scholarly journals The vascular basement membrane in the healthy and pathological brain

2017 ◽  
Vol 37 (10) ◽  
pp. 3300-3317 ◽  
Author(s):  
Maj S Thomsen ◽  
Lisa J Routhe ◽  
Torben Moos
Keyword(s):  
Drug Delivery ◽  
Basement Membrane ◽  
Proteolytic Enzymes ◽  
Three Dimensional ◽  
Matrix Proteins ◽  
Vascular Basement Membrane ◽  
Capillary Endothelial Cells ◽  
The Brain ◽  
Astrocyte Endfeet

The vascular basement membrane contributes to the integrity of the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). The BCECs receive support from pericytes embedded in the vascular basement membrane and from astrocyte endfeet. The vascular basement membrane forms a three-dimensional protein network predominantly composed of laminin, collagen IV, nidogen, and heparan sulfate proteoglycans that mutually support interactions between BCECs, pericytes, and astrocytes. Major changes in the molecular composition of the vascular basement membrane are observed in acute and chronic neuropathological settings. In the present review, we cover the significance of the vascular basement membrane in the healthy and pathological brain. In stroke, loss of BBB integrity is accompanied by upregulation of proteolytic enzymes and degradation of vascular basement membrane proteins. There is yet no causal relationship between expression or activity of matrix proteases and the degradation of vascular matrix proteins in vivo. In Alzheimer’s disease, changes in the vascular basement membrane include accumulation of Aβ, composite changes, and thickening. The physical properties of the vascular basement membrane carry the potential of obstructing drug delivery to the brain, e.g. thickening of the basement membrane can affect drug delivery to the brain, especially the delivery of nanoparticles.

Novel Phospholipid-Based Labrasol Nanomicelles Loaded Flavonoids for Oral Delivery with Enhanced Penetration and Anti-Brain Tumor Efficiency

2020 ◽  
Vol 17 (3) ◽  
pp. 229-245
Author(s):  
Gang Wang ◽  
Junjie Wang ◽  
Rui Guan
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Oral Delivery ◽  
Safe Delivery ◽  
Drug Delivery Vehicles ◽  
Therapeutic Benefits ◽  
Delivery Vehicles ◽  
The Brain

Background: Owing to the rich anticancer properties of flavonoids, there is a need for their incorporation into drug delivery vehicles like nanomicelles for safe delivery of the drug into the brain tumor microenvironment. Objective: This study, therefore, aimed to prepare the phospholipid-based Labrasol/Pluronic F68 modified nano micelles loaded with flavonoids (Nano-flavonoids) for the delivery of the drug to the target brain tumor. Methods: Myricetin, quercetin and fisetin were selected as the initial drugs to evaluate the biodistribution and acute toxicity of the drug delivery vehicles in rats with implanted C6 glioma tumors after oral administration, while the uptake, retention, release in human intestinal Caco-2 cells and the effect on the brain endothelial barrier were investigated in Human Brain Microvascular Endothelial Cells (HBMECs). Results: The results demonstrated that nano-flavonoids loaded with myricetin showed more evenly distributed targeting tissues and enhanced anti-tumor efficiency in vivo without significant cytotoxicity to Caco-2 cells and alteration in the Trans Epithelial Electric Resistance (TEER). There was no pathological evidence of renal, hepatic or other organs dysfunction after the administration of nanoflavonoids, which showed no significant influence on cytotoxicity to Caco-2 cells. Conclusion: In conclusion, Labrasol/F68-NMs loaded with MYR and quercetin could enhance antiglioma effect in vitro and in vivo, which may be better tools for medical therapy, while the pharmacokinetics and pharmacodynamics of nano-flavonoids may ensure optimal therapeutic benefits.

scholarly journals Artificial Neural Network in Drug Delivery and Pharmaceutical Research

2013 ◽  
Vol 7 (1) ◽  
pp. 49-62 ◽  
Author(s):  
Vijaykumar Sutariya ◽  
Anastasia Groshev ◽  
Prabodh Sadana ◽  
Deepak Bhatia ◽  
Yashwant Pathak
Keyword(s):  
Neural Network ◽  
Neural Networks ◽  
Drug Delivery ◽  
Pattern Recognition ◽  
Analytical Data ◽  
Pharmaceutical Research ◽  
Artificial Neural ◽  
The Brain

Artificial neural networks (ANNs) technology models the pattern recognition capabilities of the neural networks of the brain. Similarly to a single neuron in the brain, artificial neuron unit receives inputs from many external sources, processes them, and makes decisions. Interestingly, ANN simulates the biological nervous system and draws on analogues of adaptive biological neurons. ANNs do not require rigidly structured experimental designs and can map functions using historical or incomplete data, which makes them a powerful tool for simulation of various non-linear systems.ANNs have many applications in various fields, including engineering, psychology, medicinal chemistry and pharmaceutical research. Because of their capacity for making predictions, pattern recognition, and modeling, ANNs have been very useful in many aspects of pharmaceutical research including modeling of the brain neural network, analytical data analysis, drug modeling, protein structure and function, dosage optimization and manufacturing, pharmacokinetics and pharmacodynamics modeling, and in vitro in vivo correlations. This review discusses the applications of ANNs in drug delivery and pharmacological research.

