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 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 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 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.

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 Development of Polymer-Based Nanoformulations for Glioblastoma Brain Cancer Therapy and Diagnosis: An Update

Polymers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 4114
Author(s):  
Bijuli Rabha ◽  
Kaushik Kumar Bharadwaj ◽  
Siddhartha Pati ◽  
Bhabesh Kumar Choudhury ◽  
Tanmay Sarkar ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Brain Cancer ◽  
Treatment Strategies ◽  
Polymer Nanoparticles ◽  
Future Directions ◽  
Adverse Side Effects ◽  
Effective Delivery ◽  
Novel Therapeutic Strategies ◽  
Therapy And Diagnosis ◽  
The Brain

Brain cancers, mainly high-grade gliomas/glioblastoma, are characterized by uncontrolled proliferation and recurrence with an extremely poor prognosis. Despite various conventional treatment strategies, viz., resection, chemotherapy, and radiotherapy, the outcomes are still inefficient against glioblastoma. The blood–brain barrier is one of the major issues that affect the effective delivery of drugs to the brain for glioblastoma therapy. Various studies have been undergone in order to find novel therapeutic strategies for effective glioblastoma treatment. The advent of nanodiagnostics, i.e., imaging combined with therapies termed as nanotheranostics, can improve the therapeutic efficacy by determining the extent of tumour distribution prior to surgery as well as the response to a treatment regimen after surgery. Polymer nanoparticles gain tremendous attention due to their versatile nature for modification that allows precise targeting, diagnosis, and drug delivery to the brain with minimal adverse side effects. This review addresses the advancements of polymer nanoparticles in drug delivery, diagnosis, and therapy against brain cancer. The mechanisms of drug delivery to the brain of these systems and their future directions are also briefly discussed.

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.

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.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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