Nanoagonist-mediated endothelial tight junction opening: A strategy for safely increasing brain drug delivery in mice

Even though opening endothelial tight junctions is an efficient way to up-regulate brain drug delivery, the extravasation of blood-borne components from the compromised tight junctions can result in adverse consequences such as edema and neuronal injuries. In this work, we developed a nanoagonist that temporarily opened tight junctions by signaling adenosine 2A receptor, a type of G protein-coupled receptor expressed on brain capillary endothelial cells. Magnetic resonance imaging demonstrated remarkable blood–brain barrier permeability enhancements and significantly increased brain uptakes of both small molecular and macromolecular paramagnetic agents after nanoagonist administration. Gamma ray imaging and transmission electron microscope observed tight junction opening followed by spontaneous recovery after nanoagonist treatment. Immunofluorescence staining showed the unspoiled basal membrane, pericytes and astrocyte endfeet that enwrapped the vascular endothelium. Importantly, edema, apoptosis and neuronal injuries observed after hypertonic agent mediated tight junction-opening were not observed after nanoagonist intervention. The uncompromised neurovascular units may prevent the leakage of blood-borne constituents into brain parenchyma and accelerate tight junction recovery. Considering blood–brain barrier impermeability is a major obstacle in the treatment of central nervous system diseases, nanoagonist-mediated tight junction opening provides a promising strategy to enhance brain drug delivery with minimized adverse effects.

Download Full-text

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

Current Pharmaceutical Design ◽

10.2174/1381612826666200316130128 ◽

2020 ◽

Vol 26 (13) ◽

pp. 1448-1465 ◽

Cited By ~ 1

Author(s):

Jozef Hanes ◽

Eva Dobakova ◽

Petra Majerova

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Neurodegenerative Disorders ◽

Brain Barrier ◽

Neuronal Function ◽

Brain Drug Delivery ◽

Naturally Occurring ◽

Blood Brain ◽

Traditional Approaches ◽

The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

Download Full-text

Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

10.1101/2020.10.05.326843 ◽

2020 ◽

Author(s):

Xiaoqing Li ◽

Vamsidhara Vemireddy ◽

Qi Cai ◽

Hejian Xiong ◽

Peiyuan Kang ◽

...

Keyword(s):

Tight Junction ◽

Tight Junctions ◽

Blood Brain Barrier ◽

Therapeutic Interventions ◽

Brain Barrier ◽

Light Stimulation ◽

Targeted Nanoparticles ◽

Blood Brain ◽

The Brain ◽

Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

Download Full-text

The Blood-Brain Barrier and Brain Drug Delivery

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2006.441 ◽

2006 ◽

Vol 6 (9) ◽

pp. 2712-2735 ◽

Cited By ~ 55

Author(s):

J. M. Koziara ◽

P. R. Lockman ◽

D. D. Allen ◽

R. J. Mumper

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Present Report ◽

Drug Carriers ◽

Brain Barrier ◽

Brain Targeting ◽

Anatomy And Physiology ◽

Brain Drug Delivery ◽

Blood Brain

The present report encompasses a thorough review of drug delivery to the brain with a particular focus on using drug carriers such as liposomes and nanoparticles. Challenges in brain drug delivery arise from the presence of one of the strictest barriers in vivo—the blood-brain barrier (BBB). This barrier exists at the level of endothelial cells of brain vasculature and its role is to maintain brain homeostasis. To better understand the principles of brain drug delivery, relevant knowledge of the blood-brain barrier anatomy and physiology is briefly reviewed. Several approaches to overcome the BBB have been reviewed including the use of carrier systems. In addition, strategies to enhance brain drug delivery by specific brain targeting are discussed.

Download Full-text

Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes

Journal of Cell Science ◽

10.1242/jcs.107.5.1347 ◽

1994 ◽

Vol 107 (5) ◽

pp. 1347-1357 ◽

Cited By ~ 6

Author(s):

H. Wolburg ◽

J. Neuhaus ◽

U. Kniesel ◽

B. Krauss ◽

E.M. Schmid ◽

...

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Tight Junctions ◽

Blood Brain Barrier ◽

Barrier Function ◽

Primary Cultures ◽

Brain Barrier ◽

Brain Endothelial Cells ◽

Blood Brain ◽

Camp Levels

Tight junctions between endothelial cells of brain capillaries are the most important structural elements of the blood-brain barrier. Cultured brain endothelial cells are known to loose tight junction-dependent blood-brain barrier characteristics such as macromolecular impermeability and high electrical resistance. We have directly analyzed the structure and function of tight junctions in primary cultures of bovine brain endothelial cells using quantitative freeze-fracture electron microscopy, and ion and inulin permeability. The complexity of tight junctions, defined as the number of branch points per unit length of tight junctional strands, decreased 5 hours after culture but thereafter remained almost constant. In contrast, the association of tight junction particles with the cytoplasmic leaflet of the endothelial membrane bilayer (P-face) decreased continuously with a major drop between 16 hours and 24 hours. The complexity of tight junctions could be increased by elevation of intracellular cAMP levels while phorbol esters had the opposite effect. On the other hand, the P-face association of tight junction particles was enhanced by elevation of cAMP levels and by coculture of endothelial cells with astrocytes or exposure to astrocyte-conditioned medium. The latter effect on P-face association was induced by astrocytes but not fibroblasts. Elevation of cAMP levels together with astrocyte-conditioned medium synergistically increased transendothelial electrical resistance and decreased inulin permeability of primary cultures, thus confirming the effects on tight junction structure and barrier function. P-face association of tight junction particles in brain endothelial cells may therefore be a critical feature of blood-brain barrier function that can be specifically modulated by astrocytes and cAMP levels. Our results suggest an important functional role for the cytoplasmic anchorage of tight junction particles for brain endothelial barrier function in particular and probably paracellular permeability in general.

Download Full-text

Gemini quaternary ammonium-incorporated biodegradable multiblock polyurethane micelles for brain drug delivery

RSC Advances ◽

10.1039/c4ra09908g ◽

2015 ◽

Vol 5 (8) ◽

pp. 6160-6171 ◽

Cited By ~ 5

Author(s):

Rui-Chao Liang ◽

Fang Fang ◽

Yan-Chao Wang ◽

Ni-Jia Song ◽

Jie-Hua Li ◽

...

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Quaternary Ammonium ◽

Drug Accumulation ◽

Brain Barrier ◽

Brain Drug Delivery ◽

Blood Brain

Gemini quaternary ammonium (GQA) incorporated biodegradable multiblock polyurethane (BMPUs) micelles could transport drug across blood–brain barrier and improve brain drug accumulation.

Download Full-text