Nanoparticulate devices for brain drug delivery

The blood–brain barrier (BBB) limits the transport of therapeutic molecules from the blood compartment into the brain, thus greatly reducing the species of therapeutic compounds that can be efficiently accumulated in the central nervous system (CNS). Various strategies have been proposed for improving the delivery of drugs to this tissue, and numerous invasive and noninvasive methods have been proposed by different scientists in an attempt to circumvent the BBB and to increase the delivery of drug compounds into the brain. An interesting alternative, in the solution of this problem and also that of reaching a suitable target in the CNS, has recently been provided through the use of nanoparticulate colloidal devices as a noninvasive technique for brain drug delivery. These systems offer diverse advantages over invasive strategies, because (1) they are designed using biocompatible and biodegradable materials; (2) they avoid the disruption and/or modification of the BBB; and (3) they modulate the biopharmaceutical properties of the entrapped drugs. Moreover, the possibility of targeting specific brain tissue, thanks to ligands linked to the surface of the nanoparticulate colloidal devices, confers the necessary characteristics for the treatment of CNS pathologies to these drug carriers. The aim of this review is to focus on describing the main strategies in use for designing nanoparticulate colloidal devices for CNS delivery, their potentiality as noninvasive strategies in the delivery of drugs to the cerebral tissues, and their biological and clinical applications in cerebral drug delivery. © 2010 Wiley Periodicals, Inc. Med Res Rev 31:716‐756, 2011     

超声介导开放血脑屏障与药物入脑递送

目前,已有许多药物对脑部疾病的治疗具有显著作用,但由于血脑屏障的存在限制了药物在临床应用中的治疗效果。聚焦超声联合微泡技术是一种安全、高效的开放血脑屏障技术,能有效递送药物进入大脑,从而提高药物的疗效。本文介绍了血脑屏障的分子结构与转运功能,阐述了影响药物入脑递送的主要因素和相关的解决方法,分析了超声开放血脑屏障的安全性和主要机制,讨论了超声介导药物递送在临床治疗中的应用。     

Delivery of therapeutic agents to the central nervous system: the problems and the possibilities

The presence of a blood-brain barrier (BBB) and a blood-cerebrospinal fluid barrier presents a huge challenge for effective delivery of therapeutics to the central nervous system (CNS). Many potential drugs, which are effective at their site of action, have failed and have been discarded during their development for clinical use due to a failure to deliver them in sufficient quantity to the CNS. In consequence, many diseases of the CNS are undertreated. In recent years, it has become clear that the blood-CNS barriers are not only anatomical barriers to the free movement of solutes between blood and brain but also transport and metabolic barriers. The cell association, sometimes called the neurovascular unit, constitutes the BBB and is now appreciated to be a complex group of interacting cells, which in combination induce the formation of a BBB. The various strategies available and under development for enhancing drug delivery to the CNS are reviewed.     

Experimental Study on Targeted Methotrexate Delivery to the Rabbit Brain via Magnetic Resonance Imaging–Guided Focused Ultrasound

Objective. The purpose of this study was to investigate the effects of targeted and reversible disruption of the blood‐brain barrier (BBB) by magnetic resonance imaging (MRI)‐guided focused ultrasound (FUS) and delivery of methotrexate (MTX) to the rabbit brain. Methods. The brains of 20 rabbits were sonicated by MRI‐guided FUS at different exposure times, and then Evans blue extravasation, contrast‐enhanced MRI, and histologic examination were performed to determine the optimal exposure time for reversible BBB disruption with minimal damage. Five rabbits were sonicated at the optimal exposure time after MTX was injected intravenously (IV); the targeted locations were included in the sonicated group, and the nontargeted contralateral counterparts were included in the IV control group. Five other rabbits were not subjected to sonication and were administered internal carotid artery (ICA) injections of MTX; the specimens of the counterpart brain tissue were harvested as the ICA group. The MTX concentration in all of the specimens was determined by high‐performance liquid chromatography. Results. The MTX concentration in the sonicated group (mean ± SD, 7.412 ± 1.471 μg/g of tissue) was notably higher than that in both the IV control group (0.544 ± 0.084 μg/g) and ICA group (1.984 ± 0.65 μg/g; P <.01). Conclusions. Magnetic resonance imaging–guided FUS can disrupt the BBB reversibly and deliver IV administered MTX to targeted brain locations; it brings about a greater than 10‐fold increase in the drug level and is much more effective (≈3.7‐fold) than drug delivery through the ICA without sonication. This may facilitate the development of improved treatment methods for central nervous system disorders.     

