Special Issue "Non-invasive Device-Mediated Brain Drug Delivery across the Blood-Brain Barrier"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: 20 July 2023 | Viewed by 3629

Special Issue Editors

Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Université Paris-Saclay, CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, France
Interests: blood-brain barrier; organic anion transporters; breast cancer resistance protein; vanadate-sensitive ATPase; multiple drug resistance
Tashima Laboratories of Arts and Sciences, Yokohama, Japan
Interests: drug design; drug discovery; pharmacophore; drug delivery; organic synthesis; drug cell-membrane permeability; pharmaceutical sciences; medicinal chemistry; chemical biology

Special Issue Information

Dear Colleagues,

We will be serving as the Guest Editor for this very interesting Special Issue on “Non-Invasive Device-Mediated Brain Drug Delivery Across the Blood–Brain Barrier”. It is well-known that the blood–brain barrier (BBB), substantially composed of tight junctions between the capillary endothelial cells and efflux transporters such as MDR1 at the apical membrane of the capillary endothelial cells, prevents drugs from entering the brain. Accordingly, drug delivery into the brain across the BBB is a challenging task, particularly in central nervous system diseases such as Alzheimer’s disease and Parkinson’s disease as well as brain cancers such as glioma. It is true that drugs in systemic circulation go through intentional membrane disruption or intentional tight junction disruption into the brain across the BBB, but bystander harmful compounds can enter the brain together. Moreover, although craniotomy is often conducted for surgical removal or direct drug administration, this process burdens and torments patients. Thus, non-invasive, device-mediated brain drug delivery across the BBB should be developed to improve not only patient health, but also quality of life. At present, brain drug delivery systems that utilize biological transport machineries such as carrier-mediated transport, receptor-mediated transcytosis, lipid-raft-mediated transcytosis, or macropinocytosis at the BBB have been extensively investigated. This Special Issue aims to share recent progress and trends in this field. We welcome submissions of all types of original articles concerned with noninvasive drug delivery into the brain across the BBB.

Topics include, but are not limited to, the strategies outlined below:

˗ Carrier-mediated transport

  • Drugs containing transporter recognition unit;
  • Substrate–drug conjugates with cleavable linkers.

˗ Receptor-mediated transcytosis

  • Antibody-drug conjugates with cleavable or uncleavable linkers;
  • Bispecific antibodies as antibody drugs;
  • Ligand-drug conjugates using ligands such as cell-penetrating peptides or homing peptides;
  • Drug-encapsulated nanoparticles covered with ligands using nanodelivery systems.

˗ Other strategies

Dr. Nicolas Tournier
Dr. Toshihiko Tashima
Guest Editors

Manuscript Submission Information

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Keywords

  • drug delivery systems
  • the blood-brain barrier (BBB)
  • non-invasive brain drug delivery
  • nanodelivery systems
  • transporter-consciously designed drug
  • carrier-mediated transport
  • receptor-mediated transcytosis
  • central nervous system disease
  • Alzheimer's disease (AD)
  • Parkinson's disease (PD)
  • brain cancer

Published Papers (3 papers)

