Editorial pubs.acs.org/molecularpharmaceutics
Drug Delivery across the Blood−Brain Barrier
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models to guide compound selection and clinical trial design. In recognition of this continuum of approaches and challenges, this special issue highlights the recent work of investigators as they address the barrier issue in order to provide insight into the restrictive properties of the BBB. Novel methods, such as the use of image-based quantitative kinetics, are also presented and provide thoughtful and innovative strategies for improving the delivery of macromolecules to the brain. One such work tends to focus on how the structure and function of the brain allows small and large molecules to cross the BBB. Moreover, other papers tend to address some of the newer topics, such as the underlying mechanism of antibody-based drug transport and distribution to the brain through the use of preclinical studies that provide direct insight into the relationship between pathological conditions, BBB transport, and drug effects in relevant in vitro and in vivo models. The collection of four different reviews and six original research articles in this issue provide key information on current experimental methods of crossing the BBB to successfully deliver drugs to the CNS, making it a particularly exciting time to translate research to the clinic. The first four articles in this issue are focused on understanding the mechanism of drug delivery across the BBB and the physiology of the BBB. The first article, authored by Strazielle and Ghersi-Egea, is very effective at comparing the biological and physiological properties of the two main CNS barriers, the BBB and the blood−CSF barrier (BCSFB). This article tackles the structural and biochemical features of brain barriers relevant to the cerebral delivery of small and macromolecular drugs, and gives quantitative information about the possible transport mechanisms at the developing blood−CSF interface. A second review article, authored by Wolak and Thorne, introduces the basic nature of macromolecular diffusion inside the extracellular space (ECS) of the brain together with commonly utilized methodologies for analysis of diffusion in the brain ECS. This article discusses these issues in the context of drug delivery into CNS disease/ injury models, and provides mathematical models to estimate macromolecule diffusion. The third article, by Abuqayyas and Balthasar, evaluates the role of neonatal Fc receptor and Fc gamma receptor in the transport of antibodies into the brain and the implications of these findings. This is an important study for the antibody biologics field and contributes specifically to an area that is puzzled with conflicting data. This is followed by an article (Boswell et al.) describing the use of a variety of molecular probes to characterize the vascular biology of a preclinical model of neurodegenerative disease. It is believed that this experimental multiprobe approach can play a fundamental role in advancing our understanding of the BBB physiology and delivery of drugs to brain in mouse models of BBB disruption.
he delivery of drugs to the central nervous system (CNS) remains a challenge in the treatment of neurological diseases such as Alzheimer’s disease, Parkinson’s disease, and stroke. The major challenge to CNS drug delivery is the presence of the blood−brain barrier (BBB), which limits the access of drugs to the brain parenchyma. The BBB limits drug delivery by generally allowing only those molecules that are lipophilic and have low molecular weight (less than 400−500 Da) to enter the brain from the bloodstream through the transcellular route.3 In this context, it has been reported that approximately 98% of small molecules and nearly all large therapeutic molecules, such as monoclonal antibodies, antisense oligonucleotides, or viral vectors, cannot pass through this barrier.4 For these reasons, delivery of drugs to the brain is still a major challenge, and recent reports indicate that less than 10% of therapeutic agents for neurological diseases enter into clinical trials because of poor brain penetration.5 Attempts to overcome this barrier involve increasing drug delivery of intravascularly administered drugs by manipulating either the drug or capillary permeability,1 and/or by local administration into brain fluids, such as the cerebrospinal fluid of brain ventricles or the interstitial fluid of brain tissue.2 In recognition to the difficulties associated with CNS delivery across the BBB, research efforts have focused on the development of new strategies to more effectively deliver drugs to the brain. These strategies include manipulating the characteristics of the drugs or utilizing endogenous transporters or receptors at the BBB. Successful delivery into the brain tissue has been achieved in some cases through the use of nanoparticulate drug carriers6 or by antibodies that target receptors at the BBB, such as transferrin, insulin, and low density lipoprotein receptors, that facilitate their transport across the BBB via receptor mediated transcytosis (RMT).7−11 As such, the opportunities for delivery of drugs to the CNS through endogenous RMT systems are exciting,12 but greater understanding of CNS physiology and pathophysiology of the CNS as well as further validation in relevant preclinical disease models of the quantitative brain distribution kinetics and efficacy of targeted drugs is needed for translation to the clinic.13 Advances in both drug delivery strategies across the BBB and in vivo brain uptake measurement methods will be important for achieving successful end results. With this in mind, this special issue provides a snapshot of some of the ongoing research efforts in the CNS field. Although the topics adopted by the ten different papers are diverse, the common theme that unifies these papers is the need to solve the fundamental problems of drug delivery to the brain by using various strategies. Some of the problems addressed by the papers in this thematic issue have a long history, such as the need to better understand the physiology and anatomy of the BBB or the need to improve our knowledge of changes in brain proteomic profile and in BBB transport systems under pathological conditions. Other problems have also emerged as significant, such as the need to develop more predictable preclinical disease © 2013 American Chemical Society
