Special Issue "Drug Delivery to Brain"

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A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (31 March 2015)

Special Issue Editors

Guest Editor
Prof. Dr. Gert Fricker (Website)

Institut für Pharmazie und Molekulare Biotechnologie, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Phone: +49-6221-548336
Fax: +49 6221 545971
Interests: blood brain barrier; ABC transporters; drug delivery systems; drug development
Guest Editor
Dr. Anne Mahringer (Website)

Institut für Pharmazie und Molekulare Biotechnologie, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Interests: blood brain barrier; transport proteins; transporter regulation and signaling; drug delivery systems

Special Issue Information

Dear Colleagues,

Drug delivery to the brain remains one of the biggest challenges in modern pharmacotherapy. Many drug candidates for therapy of CNS diseases fail during development because they are not able to overcome the blood brain barrier (BBB) and to achieve therapeutically relevant concentrations within brain tissue. Modern drug discovery has evolved to optimize target affinity, but a parallel maturation of effective CNS drug delivery strategies is lacking. More than 98% of CNS drug development is devoted to drug discovery and only <2% is devoted to CNS drug delivery. Except for lipid-soluble molecules, which have a molecular weight under a 400-600 Da threshold, virtually all drugs that originate from either biotechnology or classical small molecule pharmacology exhibit negligible transport across the BBB.

This barrier is formed by endothelial cells of brain microvessels being connected by extremely tight junctions and surrounded by parricides, a basal membrane and astrocytes, which form—together with neurons—the so called neurovascular unit. The capillary network has impressive dimensions: the total length of capillaries in the human brain is approximate 600 km with a surface area of 20 m2, which means, in fact, that almost every neuron is perfused by its own capillary. A peculiarity of the endothelial cells is the high expression of export proteins including p-glycoprotein, breast cancer resistance protein and Mrp proteins, which act as active efflux systems for a variety of drugs. In addition, endothelial cells are equipped with a battery of other transport proteins such as a glucose transporter, amino acid transporters, organic anion transport proteins as well as with distinct receptors, e.g., transferring receptor, insulin receptor or low-density lipoprotein receptor related protein-1 (LRP or LDL like receptor). During recent years these receptors have become interesting as targets for drug
delivery using colloidal carrier systems like liposomes, polymeric nanoparticles or solid lipid nanoparticles. Specific surface modification (vector technology) enables these carriers systems to be recognized by the respective receptors, which subsequently undergo transcytosis and release their cargo at the brain side of the endothelial wall. Whereas application of normal colloidal carriers yielded more or less disillusioning results in clinical trials within the last 25 years, this vector technology offers promising tools for new therapeutic areas. Thus, the idea of unfailing “magic bullets”, which was originally developed by Paul Ehrlich at the beginning of the 20th century, appears to come closer to reality.

This special issue “Drug Delivery to Brain" will address new biological, pharmacological and technological approaches to overcome the BBB, which might help to satisfy one of the biggest therapeutic needs of the present time.

Prof. Dr. Gert Fricker
Dr. Anne Mahringer
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 500 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Published Papers (6 papers)

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Research

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Open AccessArticle Liposomal Conjugates for Drug Delivery to the Central Nervous System
Pharmaceutics 2015, 7(2), 27-42; doi:10.3390/pharmaceutics7020027
Received: 18 December 2014 / Revised: 19 March 2015 / Accepted: 23 March 2015 / Published: 1 April 2015
Cited by 6 | PDF Full-text (5008 KB) | HTML Full-text | XML Full-text
Abstract
Treatments of central nervous system (CNS) diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of [...] Read more.
Treatments of central nervous system (CNS) diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems—amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES) and to target them to specific surface epitopes at the blood–brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA) as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC) and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated) liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA) were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes. Full article
(This article belongs to the Special Issue Drug Delivery to Brain)
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Review

