Drug targeting to brain: a systematic approach to study the factors,parameters and approaches for prediction of permeability of drugs across BBB

Introduction: Drug targeting to brain by circumventing the physiological barriers is a prerequisite for drugs acting on central nervous system (CNS) and therapeutic potential of many drugs can be improved by effectively targeting the drug(s) to brain.

Areas covered: Present review describes blood–brain barrier (BBB), drug transport mechanisms and factors affecting drug transportation across BBB along with in vitro BBB models; and the approaches for evaluation of permeability of drug across BBB.

Expert opinion: The development of a still awaited perfect in vitro model to mimic BBB is a challenging task. System biologist, network biologist and computational technologist should come together to integrate the role of transporters, physiological and pathophysiological complexity of BBB to replicate vascular properties of the brain microcapillaries as a suitable model to facilitate the high-throughput screening of CNS acting biomolecules.     

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.     

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

ABSTRACT

Introduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases.

Areas covered: We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer’s disease, Parkinson’s disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington’s disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders.

Expert opinion: TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.     

New experimental models of the blood-brain barrier for CNS drug discovery

Introduction: The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases.

Area covered: This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms.

Expert opinion: Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms.     

Advances in brain drug targeting and delivery: limitations and challenges of solid lipid nanoparticles

Introduction: With the advancement in the field of medical colloids and interfacial sciences, the life expectancy has been greatly improved. In addition, changes in the human lifestyle resulted in development of various organic and functional disorders. Central nervous system (CNS) disorders are most prevalent and increasing among population worldwide. The neurological disorders are multi-systemic and difficult to treat as portal entry to brain is restricted on account of its anatomical and physiological barrier.

Areas covered: The present review discusses the limitations to CNS drug delivery, and the various approaches to bypass the blood brain barrier (BBB), focusing on the potential use of solid lipid nanoparticles (SLN) for drug targeting to brain. The methods currently in use for SLN production, physicochemical characterization and critical issues related to the formulation development suitable for targeting brain are also discussed.

Expert opinion: The potential advantages of the use of SLN over polymeric nanoparticles are due to their lower cytotoxicity, higher drug loading capacity and scalability. In addition, their production is cost effective and the systems provide a drug release in a controlled manner up to several weeks. Drug targeting potential of SLN can be enhanced by attaching ligands to their surface.     

Selective drug delivery approaches to lesioned brain through blood brain barrier disruption

Introduction: The development of therapeutics for central nervous system (CNS) disorders is still considered a challenging area in drug development due to insufficient translocation through the blood-brain barrier (BBB). Under normal conditions, BBB restrict the penetration of more than 98% of blood-borne molecules including drugs to the CNS. However, recent research findings have proven that the nature of the BBB is altered in several neurological conditions. This complexity encourages revisiting drug delivery strategies to the CNS as this can give a wide range of opportunities for CNS drug development.

Areas covered: This review focuses on nanotechnology-based drug delivery platforms designed for selective recruitment into the lesioned brain by taking advantages of BBB disruption that is associated with certain neurological conditions.

Expert opinion: Current CNS therapeutic strategies do not fully address the pathophysiological adaptation of BBB in their design. The lack of selective delivery to the brain lesions has been the culprit behind the failure of many CNS therapeutics. This highlighted the need for smart designs of advanced drug delivery systems that take advantage of BBB structural changes in CNS diseases. Recently, promising examples have been reported in this area, however, more work is still required beyond the preclinical testing.     

Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer’s disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates – such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Therapeutic potential of Panax ginseng and its constituents,ginsenosides and gintonin,in neurological and neurodegenerative disorders: a patent review

Introduction: Ginseng, Panax ginseng, has been used for various diseases and proven its great efficacy in managing central nervous system diseases.

Area covered: This article covers the therapeutic potential of patents on ginseng and its active constituents to develop therapies for neurodegenerative and neurological disorders, since 2010. The literature review was provided using multiple search engines including Google Patent, Espacenet and US Patent in the field of neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, cognitive, and neurological disorders.

