Some small lipophilic drugs diffuse across the blood-brain barrier- sufficiently well to be efficacious. However, many potentially useful drugs are excluded. This review provides an insight into the current research into technologies to target small molecules, peptides and proteins to the brain. A brief review of the nature of the blood-brain barrier and its transport mechanisms is provided. Strategies to target and improve transport across the blood-brain barrier include the prodrug-lipidisation approach, sequential metabolism chemical delivery systems, drug-vectors, liposomes and nanoparticles. Included is the discussion of techniques to minimise clearance from the circulation by the reticuloendothelial system in order to extend circulation residence time and optimise the opportunity for interaction between the drug delivery system and the blood-brain barrier.     

Brain drug delivery technologies: novel approaches for transporting therapeutics

The blood-brain barrier (BBB) denies many therapeutic agents access to brain tumours and other diseases of the central nervous system (CNS). Despite remarkable advances in our understanding of the mechanisms involved in the development of the brain diseases and the actions of neuroactive agents, drug delivery to the brain remains a challenge. For more than 20 years, extensive efforts have been made to enhance delivery of therapeutic molecules across vascular barriers of the CNS. The current challenge is to develop drug-delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner, and this review will provide an insight into some of the strategies developed to enhance drug delivery across the BBB.     

Novel Central Nervous System Drug Delivery Systems

For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood–brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood–brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection‐enhanced infusion, and ultrasound‐mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.     

Innovations in drug delivery to the central nervous system

The theoretical goal of the ideal drug - to localize specifically and directly to its intended target, have a high therapeutic index and achieve therapeutic efficacy without side effects - is becoming feasible through improved drug delivery and targeting. The clinical advantages of improved drug delivery include continuously therapeutic drug levels, decreased drug dose, improved patient compliance, increased viability of short-lived pharmaceuticals like peptides and proteins, less invasive routes of administration, reduced drug side effects and simplified dosing. Innovative techniques include antibody-mediated drug release, feedback-responsive delivery systems, manipulation of carrier-mediated transport, microspheres composed of polymers and liposomes, permeabilizers, selective delivery to localized sites and vectors to penetrate the blood-brain barrier. Several delivery systems have been approved and more are in clinical trials. Drug delivery system research has greatly influenced the management of brain tumors, central nervous system infections, chronic pain, drug addiction, epileptic disorders, migraine headaches, neurodegenerative diseases, schizophrenia, spasticity and stroke. For many disorders, optimization of drug delivery will continue to be the therapeutic focus for a long while.     

Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System

A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB’s ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB’s permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents. Hypoxia and/or inflammation are central components of a number of diseases affecting the CNS. A number of studies indicate hypoxia or inflammatory pain increase BBB paracellular permeability, induce changes in the expression and/or localization of tight junction proteins, and affect CNS drug uptake. In this review, we look at what is currently known with regard to BBB disruption following a hypoxic or inflammatory insult in vivo. Potential mechanisms involved in altering tight junction components at the BBB are also discussed. A more detailed understanding of the mediators involved in changing BBB functional integrity in response to hypoxia or inflammatory pain could potentially lead to new treatments for CNS diseases with hypoxic or inflammatory components. Additionally, greater insight into the mechanisms involved in TJ rearrangement at the BBB may lead to novel strategies to pharmacologically increase delivery of drugs to the CNS.     

Current approaches for drug delivery to central nervous system

Brain, the center of the nervous system in all vertebrate, plays the most vital role in every function of human body. However, many neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. In spite of the major advances in neuroscience, many potential therapeutics are still unable to reach the central nervous system (CNS) due to the blood-brain barrier (BBB) which is formed by the tight junctions within the capillary endothelium of the vertebrate brain. This results in the capillary wall behaving as a continuous lipid bilayer and preventing the passage of polar and lipid insoluble substances. Several approaches for delivering drugs to the CNS have been developed to enhance the capacity of therapeutic molecules to cross the BBB by modifying the drug itself, or by coupling it to a vector for receptor-mediated, carrier mediated or adsorption-mediated transcytosis. The current challenge is to develop drug delivery systems that ensure the safe and effective passage of drugs across the BBB. This review focuses on the strategies and approaches developed to enhance drug delivery to the CNS.     