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Open AccessReview Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles
Pharmaceutics 2015, 7(3), 275-293; doi:10.3390/pharmaceutics7030275
Received: 31 March 2015 / Revised: 13 August 2015 / Accepted: 14 August 2015 / Published: 31 August 2015
Cited by 3 | PDF Full-text (924 KB) | HTML Full-text | XML Full-text
Abstract
Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, [...] Read more.
Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer’s disease is presented. Full article
(This article belongs to the Special Issue Drug Delivery to Brain)
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Open AccessReview Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment
Pharmaceutics 2015, 7(3), 175-187; doi:10.3390/pharmaceutics7030175
Received: 1 April 2015 / Revised: 21 July 2015 / Accepted: 24 July 2015 / Published: 3 August 2015
Cited by 9 | PDF Full-text (1138 KB) | HTML Full-text | XML Full-text
Abstract
The blood–brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood–brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused [...] Read more.
The blood–brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood–brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood–brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal. Full article
(This article belongs to the Special Issue Drug Delivery to Brain)
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Open AccessReview Endocytosis of Nanomedicines: The Case of Glycopeptide Engineered PLGA Nanoparticles
Pharmaceutics 2015, 7(2), 74-89; doi:10.3390/pharmaceutics7020074
Received: 30 March 2015 / Revised: 15 May 2015 / Accepted: 10 June 2015 / Published: 19 June 2015
Cited by 5 | PDF Full-text (1629 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The success of nanomedicine as a new strategy for drug delivery and targeting prompted the interest in developing approaches toward basic and clinical neuroscience. Despite enormous advances on brain research, central nervous system (CNS) disorders remain the world’s leading cause of disability, [...] Read more.
The success of nanomedicine as a new strategy for drug delivery and targeting prompted the interest in developing approaches toward basic and clinical neuroscience. Despite enormous advances on brain research, central nervous system (CNS) disorders remain the world’s leading cause of disability, in part due to the inability of the majority of drugs to reach the brain parenchyma. Many attempts to use nanomedicines as CNS drug delivery systems (DDS) were made; among the various non-invasive approaches, nanoparticulate carriers and, particularly, polymeric nanoparticles (NPs) seem to be the most interesting strategies. In particular, the ability of poly-lactide-co-glycolide NPs (PLGA-NPs) specifically engineered with a glycopeptide (g7), conferring to NPs’ ability to cross the blood brain barrier (BBB) in rodents at a concentration of up to 10% of the injected dose, was demonstrated in previous studies using different routes of administrations. Most of the evidence on NP uptake mechanisms reported in the literature about intracellular pathways and processes of cell entry is based on in vitro studies. Therefore, beside the particular attention devoted to increasing the knowledge of the rate of in vivo BBB crossing of nanocarriers, the subsequent exocytosis in the brain compartments, their fate and trafficking in the brain surely represent major topics in this field. Full article
(This article belongs to the Special Issue Drug Delivery to Brain)
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Open AccessReview Influence of Chronobiology on the Nanoparticle-Mediated Drug Uptake into the Brain
Pharmaceutics 2015, 7(1), 3-9; doi:10.3390/pharmaceutics7010003
Received: 6 December 2014 / Revised: 8 January 2015 / Accepted: 21 January 2015 / Published: 3 February 2015
Cited by 3 | PDF Full-text (878 KB) | HTML Full-text | XML Full-text
Abstract
Little attention so-far has been paid to the influence of chronobiology on the processes of nanoparticle uptake and transport into the brain, even though this transport appears to be chronobiologically controlled to a significant degree. Nanoparticles with specific surface properties enable the [...] Read more.
Little attention so-far has been paid to the influence of chronobiology on the processes of nanoparticle uptake and transport into the brain, even though this transport appears to be chronobiologically controlled to a significant degree. Nanoparticles with specific surface properties enable the transport across the blood–brain barrier of many drugs that normally cannot cross this barrier. A clear dependence of the central antinociceptive (analgesic) effects of a nanoparticle-bound model drug, i.e., the hexapeptide dalargin, on the time of day was observable after intravenous injection in mice. In addition to the strongly enhanced antinociceptive effect due to the binding to the nanoparticles, the minima and maxima of the pain reaction with the nanoparticle-bound drug were shifted by almost half a day compared to the normal circadian nociception: The maximum in the pain reaction after i.v. injection of the nanoparticle-bound dalargin occurred during the later rest phase of the animals whereas the normal pain reaction and that of a dalargin solution was highest during the active phase of the mice in the night. This important shift could be caused by an enhanced endo- and exocytotic particulates transport activity of the brain capillary endothelial cells or within the brain during the rest phase. Full article
(This article belongs to the Special Issue Drug Delivery to Brain)
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Open AccessReview Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier
Pharmaceutics 2014, 6(4), 557-583; doi:10.3390/pharmaceutics6040557
Received: 24 September 2014 / Revised: 28 October 2014 / Accepted: 29 October 2014 / Published: 17 November 2014
Cited by 17 | PDF Full-text (1455 KB) | HTML Full-text | XML Full-text
Abstract
The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the [...] Read more.
The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood–brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier–drug system (“Trojan horse complex”) is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain. Full article
(This article belongs to the Special Issue Drug Delivery to Brain)
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