Nanoparticles: Novel vehicles in treatment of Glioblastoma

Glioblastoma multiform (GBM) is the most common brain tumor. The current GBM treatments comprise of radiation therapy, chemotherapy and surgery. One of the most important problems regarding the treatment of GBM is the presence of blood brain barrier (BBB) which inhibits the efficient drug delivery into central nervous system (CNS). Nanothechnology can help to deliver therapeutic drugs into CNS through crossing the BBB. There are different types of nanoparticles (Nps) which can be manipulated for clinical applications as a treatment for CNS-related disorders. In this review, we will discuss the role of Nps in the treatment of GBM.     

Chemical modification of therapeutic drugs or drug vector systems to achieve targeted therapy: looking for the grail

Most therapeutic drugs distribute to the whole body, which results in general toxicity and poor acceptance of the treatments by patients. The targeted delivery of chemotherapeutics to defined cells, either stromal or cancer cells in cancer lesions, or defined inflammatory cells in immunological disorders, is one of the main challenges and a very active field of research in the development of treatment strategies to minimize side-effects of drugs. Disease-associated cells express molecules, including proteases, receptors, or adhesion molecules, that are different or differently expressed than their normal counterparts. Therefore one goal in the field of targeted therapies is to develop chemically derivatized drugs or drug vectors able to target defined cells via specific recognition mechanisms and also able to overcome biological barriers. This article will review the approaches which have been explored to achieve these goals and will discuss in more detail three examples (i) the use of nanostructures to take advantage of increased vascular permeability in some human diseases, (ii) the targeting of therapeutic drugs to an organ, the brain, protected against foreign molecules by the blood-brain barrier, and (iii) the use of the folate receptor to target either tumor cells or activated macrophages.     

Highlights of the Annual Meeting of the Italian Association for Cell Cultures (AICC): new drug delivery strategies and technological platforms for diagnosis and therapy of tumors (Part II)

In recent decades considerable advances have been achieved in the development of new strategies based on the specific delivery of drugs into tumor tissues through the use of bio-materials and nanoparticles. The AICC meeting was divided into different sessions addressing different issues. The first section was about new delivery systems for either drugs or DNA. In detail, the pharmacokinetics and pharmaco-distribution of different carrier systems were explained. Thereafter, the possibility of drug delivery with pegylated liposomes or with nanoparticles or micelles was analyzed. The crossing of the blood–brain barrier by pegylated liposomes in order to deliver antitumor drugs to brain tumor sites was also explored.     

Drug transfer across the blood-brain barrier and improvement of brain delivery

The blood-brain barrier is formed by the endothelial cells of the brain capillaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic activity. Essential nutrients are delivered to the brain by selective transport mechanisms, such as the glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion through the endothelial cells depending on their lipophilicity, degree of ionization, molecular weight, relative brain tissue and plasma bindings, some others can use specific endogenous transporters. In such cases, binding competition on the transporter with endogenous products or nutrients can occur and limits drug transfer. The blood-brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many drugs are unable to reach this organ at therapeutic concentrations. Various attempts have been made to overcome the limiting access of drugs to the brain, e.g. chemical modification, development of more hydrophobic analogs or linking an active compound to a specific carrier. Transient opening of the blood-brain barrier in humans has been achieved by intracarotid infusion of hypertonic mannitol solutions or of bradykinin analogs. Another way to increase or decrease brain delivery of drugs is to modulate the P-glycoprotein (P-gp) whose substrates are actively pumped out the cell into the capillary lumen. Many P-gp inhibitors or inducers are available to enhance the therapeutic effects of centrally acting drugs or to decrease central adverse effects of peripherally active drugs.     

