scholarly journals Zebrafish: A Promising Real-Time Model System for Nanotechnology-Mediated Neurospecific Drug Delivery

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Suraiya Saleem ◽  
Rajaretinam Rajesh Kannan
Keyword(s):  
Drug Delivery ◽  
Model System ◽  
Research Community ◽  
Therapeutic Interventions ◽  
Brain Diseases ◽  
Zebrafish Model ◽  
Time Model ◽  
High Fecundity ◽  
Novel Technologies ◽  
The Brain

AbstractDelivering drugs to the brain has always remained a challenge for the research community and physicians. The blood–brain barrier (BBB) acts as a major hurdle for delivering drugs to specific parts of the brain and the central nervous system. It is physiologically comprised of complex network of capillaries to protect the brain from any invasive agents or foreign particles. Therefore, there is an absolute need for understanding of the BBB for successful therapeutic interventions. Recent research indicates the strong emergence of zebrafish as a model for assessing the permeability of the BBB, which is highly conserved in its structure and function between the zebrafish and mammals. The zebrafish model system offers a plethora of advantages including easy maintenance, high fecundity and transparency of embryos and larvae. Therefore, it has the potential to be developed as a model for analysing and elucidating the permeability of BBB to novel permeation technologies with neurospecificity. Nanotechnology has now become a focus area within the industrial and research community for delivering drugs to the brain. Nanoparticles are being developed with increased efficiency and accuracy for overcoming the BBB and delivering neurospecific drugs to the brain. The zebrafish stands as an excellent model system to assess nanoparticle biocompatibility and toxicity. Hence, the zebrafish model is indispensable for the discovery or development of novel technologies for neurospecific drug delivery and potential therapies for brain diseases.

scholarly journals Intranasal Administration as a Route to Deliver Drugs to the Brain (Review)

2021 ◽  
Vol 10 (4) ◽  
pp. 117-127
Author(s):  
N. N. Porfiryeva ◽  
I. I. Semina ◽  
R. I. Moustafine ◽  
V. V. Khutoryanskiy
Keyword(s):  
Phase Transition ◽  
Drug Delivery ◽  
Intranasal Administration ◽  
Proteolytic Enzymes ◽  
Rapid Onset ◽  
The Body ◽  
Brain Diseases ◽  
External Stimulation ◽  
In Situ Gelling ◽  
The Brain

Introduction. Intranasal drug delivery from nose-to-brain is one of the promising approaches for the treatment of brain diseases including neurodegenerative diseases, stroke, brain tumors, etc.Text. Delivery of drugs through the nose has a number of advantages, including the rapid onset of a pharmacological effect, the ability to bypass the blood-brain barrier, avoidance of some side effects and fast and non-invasive route of administration. However, the significant disadvantages of this route are rapid elimination of the drug from the surface of the mucosal membrane, poor penetration of the drug through the nasal mucosa, mucociliary clearance and effects of proteolytic enzymes. Currently, to overcome the above limitations, various approaches are used, including the development of delivery systems from nose-to-brain, which are mucoadhesive, mucus-penetrating and gel-forming systems that facilitate the retention or penetration of drugs through the mucosal membranes. At the same time, high-molecular weight compounds play a significant role in the design of these systems. In particular, mucoadhesive systems can be prepared from cationic and anionic polymers. Recent studies have also shown that interpolyelectrolyte complexes also exhibit mucoadhesive properties. An improvement in mucoadhesive properties of polymers can also be achieved by conjugating various functional groups such as thiols, maleimides, acrylates, methacrylates, catechols, etc. Mucus-penetrating systems can be prepared by PEGylation of nanoparticles, as well as functionalization with some poly(2-oxazolines), polyvinyl alcohol, etc. The mucus-penetrating ability of these polymers has been shown in other mucosal membranes in the body. Finally, increased penetration can be achieved by using mucolytic agents in combination with non-ionic surfactants. Another approach to increase the efficiency of drug delivery from nose-to-brain is the use of in situ gelling systems. Initially, this type of formulation exists as a solution; then a phase transition to gel is observed in response to chemical and physical effects. Depending on the external stimulation of the phase transition, thermo-, pH-, ion-reversible and other systems are known. These systems have shown effectiveness for delivery to the brain by intranasal administration.Conclusion. Effective intranasal delivery of drugs and therapeutic agents to the brain can be achieved by using mucoadhesive, mucus-penetrating, gelling systems and/or their combinations.