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

scholarly journals Shortcut Approaches to Substance Delivery into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5188
Author(s):  
Toshihiko Tashima
Keyword(s):  
Drug Delivery ◽  
Olfactory Epithelium ◽  
Olfactory Nerve ◽  
Brain Drug Delivery ◽  
Cns Drug Delivery ◽  
Capillary Endothelial Cells ◽  
Alternative Approaches ◽  
Cns Drugs ◽  
Direct Delivery ◽  
The Brain

The direct delivery of central nervous system (CNS) drugs into the brain after administration is an ideal concept due to its effectiveness and non-toxicity. However, the blood–brain barrier (BBB) prevents drugs from penetrating the capillary endothelial cells, blocking their entry into the brain. Thus, alternative approaches must be developed. The nasal cavity directly leads from the olfactory epithelium to the brain through the cribriform plate of the skull bone. Nose-to-brain drug delivery could solve the BBB-related repulsion problem. Recently, it has been revealed that insulin improved Alzheimer’s disease (AD)-related dementia. Several ongoing AD clinical trials investigate the use of intranasal insulin delivery. Related to the real trajectory, intranasal labeled-insulins demonstrated distribution into the brain not only along the olfactory nerve but also the trigeminal nerve. Nonetheless, intranasally administered insulin was delivered into the brain. Therefore, insulin conjugates with covalent or non-covalent cargos, such as AD or other CNS drugs, could potentially contribute to a promising strategy to cure CNS-related diseases. In this review, I will introduce the CNS drug delivery approach into the brain using nanodelivery strategies for insulin through transcellular routes based on receptor-mediated transcytosis or through paracellular routes based on escaping the tight junction at the olfactory epithelium.

Fabrication of Bio-Composite Drug Delivery System Using Rapid Prototyping Technology

2007 ◽  
Vol 342-343 ◽  
pp. 497-500 ◽  
Author(s):  
Won Shik Chu ◽  
Sung Geun Kim ◽  
Hyung Jung Kim ◽  
Caroline S. Lee ◽  
Sung Hoon Ahn
Keyword(s):  
Drug Delivery ◽  
Composite Materials ◽  
Rapid Prototyping ◽  
Drug Delivery System ◽  
Delivery System ◽  
Release Rate ◽  
Three Dimensional ◽  
Deposition Process ◽  
Porous Microstructure

The rapid prototyping (RP) technology has advanced in various fields such as verification of design, and functional test. Recently, researchers have studied bio-materials to fabricate functional bio-RP parts. In this research, a nano composite deposition system (NCDS) was developed to fabricate three-dimensional functional parts for bio-applications. In the hybrid process, the material removal process by mechanical micro machining and/or the deposition process are combined. NCDS uses biocompatible or biodegradable polymer resin as matrix and various bioceramics to form bio-composite materials. To test drug release rate in vivo environment, two different types of drug delivery system (DDS) were fabricated using the bio-composite materials. 1) Container type DDS used poly(DL-lactide-co-glycolide acid)(50:50) and 5-fluorouracil as the drug composite while polycaprolactone(PCL) served as the container of the drug. 2) Scaffold type DDS formed porous microstructure with poly(DL-lactide-co-glycolide acid)(50:50) and 5-fluorouracil composite. The effect of geometry of the DDS on release rate of drug is under investigation.

scholarly journals Internalization of targeted quantum dots by brain capillary endothelial cells in vivo

2015 ◽  
Vol 36 (4) ◽  
pp. 731-742 ◽  
Author(s):  
Sarah Paris-Robidas ◽  
Danny Brouard ◽  
Vincent Emond ◽  
Martin Parent ◽  
Frédéric Calon
Keyword(s):  
Drug Delivery ◽  
Quantum Dots ◽  
Endothelial Cells ◽  
Transferrin Receptor ◽  
Volume Of Distribution ◽  
Electron Microscopic ◽  
Brain Capillary ◽  
Brain Capillary Endothelial Cells ◽  
Capillary Endothelial Cells

Receptors located on brain capillary endothelial cells forming the blood–brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery.