Prodrug based optimal drug delivery via membrane transporter/receptor

The carrier-mediated absorption of drugs and prodrugs across epithelial and endothelial barriers is emerging as a novel trend in biotherapeutics. This review examines the important advances in this field in the past decade. The feasibility of drug absorption of the parent drug or the appropriately modified prodrug via these transporters is discussed in detail. Several successful examples of synthesis of prodrugs recognised by the targeted transporters are described. The applicability of this approach in translocating drugs across the almost impenetrable blood-brain barrier (BBB) has also been examined.     

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

Organophosphorus (OP) compounds are highly toxic synthetic compounds which have been used as pesticides and developed as warfare nerve agents. They represent a threat to both military and civilian populations. OP pesticides affect the nervous system and are thought to have caused at least 5 million deaths since their discovery in the 1930s. At present the treatment of OP nerve agent poisoning commonly involves the use of parenteral oximes. However, the blood brain barrier (BBB) remains a challenge in the delivery of oximes to the central nervous system (CNS). This is because almost all macromolecule drugs (including oximes) fail to pass through the BBB to reach the CNS structures. The presence of a permanent cationic charge in oximes has made these compounds inefficient in crossing the BBB. Thus, oximes are unable to reactivate acetylcholinesterase (AChE) in the CNS. Using current structural and mechanistic understanding of the BBB under both physiological and pathological conditions, it becomes possible to design delivery systems for oximes and other drugs that are able to cross the BBB effectively. This review summarises the recent strategies in the development of oximes which are capable of crossing the BBB to treat OP poisoning. Several new developments using oximes are reviewed along with their advantages and disadvantages. This review could be beneficial for future directions in the development of oxime and other drug delivery systems into the CNS.

Organophosphorus (OP) compounds are highly toxic synthetic compounds which have been used as pesticides and developed as warfare nerve agents.     

Non-viral gene therapy for neurological diseases, with an emphasis on targeted gene delivery

Non-viral gene therapy systems are considered safer than viral delivery. This article reviews recent research describing novel, non-viral gene delivery to the central nervous system, with a special emphasis on receptor mediated gene delivery using antibodies (termed immunogenes) to specific receptors. By using targeting agents such as antibodies that can be retrogradely transported within neurons, non-viral gene therapies can deliver genes to specific neurons protected by the blood brain barrier. Components of effective non-viral gene therapy are described including DNA/RNA carriers, receptor-mediated endocytosis, endosomal escape and nuclear entry. In addition, stealth agents such as polyethylene glycol that can be used to improve in-vivo delivery are discussed. The value of immunogenes as therapeutic agents for fatal diseases such as Amyotrophic Lateral Sclerosis is significant but further in-vivo work to confirm efficacy is required before truly effective therapies can be achieved.     

Intrathecal delivery of protein therapeutics to the brain: A critical reassessment

Disorders of the central nervous system (CNS), including stroke, neurodegenerative diseases, and brain tumors, are the world’s leading causes of disability. Delivery of drugs to the CNS is complicated by the blood–brain barriers that protect the brain from the unregulated leakage and entry of substances, including proteins, from the blood. Yet proteins represent one of the most promising classes of therapeutics for the treatment of CNS diseases. Many strategies for overcoming these obstacles are in development, but the relatively straightforward approach of bypassing these barriers through direct intrathecal administration has been largely overlooked. Originally discounted because of its lack of usefulness for delivering small, lipid-soluble drugs to the brain, the intrathecal route has emerged as a useful, in some cases perhaps the ideal, route of administration for certain therapeutic protein and targeted disease combinations. Here, we review blood–brain barrier functions and cerebrospinal fluid dynamics and their relevance to drug delivery via the intrathecal route, discuss animal and human studies that have investigated intrathecal delivery of protein therapeutics, and outline several characteristics of protein therapeutics that can allow them to be successfully delivered intrathecally.     