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Research

Article
Non-Invasive, Targeted Nanoparticle-Mediated Drug Delivery across a Novel Human BBB Model
Pharmaceutics 2023, 15(5), 1382; https://doi.org/10.3390/pharmaceutics15051382 - 30 Apr 2023
Viewed by 512
Abstract
The blood–brain barrier (BBB) is a highly sophisticated system with the ability to regulate compounds transporting through the barrier and reaching the central nervous system (CNS). The BBB protects the CNS from toxins and pathogens but can cause major issues when developing novel [...] Read more.
The blood–brain barrier (BBB) is a highly sophisticated system with the ability to regulate compounds transporting through the barrier and reaching the central nervous system (CNS). The BBB protects the CNS from toxins and pathogens but can cause major issues when developing novel therapeutics to treat neurological disorders. PLGA nanoparticles have been developed to successfully encapsulate large hydrophilic compounds for drug delivery. Within this paper, we discuss the encapsulation of a model compound Fitc-dextran, a large molecular weight (70 kDa), hydrophilic compound, with over 60% encapsulation efficiency (EE) within a PLGA nanoparticle (NP). The NP surface was chemically modified with DAS peptide, a ligand that we designed which has an affinity for nicotinic receptors, specifically alpha 7 nicotinic receptors, found on the surface of brain endothelial cells. The attachment of DAS transports the NP across the BBB by receptor-mediated transcytosis (RMT). Assessment of the delivery efficacy of the DAS-conjugated Fitc-dextran-loaded PLGA NP was studied in vitro using our optimal triculture in vitro BBB model, which successfully replicates the in vivo BBB environment, producing high TEER (≥230 ) and high expression of ZO1 protein. Utilising our optimal BBB model, we successfully transported fourteen times the concentration of DAS-Fitc-dextran-PLGA NP compared to non-conjugated Fitc-dextran-PLGA NP. Our novel in vitro model is a viable method of high-throughput screening of potential therapeutic delivery systems to the CNS, such as our receptor-targeted DAS ligand-conjugated NP, whereby only lead therapeutic compounds will progress to in vivo studies. Full article
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Article
Self-Assembled Lecithin-Chitosan Nanoparticles Improved Rotigotine Nose-to-Brain Delivery and Brain Targeting Efficiency
Pharmaceutics 2023, 15(3), 851; https://doi.org/10.3390/pharmaceutics15030851 - 05 Mar 2023
Cited by 1 | Viewed by 1046
Abstract
Rotigotine (RTG) is a non-ergoline dopamine agonist and an approved drug for treating Parkinson’s disease. However, its clinical use is limited due to various problems, viz. poor oral bioavailability (<1%), low aqueous solubility, and extensive first-pass metabolism. In this study, rotigotine-loaded lecithin-chitosan nanoparticles [...] Read more.
Rotigotine (RTG) is a non-ergoline dopamine agonist and an approved drug for treating Parkinson’s disease. However, its clinical use is limited due to various problems, viz. poor oral bioavailability (<1%), low aqueous solubility, and extensive first-pass metabolism. In this study, rotigotine-loaded lecithin-chitosan nanoparticles (RTG-LCNP) were formulated to enhance its nose-to-brain delivery. RTG-LCNP was prepared by self-assembly of chitosan and lecithin due to ionic interactions. The optimized RTG-LCNP had an average diameter of 108 nm with 14.43 ± 2.77% drug loading. RTG-LCNP exhibited spherical morphology and good storage stability. Intranasal RTG-LCNP improved the brain availability of RTG by 7.86 fold with a 3.84-fold increase in the peak brain drug concentration (Cmax(brain)) compared to intranasal drug suspensions. Further, the intranasal RTG-LCNP significantly reduced the peak plasma drug concentration (Cmax(plasma)) compared to intranasal RTG suspensions. The direct drug transport percentage (DTP (%)) of optimized RTG-LCNP was found to be 97.3%, which shows effective direct nose-to-brain drug uptake and good targeting efficiency. In conclusion, RTG-LCNP enhanced drug brain availability, showing the potential for clinical application. Full article
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Article
Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model
Pharmaceutics 2022, 14(10), 2227; https://doi.org/10.3390/pharmaceutics14102227 - 19 Oct 2022
Cited by 1 | Viewed by 1368
Abstract
Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain [...] Read more.
Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain and tumor concentration of drugs administered systemically. Non-invasive, sensitive, and reliable imaging approaches are required to better understand the impact of FUS on the BBB and brain microenvironment. In this study, nuclear imaging (SPECT/CT and PET/CT) was used to quantify neuroinflammation 48 h post-FUS and estimate the influence of FUS on BBB opening and tumor growth in vivo. BBB disruptions were performed on healthy and GBM-bearing mice (U-87 MG xenograft orthotopic model). The BBB recovery kinetics were followed and quantified by [99mTc]Tc-DTPA SPECT/CT imaging at 0.5 h, 3 h and 24 h post-FUS. The absence of neuroinflammation was confirmed by [18F]FDG PET/CT imaging 48 h post-FUS. The presence of the tumor and its growth were evaluated by [68Ga]Ga-RGD2 PET/CT imaging and post-mortem histological analysis, showing that tumor growth was not influenced by FUS. In conclusion, molecular imaging can be used to evaluate the time frame for systemic treatment combined with transient BBB opening and to test its efficacy over time. Full article
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