An Investigation of Nano-structured Polymers for Use as Bladder Tissue Replacement Constructs

2001 ◽  
Vol 711 ◽  
Author(s):  
Anil Thapa ◽  
Thomas J. Webster ◽  
Karen M. Haberstroh
Keyword(s):  
Bladder Wall ◽  
Three Dimensional ◽  
The Body ◽  
Matrix Proteins ◽  
Bladder Smooth Muscle ◽  
Bladder Tissue ◽  
Tissue Replacement ◽  
Tissue Constructs

ABSTRACTConventionally, studies investigating the design of synthetic bladder wall substitutes have involved polymers with micro-dimensional structures. Since the body is made up of nano-structured components (e.g., extracellular matrix proteins), our focus has been in the use of nano-structured polymers in order to design a three-dimensional synthetic bladder construct that mimics bladder tissue in vivo. In order to complete this task, we fabricated novel, nano-structured, biodegradable materials to serve as substrates for bladder tissue constructs and tested the cytocompatibility properties of these biomaterials in vitro. The results from our in vitro work to date have provided the first evidence that cellular responses (such as adhesion and proliferation) of bladder smooth muscle cells are enhanced as poly (lactic-co-glycolic acid) (PLGA) surface feature dimensions are reduced into the nanometer range.

scholarly journals Capillary endothelial cell cultures: phenotypic modulation by matrix components.

1983 ◽  
Vol 97 (1) ◽  
pp. 153-165 ◽  
Author(s):  
J A Madri ◽  
S K Williams
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
Membrane Surface ◽  
Phenotypic Expression ◽  
Aortic Endothelial Cells ◽  
Capillary Endothelial Cells ◽  
Endothelial Cell Cultures ◽  
Cell Densities

Capillary endothelial cells of rat epididymal fat pad were isolated and cultured in media conditioned by bovine aortic endothelial cells and substrata consisting of interstitial or basement membrane collagens. When these cells were grown on interstitial collagens they underwent proliferation, formed a continuous cell layer and, if cultured for long periods of time, formed occasional tubelike structures. In contrast, when these cells were grown on basement membrane collagens, they did not proliferate but did aggregate and form tubelike structures at early culture times. In addition, cells grown on basement membrane substrata expressed more basement membrane constituents as compared with cells grown on interstitial matrices when assayed by immunoperoxidase methods and quantitated by enzyme-linked immunosorbent inhibition assays. Furthermore, when cells were grown on either side of washed, acellular amnionic membranes their phenotypes were markedly different. On the basement membrane surface they adhered, spread, and formed tubelike structures but did not migrate through the basement membrane. In contrast, when seeded on the stromal surface, these cells were observed to proliferate and migrate into the stromal aspect of the amnion and ultimately formed tubelike structures at high cell densities at longer culture periods (21 d). Thus, connective tissue components play important roles in regulating the phenotypic expression of capillary endothelial cells in vitro, and similar roles of the collagenous components of the extracellular matrix may exist in vivo following injury and during angiogenesis. Furthermore, the culture systems outlined here may be of use in the further study of differentiated, organized capillary endothelial cells in culture.

scholarly journals In vivo biodistribution of carboxymethylchitosan/poly(amidoamine) dendrimer nanoparticles in rats

2011 ◽  
Vol 26 (6) ◽  
pp. 619-627 ◽  
Author(s):  
V.H. Pereira ◽  
A.J. Salgado ◽  
J.M. Oliveira ◽  
S.R. Cerqueira ◽  
A.M. Frias ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fluorescein Isothiocyanate ◽  
Pamam Dendrimer ◽  
Brain Parenchyma ◽  
Morphological Alterations ◽  
Intracellular Drug Delivery ◽  
In Vivo Biodistribution ◽  
Tetramethylrhodamine Isothiocyanate ◽  
The Brain

Carboxymethylchitosan/poly(amidoamine) (CMCht/PAMAM) dendrimer nanoparticles, comprised of a PAMAM dendrimer core grafted with chains of CMCht, have recently been proposed for intracellular drug delivery. In previous reports, these nanoparticles had lower levels of cytotoxicity when compared with traditional dendrimers. In this study, the short-term in vivo biodistribution of fluorescein isothiocyanate (FITC)-labeled CMCht/PAMAM dendrimer nanoparticles after intravenous (IV) injections in Wistar Han rats was determined. The brain, liver, kidney, and lung were collected at 24, 48, and 72 h after injection and stained with phalloidin–tetramethylrhodamine isothiocyanate (TRITC, red) and 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI, blue) to trace the nanoparticles within these tissues. The liver, kidney, and lung were also stained for hematoxylin and eosin to assess any morphological alterations of these organs. CMCht/PAMAM dendrimer nanoparticles were observed within the vascular space and parenchyma of liver, kidney, and lung and in the choroid plexus, after each injection period. No particles were observed in the brain parenchyma, nor any apparent deleterious histological changes were observed within these organs. The CMCht/PAMAM dendrimer nanoparticles were stable in circulation for a period of up to 72 h, targeting the main organs/systems through internalization by the cells present in their parenchyma. These results provide positive indicators to their potential use in the future as intracellular drug delivery systems.

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