scholarly journals Chitosan-Based Nanocarriers for Nose to Brain Delivery

2019 ◽  
Vol 9 (11) ◽  
pp. 2219 ◽  
Author(s):  
Blessing Atim Aderibigbe ◽  
Tobeka Naki
Keyword(s):  
Drug Delivery ◽  
Nasal Mucosa ◽  
Targeted Drug Delivery ◽  
Drug Uptake ◽  
Brain Diseases ◽  
In Vivo Studies ◽  
Brain Targeting ◽  
Prolonged Contact ◽  
Targeted Drug ◽  
The Brain

In the treatment of brain diseases, most potent drugs that have been developed exhibit poor therapeutic outcomes resulting from the inability of a therapeutic amount of the drug to reach the brain. These drugs do not exhibit targeted drug delivery mechanisms, resulting in a high concentration of the drugs in vital organs leading to drug toxicity. Chitosan (CS) is a natural-based polymer. It has unique properties such as good biodegradability, biocompatibility, mucoadhesive properties, and it has been approved for biomedical applications. It has been used to develop nanocarriers for brain targeting via intranasal administration. Nanocarriers such as nanoparticles, in situ gels, nanoemulsions, and liposomes have been developed. In vitro and in vivo studies revealed that these nanocarriers exhibited enhanced drug uptake to the brain with reduced side effects resulting from the prolonged contact time of the nanocarriers with the nasal mucosa, the surface charge of the nanocarriers, the nano size of the nanocarriers, and their capability to stretch the tight junctions within the nasal mucosa. The aforementioned unique properties make chitosan a potential material for the development of nanocarriers for targeted drug delivery to the brain. This review will focus on chitosan-based carriers for brain targeting.

Dissecting metabolism using zebrafish models of disease

2019 ◽  
Vol 47 (1) ◽  
pp. 305-315 ◽  
Author(s):  
Talhah M. Salmi ◽  
Vicky W. T. Tan ◽  
Andrew G. Cox
Keyword(s):  
Liver Disease ◽  
Danio Rerio ◽  
Fatty Liver Disease ◽  
Model Organism ◽  
Model System ◽  
Genetic Screens ◽  
Zebrafish Model ◽  
High Fecundity ◽  
Models Of Disease

Abstract Zebrafish (Danio rerio) are becoming an increasingly powerful model organism to study the role of metabolism in disease. Since its inception, the zebrafish model has relied on unique attributes such as the transparency of embryos, high fecundity and conservation with higher vertebrates, to perform phenotype-driven chemical and genetic screens. In this review, we describe how zebrafish have been used to reveal novel mechanisms by which metabolism regulates embryonic development, obesity, fatty liver disease and cancer. In addition, we will highlight how new approaches in advanced microscopy, transcriptomics and metabolomics using zebrafish as a model system have yielded fundamental insights into the mechanistic underpinnings of disease.

scholarly journals TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 946
Author(s):  
Udi Vazana ◽  
Lior Schori ◽  
Uri Monsonego ◽  
Evyatar Swissa ◽  
Gabriel S. Pell ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Unmet Need ◽  
High Amplitude ◽  
Brain Diseases ◽  
Normal Brain ◽  
Safety Level ◽  
The Impact ◽  
The Brain ◽  
Bbb Opening

Proper neuronal function requires strict maintenance of the brain’s extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood–brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain.

scholarly journals Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 966
Author(s):  
Wolfgang Löscher ◽  
Birthe Gericke
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Active Drug ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Metabolic Characteristics ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Blood Neutrophils ◽  
The Brain

The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.