Expert opinion: The gathered data represented outstanding merits of ginseng in treatment of neurodegenerative and neurological disorders. These effects have been mediated by neurogenesis, anti-apoptotic and antioxidant properties, inhibition of mitochondrial dysfunction, receptor-operated Ca²⁺ channels, amyloid beta aggregation, and microglial activation as well as neurotransmitters modulation. However, these compounds have limited clinical application of for the prevention or treatment of neurodegenerative and neurological disorders. This might be due to incomplete data on their clinical pharmacokinetic and toxicity properties, and limited economic investments. There is an increasing trend in use of herbal medicines instead of chemical drugs, so it is time to make more attention to the application of ginseng, the grandfather of medicinal plants, from basic sciences to patients’ bed.     

Advances in brain targeting and drug delivery of anti-HIV therapeutic agents

Introduction: Human immunodeficiency virus (HIV) is a neurotropic virus that enters the central nervous system (CNS) early in the course of infection. Although antiretroviral drugs are able to eliminate the majority of the HIV virus in the bloodstream, however, no specific treatment currently exist for CNS infections related to HIV. This is mainly attributed to the poor penetrability of antiretroviral therapy across the blood–brain barrier (BBB), and the protective nature of the BBB. Therefore, in order to increase the efficacy of anti-HIV drugs, novel drug delivery methodologies that can exhibit activity in the CNS are most needed and warranted.

Areas covered: In this review article, the authors discussed the challenges with delivering drugs to the brain especially under HIV infection pathophysiology status. Also, they discussed the approaches currently being investigated to enhance brain targeting of anti-HIV drugs. A literature search was performed to cover advances in major approaches used to enhance drug delivery to the brain.

Expert opinion: If drugs could reach the CNS in sufficient quantity by the methodologies discussed, mainly through intranasal administration and the utilization of nanotechnology, this could generate interest in previously abandoned therapeutic agents and enable an entirely novel approach to CNS drug delivery.     

Intranasal delivery of therapeutic proteins for neurological diseases

Introduction: Among the range of therapeutic protein candidates for new generation treatments of neurological diseases, neurotrophic factors and recombinant antibodies hold the greatest potential. However, major difficulties in their safe and effective delivery to the brain severely limit these applications. The BBB restricts the exchange of proteins between the plasma and the CNS. Moreover, therapeutic proteins often need to be selectively targeted to the brain, while minimizing their biodistribution to systemic compartments, to avoid peripheral side effects. The intranasal delivery of proteins has recently emerged as a non-invasive, safe and effective method to target proteins to the CNS, bypassing the BBB and minimizing systemic exposure.

Areas covered: We critically summarize the main experimental and mechanistic facts about the simple and non-invasive nasal delivery approach, which provides a promising strategy and a potential solution for the severe unmet medical need of safely and effectively delivering protein therapeutics to the brain.

Expert opinion: The intranasal route for the effective delivery of recombinant therapeutic proteins represents an emerging and promising non-invasive strategy. Future studies will achieve a detailed understanding of pharmacokinetic and mechanisms of delivery to optimize formulations and fully exploit the nose-to-brain interface in order to deliver proteins for the treatment of neurological diseases. This expanding research area will most likely produce exciting results in the near future towards new therapeutical approaches for the CNS.     

Investigational drugs for the management of Huntington’s disease: are we there yet?

Introduction: Huntington’s disease is a hereditary neurodegenerative disease. It is designated as a rare disease in the US, which means there are < 200,000 patients in the country who suffer from it. The drugs that are currently used to treat this disease were not designed specifically for it but developed for other diseases. Presently, two classes of drugs are being developed; those that provide symptomatic relief and those that may modify course of the disease.

Areas covered: This review is focused on seven selected drugs currently in clinical testing and describes their progress. Five of the seven drugs that are reviewed here, can be categorized as ‘symptomatic’ drugs, and, selisistat and PBT-2 are amongst the ones that would qualify as ‘disease modifying’ drugs.