Targeted drug delivery to the brain using focused ultrasound

Drug delivery to the brain remains a challenging field. The presence of a physiological barrier, the blood-brain barrier (BBB), complicates the delivery of drugs to the brain. Although several methods have been developed for drug delivery to the brain, they have problems such as being invasive or lacking in target specificity. On the other hand, ultrasound has emerged as a treatment method and a diagnostic technology. Several studies have shown the feasibility of using ultrasound for the localized and reversible disruption of the BBB. In this review, I would like to review the recent advancement of ultrasound-induced MRI-guided BBB disruption technique and other methods for delivering drugs to the brain.     

Fibrinogen signal transduction in the nervous system

Summary.  Fibrinogen is a pleiotropic blood protein that regulates coagulation, inflammation and tissue repair. Fibrinogen extravasates in the nervous system after injury or disease associated with vascular damage or blood–brain barrier (BBB) disruption. Fibrinogen is not merely a marker of BBB disruption, but plays a causative role in neurologic disease as a potent inducer of inflammation and an inhibitor of neurite outgrowth. Fibrinogen mediates functions in the nervous system as a ligand for cell-specific receptors. In microglia, fibrinogen mediates activation of Akt and Rho via the CD11b/CD18 integrin receptor, while in neurons fibrinogen induces phosphorylation of epidermal growth factor (EGF) receptor via the αvβ3 integrin. Pharmacologic targeting of the interactions of fibrinogen with its nervous system receptors could provide novel strategies for therapeutic intervention in neuroinflammatory and neurodegenerative diseases.     

Targeted drug delivery for brain cancer treatment.

The blood brain barrier (BBB) and the systemic toxicity of conventional chemotherapy present obstacles to the success of future blood-borne drug therapies of brain tumors. The work with polymer-encapsulated cancer drugs suggests an alternative and more focused treatment approach. Our experimental strategy integrates direct intracerebral drug delivery, sustained drug release from liposomes or polymer implants, and increased targeting of the drug either by chemically modifying the drug or by using tumor-specific carriers. This review will present some of the recent work on targeted drug delivery for brain cancer treatment.     

Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation.

Neuropeptide pharmaceuticals have potential for the treatment of neurological disorders, but the blood-brain barrier (BBB) limits entry of peptides to the brain. Several strategies to improve brain delivery are currently under investigation, including glycosylation. In this study we investigated the effect of O-linked glycosylation on Ser(6) of a linear opioid peptide amide Tyr-D-Thr-Gly-Phe-Leu-Ser-NH(2) on metabolic stability, BBB transport, and analgesia. Peptide stability was studied in brain and serum from both rat and mouse by high-performance liquid chromatography. BBB transport properties were investigated by rat in situ perfusion. Tail-flick analgesia studies were performed on male ICR mice, injected i.v. with 100 microg of peptide ligand. Glycosylation of Ser(6) of the peptide led to a significant increase in enzymatic stability in both serum and brain. Glycosylation significantly increased the BBB permeability of the peptide from a value of 1.0 +/- 0.2 microl x min(-1) x g(-1) to 2.2 +/- 0.2 microl x min(-1) x g(-1) (p < 0.05), without significantly altering the initial volume of distribution. Analgesia studies showed that the glycosylated peptide gave a significantly improved analgesia after i.v. administration compared with nonglycosylated peptide. The improved analgesia profile shown by the glycosylated peptide is due in part to an improvement in bioavailability to the central nervous system. The bioavailability is increased by improving stability and transport into the brain.     

Challenging the great vascular wall: Can we envision a simple yet comprehensive therapy for stroke?