Shining Light on the Nervous System: From Biomaterials to Bioelectronics

2019 ◽  
Vol MA2019-02 (55) ◽  
pp. 2421-2421
Author(s):  
Jing Tang
Keyword(s):  
Drug Delivery ◽  
Nervous System ◽  
Drug Delivery Systems ◽  
Uv Light ◽  
Delivery Systems ◽  
Nanowire Arrays ◽  
Opioid Overdose ◽  
Visual Responses ◽  
Novel Technologies ◽  
The Brain

The dichotomy between advanced materials and brain has driven the curiosity of scientists to explore the wonders of the brain, as well as motivated the continued innovations of novel technologies based on advances in materials science and engineering to understand the brain. To improve treatments of brain-related diseases will require new tools and methods to map and to repair the brain with precision and biocompatibility. Current treatments of pain heavily rely on opioids, resulting in significant side effects such as addiction, tolerance, leading to the Opioid Overdose Crisis as we know of today. Smart drug delivery systems may provide an effective solution. Here I present the development of polymer-based externally-triggerable drug delivery systems for on-demand, repeatable and adjustable local anesthesia, where the timing, duration, and intensity of nerve block can be controlled through external energy triggers such as light. In addition to the new pharmacological approaches, bioelectronic platforms to enhance our insights into the eye and will also be discussed. The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, I develop artificial retina based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. My study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices. Through pharmacological, optical, and electrical toolsets, I aim to develop effective therapeutic solutions to neurological disease states. These results, along with a discussion of future neural interfaces, aim to improve our understanding of the nervous system and to inform new therapeutic approaches for biomaterials and bioelectronics.

Polymer Nanoparticles as Smart Carriers for the Enhanced Release of Therapeutic Agents to the CNS

2017 ◽  
Vol 23 (3) ◽  
pp. 393-410 ◽  
Author(s):  
Mariacristina Gagliardi ◽  
Claudia Borri
Keyword(s):  
Drug Delivery ◽  
Multidisciplinary Approach ◽  
Polymer Nanoparticles ◽  
Fine Tuning ◽  
Brain Diseases ◽  
Polymer Science ◽  
Brain Protection ◽  
Pharmacological Treatments ◽  
Protective Shield ◽  
The Brain

Background: The brain is the most protected organ in the human body; its protective shield, relying on a complex system of cells, proteins and transporters, prevents potentially harmful substances from entering the brain from the bloodstream but, on the other hand, it also stops drugs administered via the systemic route. To improve the efficacy of pharmacological treatments, targeted drug delivery by means of polymer nanoparticles is a challenging but, at the same time, efficient strategy. Methods: Thanks to a highly multidisciplinary approach, several ways to overcome the brain protection have provided effective solutions to treat a large number of diseases. Important advances in polymer science, together with the development of novel techniques for nanocarrier preparation, and the discovery of novel targeting ligands and molecules, allow a fine-tuning of size, shape, chemicophysical properties and surface chemistry of functional particulate systems; it enables the improvement of the therapeutic performances for several drugs, also toward districts that are difficult to be treated, such as the brain. Conclusion: This review focuses on the great strides made from scientists and doctors in the development of polymer nano-sized drug delivery systems for brain diseases. Even though the optimal nanocarrier was not yet discovered, important advances were made to strive for safer, performant and successful systems, with the expectation to find soon better solutions to cure some still untreatable pathologies. <p></p>

scholarly journals Targeting of Perforin Inhibitor into the Brain Parenchyma Via a Prodrug Approach Can Decrease Oxidative Stress and Neuroinflammation and Improve Cell Survival