Expert opinion: The authors believe that the future treatment paradigm for this disease is best met by using a disease-modifying drug that can be administered together with symptomatic drugs. Towards that end, it is important for the industry to focus on disease-modifying drugs by targeting unique pathways and targets. Furthermore, they propose that neuroprotective drugs, that is, drugs that directly work by preserving neuronal health and function is an opportunity for such disease-modifying drugs.     

阿尔茨海默病的纳米疗法研究进展

阿尔茨海默病(alzheimer's disease,AD)是一种中枢神经退行性疾病,在社会人口老龄化日益加剧的今天,AD患病率不断上升,其严重程度足以干扰人类的日常生活,危害人类的健康.目前AD的发病机制尚不明确,没有有效的药物可以治愈AD.血脑屏障(Blood brain barrier,BBB)是血液循环与中枢神经系统之间的生物屏障,药物不能穿过BBB,使其在治疗中枢神经系统疾病时有一定的局限性.纳米释药系统可以非侵入性地将药物递送至大脑,通过靶向药物递送,可以降低药物的毒性,增加药物的生物利用度.本文简述了AD发病的几种假说,介绍了与AD相关的纳米药物(Nanomedicines,NMs)种类和研究进展,对纳米递药技术在AD治疗策略中的应用进行阐述和列举,为AD的NMs研究提供思路和参考.     

Galanin receptors as a potential target for neurological disease

Introduction: Galanin is a 29/30 amino acid long neuropeptide that is widely expressed in the brains of many mammals. Galanin exerts its biological activities through three different G protein-coupled receptors, GalR1, GalR2 and GalR3. The widespread distribution of galanin and its receptors in the CNS and the various physiological and pharmacological effects of galanin make the galanin receptors attractive drug targets.

Areas covered: This review provides an overview of the role of galanin and its receptors in the CNS, the involvement of the galaninergic system in various neurological diseases and the development of new galanin receptor-specific ligands.

Expert opinion: Recent advances and novel approaches in migrating the directions of subtype-selective ligand development and chemical modifications of the peptide backbone highlight the importance of the galanin neurochemical system as a potential target for drug development.     

Improving drug delivery technology for treating neurodegenerative diseases

ABSTRACT

Introduction: Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified.

Areas covered: This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms.

Expert Opinion: Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer’s disease and Parkinson’s disease. However, much work is still required in this field beyond the preclinical testing phase.     

Advances in prodrug design for Parkinson’s disease

Introduction: Parkinson’s Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity, neuropsychiatric symptoms, and others. The pharmacological treatment of the disease is only symptomatic since, to date, there is no treatment to stop or slow PD. Currently, L-Dopa (LD) remains the gold standard therapy even though it undergoes peripheral metabolism causing several side effects, such as nausea, vomiting and orthostatic hypotension.

Areas covered: This review is focused on recent developments in strategies involving prodrugs to enhance DA and/or LD absorption, their chemical and enzymatic stabilities, and selective targeting to the central nervous system.

Expert opinion: The prodrug strategy remains one of the most promising approaches to improve pharmaceutical, pharmacokinetic, and pharmacodynamic properties of hydrophilic compounds, such as anti-Parkinson drugs (DA and LD). Prodrugs developed in recent years have demonstrated good pharmacokinetic profiles, affording a sustained release of LD and reducing its plasma level fluctuations. The development of new prodrugs that may reach the BBB unaltered and with a good ADME (Absorption, Distribution, Metabolism, Elimination) profile and pharmacological efficacy represents an exciting challenge for medicinal chemists.     

Topical drug delivery systems: a patent review

Introduction: Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration.

Areas covered: This review summarizes innovations from the past 3 years (2012–2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically.

Expert opinion: Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems.     

Borneol,a novel agent that improves central nervous system drug delivery by enhancing blood–brain barrier permeability

The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood–brain barrier (BBB). Borneol is a naturally occurring compound in a class of ‘orifice-opening’ agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the ‘orifice-opening’ effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol’s chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose- and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery.