Special Issue "Drug Delivery to Brain"


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

Deadline for manuscript submissions: 19 December 2014

Special Issue Editors

Guest Editor
Prof. Dr. Gert Fricker
Institut für Pharmazie und Molekulare Biotechnologie, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Website: http://www.ipmb.uni-heidelberg.de/phazt/
E-Mail: gert.fricker@uni-hd.de
Phone: +49 6221 548336
Fax: +49 6221 545971
Interests: blood brain barrier; ABC transporters; drug delivery systems; drug development

Guest Editor
Dr. Anne Mahringer
Institut für Pharmazie und Molekulare Biotechnologie, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Website: http://www.ipmb.uni-heidelberg.de/phazt/
E-Mail: Mahringer@urz.uni-heidelberg.de
Phone: +49 6221 548336
Fax: +49 6221 545971
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


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.

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Published Papers

No papers have been published in this special issue yet, see below for planned papers.

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Receptor-ligand complexes in targeted brain delivery
Authors: Julia V. Georgieva, Dick Hoekstra, Inge S. Zuhorn
Abstract: The blood-brain barrier is a limiting factor in developing novel medicines for neurological pathologies. It acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. A drug targeting technology that allows for non-invasive delivery of therapeutics to the brain are the molecular Trojan horses. Proteins or small peptides in nature, these are vectors to ferry drug-payload across the blood-brain barrier via endogenous receptor-mediated transcytosis. In this process the drug-Trojan horse complex is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by native receptors. Naturally, only certain properties would favor a receptor to serve as drug carrier. Here we list the brain microvascular endothelial receptors used until now in advanced drug delivery into the brain, and draw the attention on important features warranted for their future use.

Type of paper: Research article
Liposomal conjugates for drug delivery to the central nervous system
Authors: Frieder Helm, Gert Fricker
Abstract: Many treatments of diseases of the central nervous system 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 a successful drug delivery by colloidal carriers to the brain is the modification of their surface to make them invisible to the reticuloendothelial system (RES) and to target them to specific surface epitopes at the blood brain barrier. This study shows the behaviour of liposomes conjugated with cationized albumin (cBSA) as a transport vector both in-vitro on brain capillary endothelial cells (BCEC) isolated from pig brains and in-vivo on rats through fluorescently labelled liposomes.
Experiments on BCEC’s showed that sterically stabilized (PEGylated) liposomes without protein and liposomes conjugated to native BSA were not taken up. Only cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependant manner. Free BSA and free cBSA inhibited uptake, other endocytotic inhibitors, however, did not. Confocal fluorescence microscopy of brain cryosections from male Wistar rats after intravenous application of cBSA-liposomes showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 hours, for liposomes with a diameter between 120 and 150 nm. For a size above 180 nm no fluorescence could be detected. Liposomes with native BSA and without protein vector showed only little to no uptake into brain tissue.
liposomes, blood-brain barrier, cationized albumin, liposomal conjugates, brain capillary endothelial cells

Type of Paper: Research/Review
Title: Endocytosis of Nanomedicine in Central Nervous System
Authors: B. Ruozi, D. Belletti, A. Vilella, F. Forni, M.A. Vandelli, M. Zoli, G. Tosi.
Affiliation: Department of Life Sciences and Biomedical Sciences, University of Modena and Reggio Emilia, Italy
Keywords: Nanomedicine, Blood Brain Barrier, Neurons, Endocytosis, Uptake

Last update: 13 October 2014

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