Polymeric nanoparticles for the drug delivery to the central nervous system

BACKGROUND: Nanoparticulate polymeric systems (nanoparticles [Np]) have been widely studied for the delivery of drugs to a specific target site. This approach has been recently considered for the therapy of brain diseases. The major problem in accessing the CNS is linked to the presence of the blood-brain barrier. OBJECTIVE: The present review deals with the different strategies that have been developed in order to allow Np drug carriers entry into the CNS parenchyma. Among these, the use of magnetic Np, Np conjugation with ligands for blood-brain barrier receptors, with antibodies, and the use of surfactants have been considered. METHODS: All the literature available is reviewed in order to highlight the potential of this drug delivery system to be used as a drug carrier for the treatment of CNS pathologies. CONCLUSIONS: Polymeric Np have been shown to be promising carriers for CNS drug delivery due to their potential both in encapsulating drugs, hence protecting them from excretion and metabolism, and in delivering active agents across the blood-brain barrier without inflicting any damage to the barrier. Different polymers have been used and different strategies have been applied; among these, the use of specific ligands to enhance the specificity of drugs delivered to the CNS has recently been considered. At present, clinical trials are being conducted appeared for the use of these drug carriers but none related to the treatment of CNS diseases.     

神经退行性疾病状态下血-脑屏障变化机制及中药对血脑屏障的影响研究进展

血-脑屏障（BBB）结构和功能的完整性是维持中枢神经系统动态平衡的关键因素。BBB异常伴随神经退行性疾病的发展过程,不同的神经退行性疾病,其BBB异常的病理机制不同,而药物对BBB异常的改善作用也严重影响药物对神经退行性疾病的疗效。本文主要针对神经退行性疾病状态下BBB异常的分子机制及中药的调控作用及其机制两方面进行综述,为神经退行性疾病靶向血脑屏障药物的研发提供基础理论参考     

Modulation of drug transporters at the blood-brain barrier

A major challenge in the management of diseases of the central nervous system is the limited penetration of drugs into the brain. The structures responsible are the capillaries of the brain, whose endothelial cells form the so-called blood-brain barrier. Understanding the cellular and molecular structure as well as integrated function of this barrier is a prerequisite for successful drug delivery to the brain. Here we briefly review current knowledge about the active transport proteins (ABC and organic anion transporters) which function at the blood-brain barrier. We describe novel approaches to (1). modulate carrier protein function, and (2). circumvent the transporter-based carrier by targeted site-specific drug delivery systems, such as immunoliposome and nanoparticulate systems.     

Toward an improved prediction of human in vivo brain penetration

The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood-brain barrier and the extent of distribution into brain tissue compartments. Clinically, positron emission tomography (PET) is the primary technique for deriving information on drug biodistribution as well as target receptor occupancy. In contrast, rodent models have formed the basis for much of the current understanding of brain penetration within pharmaceutical Drug Discovery. Linking these two areas more effectively would greatly improve the translation of candidate compounds into therapeutic agents. This paper examines two of the major influences on the extent of brain penetration across species, namely plasma protein binding and brain tissue binding. An excellent correlation was noted between unbound brain fractions across species (R(2) > 0.9 rat, pig, and human, n = 21), which is indicative of the high degree of conservation of the central nervous system environment. In vitro estimates of human brain-blood or brain-plasma ratios of marketed central nervous system drugs and PET tracers agree well with in vivo values derived from clinical PET and post-mortem studies. These results suggest that passive diffusion across the blood-brain barrier is an important process for many drugs in humans and highlights the possibility for improved prediction of brain penetration across species.     

Drug delivery to brain tumours: challenges and progress

Nearly 12.5 million new cancer cases are diagnosed worldwide each year. Although new treatments have been developed, most new anticancer drugs that are effective outside the brain have failed in clinical trials against brain tumours, in part due to poor penetration across the blood-brain barrier and the blood-brain tumour barrier. This review will discuss the challenges of drug delivery across the blood-brain barrier/blood-brain tumour barrier to cancer cells, as well as progress made so far. This will include a biochemical modulation strategy that transiently opens the barrier to increase anticancer drug delivery selectively to brain tumours. It will also briefly discuss a quantitative non-invasive method to measure permeability changes and tumour response to treatment in the human brain.     