Stroke is a leading cause of death in adult life, closely behind ischemic heart disease, and causes a significant and abiding socioeconomic burden. However, current therapies are not able to ensure full neurologic and/or sequelae‐free recovery to all stroke survivors. We believe treatment efficacy and patient rehabilitation could be enhanced significantly by targeting blood‐brain barrier (BBB) deregulation and inflammation‐induced barrier loss that occurs after stroke. In this pathological context, bone marrow‐derived endothelial progenitor cells (EPC) enter the bloodstream towards the lesion site, but their insufficient numbers and impaired angiogenic ability compromise neurovascular regeneration. In this context, cell‐based therapies have become increasingly appealing since treating patients with large numbers of mesenchymal or hematopoietic stem/progenitor cells alone may boost repair. However, this approach could be met with several challenges in terms of logistics and cost; hence, the development of a drug delivery system suitable for intravenous administration and functionalized for selective uptake by circulating EPC could enhance their restorative potential without perceived complications. The ability to encapsulate proangiogenic and anti‐inflammatory agents, such as retinoic acid, and to safely and easily deliver them systemically may open new therapeutic perspectives for the treatment of cerebrovascular disorders. Copyright © 2017 John Wiley & Sons, Ltd.     

The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers

Nifurtimox, an antiparasitic drug, is used to treat American trypanosomiasis (Chagas disease) and has shown promise in treating central nervous system (CNS)-stage human African trypanosomiasis (HAT; sleeping sickness). In combination with other antiparasitic drugs, the efficacy of nifurtimox against HAT improves, although why this happens is unclear. Studying how nifurtimox crosses the blood-brain barrier (BBB) and reaches the CNS may clarify this issue and is the focus of this study. To study the interaction of nifurtimox with the blood-CNS interfaces, we used the in situ brain/choroid plexus perfusion technique in healthy and trypanosome-infected mice and the isolated incubated choroid plexus. Results revealed that nifurtimox could cross the healthy and infected blood-brain and blood-cerebrospinal fluid (CSF) barriers (K(in) brain parenchyma was 50.8 ± 9.0 μl · min(-1) · g(-1)). In fact, the loss of barrier integrity associated with trypanosome infection failed to change the distribution of [(3)H]nifurtimox to any significant extent, suggesting there is not an effective paracellular barrier for [(3)H]nifurtimox entry into the CNS. Our studies also indicate that [(3)H]nifurtimox is not a substrate for P-glycoprotein, an efflux transporter expressed on the luminal membrane of the BBB. However, there was evidence of [(3)H]nifurtimox interaction with transporters at both the blood-brain and blood-CSF barriers as demonstrated by cross-competition studies with the other antitrypanosomal agents, eflornithine, suramin, melarsoprol, and pentamidine. Consequently, CNS efficacy may be improved with nifurtimox-pentamidine combinations, but over time may be reduced when nifurtimox is combined with eflornithine, suramin, or melarsoprol.     

A fluorescent chromophore TOTO‐3 as a ‘smart probe’ for the assessment of ultrasound‐mediated local drug delivery in vivo

Many potent anti‐cancer drugs have an intracellular mode of action, but are limited in crossing the cell membrane, resulting in a reduced clinical efficacy. Ultrasound (US) is known to facilitate the penetration of drugs into tumors cells. However (molecular) imaging techniques that monitor in vivo the underlying processes of US‐triggered drug delivery are lacking. The objective of this study was to demonstrate the feasibility of using a fluorescent nuclear acid stain (TOTO‐3) as a model drug to monitor in real‐time US‐mediated delivery by in vivo fluorescence imaging. Following co‐injection of TOTO‐3 and microbubbles US was applied to the tumor. The time course of the drug delivery process was monitored by fluorescence imaging. Immunohistological analysis and in vitro experiments were performed to investigate the results in more detail. A significant signal intensity enhancement of the US‐treated tumor was observed that indicates intracellular delivery of the dye. In the control tumor TOTO‐3 signal was strongly associated with macrophages, which was not the case for the sonicated tumor. The capability of macrophages to uptake TOTO‐3 was confirmed in vitro. This study demonstrates that an optical contrast agent with similar characteristics to an anti‐cancer drug may be used for continuous in vivo monitoring of the drug delivery process. Copyright © 2010 John Wiley & Sons, Ltd.