Special Issue: Drug Delivery across the Blood-Brain Barrier Published: May 6, 2013 1471
dx.doi.org/10.1021/mp400170b | Mol. Pharmaceutics 2013, 10, 1471−1472
Molecular Pharmaceutics
Editorial
special emphasis given on the proposed impact of disease states and species on the BBB function. As a whole, this thematic issue demonstrates how the field of CNS delivery has evolved into a real mainstream scientific domain. Exploration of a variety of strategies for enhancing drug transport across the BBB along with more rigorous determination of kinetic measures at the site of action can offer not only solutions to pressing existing challenges but also revolutionary approaches to growing and emerging needs. The diversity of published papers reinforced our belief that the domain of CNS drug delivery is better positioned for designing and developing novel therapeutic agents in order to increase drug exposure to the brain. We would like to extend our thanks to all the authors, who had high quality submissions and provided great insight into the current state of the field, which has put us ahead in the quest for understanding CNS anatomy and physiology. We would particularly like to thank the special issue reviewers, whose efforts substantially contributed to the improvement of the overall quality of this thematic issue. Special thanks to our colleagues at Genentech, Ryan Watts, Daniela Bumbaca, C. Andrew Boswell, and Joseph Ware for scientific exchange and discussions. And of course we would like to thank the journal staff, for providing support and input, and for giving us the opportunity to showcase the recent advances in the field of CNS drug delivery systems.
The next three articles in this issue focus on CNS drug delivery systems involving different approaches to enhance drug delivery to the brain. A timely review by Papisov et al. concentrates on evaluating the impact of administration route on the delivery of macromolecular drugs through the use of image-based quantitative kinetics. It includes a general discussion of the anatomy of the subarachnoid space, the pathways and mechanisms of CSF secretion and reabsorption, and describes the exchange between the subarachnoid CSF compartments and the brain interstitium. The review concludes with a brief discussion on potential changes to the function of these pathways in pathophysiological conditions. Another article, by Lindqvist et al., presents nanocarriers as a promising delivery system to enhance transport at the BBB. One of the key innovations of this approach is to change the systemic pharmacokinetics (PK) of the released drug using liposomes and polymeric nanoparticles that can potentially facilitate the transport of large molecules. Indeed, the results showing the enhanced transport to the brain are impressive, for which both the PK and pharmacological response between plasma and brain were measured with microdialysis. This is followed by an article (Haqqani et al.) suggesting that the use of selected peptides as a carrier system for protein delivery may enhance the delivery of protein drugs to the brain. This research article describes the development of a sensitive and selective mass spectrometry-based method to monitor and quantify panels of unlabeled single domain antibodies in body fluids, including CSF. Therefore, these techniques represent an elegant approach for dealing with the difficult problem of quantitatively assessing biologic penetration into the CNS. Two additional research articles are of interest to the readers in this special issue and provide unique insights into the CNS field which create even more valuable knowledge critical for developing therapies to treat CNS disorders. One such work, by Agyare et al., presents an experimentally verifiable mechanism describing how Alzheimer’s disease amyloid β (Aβ) proteins accumulate in the cerebral vasculature to cause cerebral amyloid angiopathy (CAA). It is widely believed that the accumulation of Aβ40 and DutchAβ40 in the cerebral vasculature is due to their inefficient clearance from the brain. These investigators provide experimental evidence in support of this theory and isolate the key kinetic events that promote cerebrovascular versus parenchymal Aβ deposition. Moreover, this study establishes that the accumulation of Aβ proteins in the cerebrovascular endothelium is the earliest pathological event that triggers CAA. In another article, by Harati et al., the interconnected features related to the regulation of ABC and SLC transporters occurring during BBB maturation was addressed. These investigators have characterized the brain capillary expression and activity profiles of 4 proteins implicated in transport of drugs across the BBB, and also decipher a role for β-catenin and endothelin-1 (ET-1). These findings provide novel insight into the functional expression of ABC and SLC transporters under β-catenin regulation and illustrate a major role of the inflammatory component ET-1 in the functional regulation of both ABC and SLC transporters at the BBB. Such work uncovers new knowledge on regulation of drug transporters at the BBB. The final article, by Deo et al., presents the challenges in the translation of preclinical findings in CNS drug development to the clinic, particularly focusing on the predictive value of preclinical rodent models. This review describes different approaches to measuring drug disposition in the brain with
Leslie A. Khawli,* Guest Editor Saileta Prabhu
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Genentech Research & Early Development, One DNA Way, South San Francisco, California 94080, United States
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
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