2020 ◽  
Vol 57 (11) ◽  
pp. 4563-4577
Author(s):  
Janne Tampio ◽  
Johanna Huttunen ◽  
Ahmed Montaser ◽  
Kristiina M. Huttunen
Keyword(s):  
Oxidative Stress ◽  
Drug Delivery ◽  
Brain Parenchyma ◽  
Brain Diseases ◽  
Drug Candidate ◽  
Prostaglandin E ◽  
Pharmacological Effects ◽  
Brain Drug Delivery ◽  
Brain Parenchymal ◽  
The Brain

Abstract The cytolytic protein perforin has a crucial role in infections and tumor surveillance. Recently, it has also been associated with many brain diseases, such as neurodegenerative diseases and stroke. Therefore, inhibitors of perforin have attracted interest as novel drug candidates. We have previously reported that converting a perforin inhibitor into an L-type amino acid transporter 1 (LAT1)-utilizing prodrug can improve the compound’s brain drug delivery not only across the blood–brain barrier (BBB) but also into the brain parenchymal cells: neurons, astrocytes, and microglia. The present study evaluated whether the increased uptake into mouse primary cortical astrocytes and subsequently improvements in the cellular bioavailability of this brain-targeted perforin inhibitor prodrug could enhance its pharmacological effects, such as inhibition of production of caspase-3/-7, lipid peroxidation products and prostaglandin E2 (PGE2) in the lipopolysaccharide (LPS)-induced neuroinflammation mouse model. It was demonstrated that increased brain and cellular drug delivery could improve the ability of perforin inhibitors to elicit their pharmacological effects in the brain at nano- to picomolar levels. Furthermore, the prodrug displayed multifunctional properties since it also inhibited the activity of several key enzymes related to Alzheimer’s disease (AD), such as the β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), and most probably also cyclooxygenases (COX) at micromolar concentrations. Therefore, this prodrug is a potential drug candidate for preventing Aβ-accumulation and ACh-depletion in addition to combatting neuroinflammation, oxidative stress, and neural apoptosis within the brain.

scholarly journals Novel technologies for antiangiogenic drug delivery in the brain

2009 ◽  
Vol 3 (2) ◽  
pp. 224-229 ◽  
Author(s):  
Ofra Benny ◽  
Pouya Pakneshan
Keyword(s):  
Drug Delivery ◽  
Novel Technologies ◽  
Antiangiogenic Drug ◽  
The Brain

scholarly journals Revisiting intra-arterial drug delivery for treating brain diseases or is it “déjà-vu, all over again”?

2014 ◽  
Vol 01 (02) ◽  
pp. 108-115 ◽  
Author(s):  
Shailendra Joshi ◽  
Jason Ellis ◽  
Charles Emala
Keyword(s):  
Drug Delivery ◽  
Interventional Neuroradiology ◽  
Time Frame ◽  
Therapeutic Interventions ◽  
Brain Diseases ◽  
Breast Cancers ◽  
Delivery Methods ◽  
Drug Concentrations ◽  
Development Levels ◽  
Made In

AbstractFor over six decades intra-arterial (IA) drugs have been sporadically used for the treatment of lethal brain diseases. In recent years considerable advance has been made in the IA treatment of retinoblastomas, liver and locally invasive breast cancers, but relatively little progress has been made in the treatment of brain cancers. High resting blood flow and the presence of the blood-brain barrier (BBB), makes IA delivery to the brain tissue far more challenging, compared to other organs. The lack of advance in the field is also partly due to the inability to understand the complex pharmacokinetics of IA drugs as it is difficult to track drug concentrations in sub-second time frame by conventional chemical methods. The advances in optical imaging now provide unprecedented insights into the pharmacokinetics of IA drug and optical tracer delivery. Novel delivery methods, improved IA drug formulations, and optical pharmacokinetics, present us with untested paradigms in pharmacology that could lead to new therapeutic interventions for brain cancers and stroke. The object of this review is to bring into focus the current practice, problems, and the potential of IA drug delivery for treating brain diseases. A concerted effort is needed at basic sciences (pharmacology and drug imaging), and translational (drug delivery techniques and protocol development) levels by the interventional neuroradiology community to advance the field.

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