A focus on glucose-mediated drug delivery to the central nervous system

Drug delivery to the central nervous system (CNS) is a timely and challenging issue: 95 percent; of the pharmacological drugs cannot be delivered to the brain. This is mainly due to the blood-brain barrier (BBB), a highly selective boundary that hampers the passage of most compounds into the CNS. To overcome this problem, several approaches exist to deliver a therapeutic drug to the brain that takes into account not only the chemical properties of the drug but also the type of transport used at the BBB. One of those strategies is the glucose-mediated drug delivery which will be the focus of the present review. Glucose-mediated drug delivery requires the attachment of glycosyl moieties to a drug and the use of endogenous glucose transporters as a way to circumvent the blood-brain barrier. Glycosylated drugs display improved cell penetrability, enhanced biodistribution, stability and low toxicity. Examples such as glycosylation of ibuprofen and different opioids result in an enhanced central effect and will be discussed.     

Exploiting the properties of biomolecules for brain targeting of nanoparticulate systems

The main obstacle in the treatment of central nervous system diseases is represented by a limited passage of diagnostic and therapeutic agents across the blood-brain barrier, which separates the blood stream from the cerebral parenchyma and maintains the homeostasis of the brain. The growing knowledge about the brain capillary endothelium and the discovery of specific mechanisms for the uptake of substances enables the development of various strategies to enhance the drug delivery rate into the brain. Among the different strategies, nanoparticles are promising candidates for drug delivery to the brain due to their potential in encapsulating drugs and thereby disguising their permeation limiting characteristics. Furthermore a surface functionalization of many nanoparticles can easily be achieved allowing the active targeting of nanoparticles to the brain. For this non-invasive approach, the surface functionalization of nanoparticles with biomolecules has shown promising potential for effective drug delivery to the brain. This review indexes the main classes of biomolecules used for the surface functionalization of nanoparticles and discusses their potential as drug delivery systems for an enhanced passage of diagnostic and therapeutic agents into the brain parenchyma.     

Transport of drugs across the blood-brain barrier in Alzheimer's disease

Alzheimer's disease, a neurodegenerative disorder, is associated with various pathological alterations to the blood-brain barrier, including disruption to the inter-endothelial tight junction proteins, altered expression of transport proteins involved in drug efflux, a reduction in cerebral blood flow and a thickening of the brain capillary basement membrane. There are many conflicting reports on whether such changes alter the ability of endogenous proteins to extravasate into the brain parenchyma, and there are even fewer reports focusing on the potential impact of these changes on drug transport into the CNS. The purpose of this review is to critically evaluate how the reported changes to the blood-brain barrier in Alzheimer's disease have (or have not) resulted in altered CNS drug delivery, and to highlight the requirement for more rigorous and systematic studies in this field for the benefit of drug discovery and delivery scientists.     

Vector-mediated drug delivery to the brain

Vector-mediated drug delivery to the brain employs the chimeric peptide technology, wherein a non-transportable drug is conjugated to a blood-brain barrier (BBB) transport vector. The latter is a modified protein or receptor-specific monoclonal antibody that undergoes receptor-mediated transcytosis through the BBB in vivo. Conjugation of drug to transport vector is facilitated with either chemical linkers, avidin-biotin technology, polyethylene glycol linkers, or liposomes. Multiple classes of therapeutics have been delivered to the brain with the chimeric peptide technology, including peptide-based pharmaceuticals, such as a vasoactive intestinal peptide analog or neurotrophins such as brain-derived neurotrophic factor, antisense therapeutics including peptide nucleic acids, and small molecules incorporated within liposomes. The successful delivery of a drug through the BBB in vivo requires special molecular formulation of the drug. Therefore, it is important to merge central nervous system drug discovery and delivery as early as possible in the overall CNS drug development process.