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Drug Delivery Across or Bypassing the Blood–Brain Barrier

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (22 March 2022) | Viewed by 8691

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Special Issue Editors

Prof. Dr. Yael Mardor

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Guest Editor

1. The Advanced Technology Center, Sheba Medical Center, Ramat Gan 52621, Israel
2. Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Interests: brain; brain tumors; drug delivery into the brain; brain MRI; BBB
Special Issues, Collections and Topics in MDPI journals

Dr. Shirley Sharabi

E-Mail Website
Guest Editor

The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel
Interests: brain; BBB; brain tumors; drug delivery into the brain; MRI; pulsed electric fields; electroporation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The blood–brain barrier (BBB), the blood–central-system–fluid barrier, and the blood–tumor barrier are major hurdles for treating central nervous system (CNS) diseases of the brain and spine as they limit the passage of most therapeutic agents from the blood into CNS tissues. Currently, there is no standard treatment approach for penetrating/bypassing these barriers. Increasing worldwide lifespan has led to a rise in the prevalence of neurodegenerative disorders, having a huge impact on society and the economy. However, the majority of currently available treatments are ineffective due to low or no penetration of most therapeutic agents across the BBB. Thus, means to bypass these barriers or transiently disrupt them in a safe and controlled manner are in desperate need. This Special Issue summarizes the most recent advances made in the field of therapeutic agent delivery into the CNS.

Prof. Dr. Yael Mardor
Dr. Shirley Sharabi
Guest Editors

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

blood–brain barrier
blood–csf barrier
blood–tumor barrier
neurodegenerative diseases
brain tumors
neurovascular unit

Published Papers (2 papers)

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Research

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22 pages, 6524 KiB

Open AccessArticle

An Investigation for Large Volume, Focal Blood-Brain Barrier Disruption with High-Frequency Pulsed Electric Fields

by Melvin F. Lorenzo, Sabrina N. Campelo, Julio P. Arroyo, Kenneth N. Aycock, Jonathan Hinckley, Christopher B. Arena, John H. Rossmeisl, Jr. and Rafael V. Davalos

Pharmaceuticals 2021, 14(12), 1333; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121333 - 20 Dec 2021

Cited by 8 | Viewed by 3402

Abstract

The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell ablation. Eighteen male Fisher rats underwent craniectomy procedures and two blunt-tipped electrodes were advanced into the brain for pulsing. BBB disruption was verified with contrast T1W MRI and pathologically with Evans blue dye. High-frequency irreversible electroporation cell death of healthy rodent astrocytes was investigated in vitro using a collagen hydrogel tissue mimic. Numerical analysis was conducted to determine the electric fields in which BBB disruption and cell ablation occur. Differences between the BBB disruption and ablation thresholds for each waveform are as follows: 2-2-2

μ

s (1028 V/cm), 5-2-5

μ

s (721 V/cm), 10-1-10

μ

s (547 V/cm), 2-5-2

μ

s (1043 V/cm), and 5-5-5

μ

s (751 V/cm). These data suggest that HF-PEFs can be fine-tuned to modulate the extent of cell death while maximizing peri-ablative BBB disruption. Furthermore, numerical modeling elucidated the diffuse field gradients of a single-needle grounding pad configuration to favor large-volume BBB disruption, while the monopolar probe configuration is more amenable to ablation and reversible electroporation effects. Full article

(This article belongs to the Special Issue Drug Delivery Across or Bypassing the Blood–Brain Barrier)

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Review

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23 pages, 2473 KiB

Open AccessReview

Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

by William M. Pardridge

Pharmaceuticals 2022, 15(1), 3; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010003 - 21 Dec 2021

Cited by 20 | Viewed by 4785

Abstract

Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment. Full article

(This article belongs to the Special Issue Drug Delivery Across or Bypassing the Blood–Brain Barrier)

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