Brain Drug Delivery Research Articles

FUS and surfactant-based nanocarriers: A combined strategy for nose to brain drug delivery

Brain drug delivery is hampered by the presence of the blood brain barrier and nanocarriers, administered by intranasal route, could represent an alternative and efficient strategy to improve drug localization in the Central Nervous System (CNS). The aim of this work is to design and characterize non-ionic surfactant vesicles (NSVs) and perfluorocarbon gas non-ionic surfactant based nanobubbles (VNBs) suitable for Nose to Brain Delivery (N2B). In particular, Pluronic F127, Span 85 and cholesterol have been employed to prepare NSVs and VNBs. Both systems have been characterized in terms of (a) hydrodynamic diameter, ζ-potential and morphology (b) vesicle bilayer feature (anisotropy), (c) physical-chemical stability and (d) fluorescent model probe release capability. VNBs have been also studied in terms of gas entrapment and acoustic efficiency. In addition, in order to understand optimal ultrasound (US) parameters to obtain in vitro stable cavitation, the acoustic pressure effect on VNBs fluorescent probes release kinetics was evaluated. The obtained results suggest that NSVs and VNBs show a hydrodynamic diameter suitable for N2B delivery. Moreover, in this study, we develop a new kind of protocol to evaluate an in vitro US characterization of VNBs and our data suggest a stable and controlled probe release, encouraging the possibility to deliver VNBs in mixture with NSVs loaded neuroprotective drugs for brain delivery coupled to US obtaining stable cavitation. In this context, extracellular field recordings in specific area of hippocampus (CA1-CA3) have been carried out in order to assure that empty NSVs do not affect synaptic plasticity in the form of long-term potentiation, a molecular mechanism which underlies learning and memory.

Injectable nanogel systems for brain drug delivery

<img src=” https://s3.amazonaws.com/production.scholastica/article/88217/large/prnano_912023ga.jpg?1695507286”> The central nervous system (CNS) controls many critical functions, such as intelligence, emotion, sense, and memory, and modulates many other functions of the entire human body. Diseases affecting the CNS are challenging to treat because of the CNS’s sensitive functional and structural features and limited accessibility. The brain is secured from the systemic circulation by a unique biological fence, the blood-brain barrier (BBB), that limits molecular exchange between the peripheral and CNS systems. Most drugs used for treating CNS diseases fail to reach the brain in effective therapeutic concentrations due to the presence of BBB. During the last decade, specifically engineered drug delivery systems (DDS) have offered the opportunity to overcome systemic barriers in brain drug delivery. However, even with the best-engineered nano-carriers, delivering sufficient drug doses into the brain through systemic circulation remains challenging. Here, we review various systems for ‘direct’ drug delivery to the brain using im-plantable or injectable intracranial nano-drug delivery systems (nDDS), which can ensure 100% release of drug to the brain in a sustained or controlled fashion for prolonged periods, bypassing the BBB, thereby radically improving the therapeutic efficacy while minimizing systemic toxicity. Brain injectable nanogels or nanoparticle systems can be considered superior compared to other local drug-delivery systems because they possess better diffusivity of drugs. The nanogels can be injected through minimally invasive procedures, precisely delivering drugs to specific target sites. This review covers a detailed discussion about locally injectable DDS and various nanogel-based drugs, oligonucleotide, and theragnostic delivery systems used for treating brain malignancies, infections, and neurodegenerative diseases.

Formulation and In vitro Cytotoxicity Studies of Avastin Nanoparticle Mediated Targeted Nose to Brain Drug Delivery System

Nanoparticles (NPs) occupy a superior place among the recent approaches experimented to deliver drugs into brain by circumventing the BBB such as chemical modifications. The Emulsification PEG-PLGA nanoparticles carrying drug were made using the solvent evaporation method. In summary, PEG-PLGA was dissolved in acetone (50 mL) and PLGA was dissolved in PEG-PLGA (50:50, 7-11 mg/mL). The Chitosan-Avastin conjugates were created in the lab in accordance with the procedures and guidelines outlined in Chitosan (3.25 m mol) was hydrated in 1 N HCl, then the appropriate amount of distilled water was added. After adding NaOH (5N) to the reaction mixture to get the pH down to 5, Avastin (6.48 mmol) was added while the mixture was continuously stirred. In-vitro studies the basic aim is to check the effect of various drugs on various cancer cell lines. For testing purpose a large number of human cancer cell lines have been screened. Cells are cultivated in 96-well culture plates, and the rate of cell multiplication, which determines the rate of cell growth, is indirectly measured by the dye's color intensity, which is directly inversely proportional to the number of cells present. Using doses between 10 and 100 g/mL, the MTT test was performed to examine the cytotoxicity various polymer ratios and formulations on human lung cancer lines-A549. For the determination of the percentage of viability of various samples, the cancer cells without receiving therapy were utilized as the control.

Olfactory drug delivery with intranasal sprays after nasal midvault reconstruction

Conductive olfaction and nose to brain drug delivery are important processes that remain limited by inadequate odorant or drug delivery to the olfactory airspace. Primary challenges include anatomic barriers and poor targeting to the olfactory region. This study uses computational fluid dynamics to investigate the effects of nasal midvault surgery on olfactory drug delivery with intranasal sprays. Soft tissue elevation, spreader flaps, and spreader grafts were performed on two fresh cadaveric specimens, using computed tomography for airway reconstruction. Nasal airflow and drug particle transport simulations were performed under these conditions: inhalation rate (15, 30 L/min), spray velocity (1, 5, 10 m/s), spray location (top, bottom, center, medial, lateral), head position (upright, supine, forward, backward), and particle size (1–100 µm). Simulation results were used to calculate drug particle deposition to the olfactory airspaces and bulbs. Total olfactory deposition was < 5% but attained a maximum of 36.33% when sorted by particle size. There was no association between nasal midvault surgery and olfactory deposition. No single parameter or technique demonstrated superior olfactory deposition, but smaller particle size, slower spray velocity, and higher inhalation rate tended to optimize olfactory deposition, providing important implications for future intranasal spray and drug design to target the olfactory airspace.

Riluzole-loaded lipid nanoparticles for brain delivery: Preparation, optimization and characterization

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with a median survival of only 2 to 4 years. Riluzole, a drug commonly used in the management of ALS, has a low aqueous solubility and limited bioavailability. ALS treatment is also hindered by the presence of the blood–brain barrier (BBB) that preserves the delicate homeostasis of the cerebral milieu, isolating it and making brain drug delivery exceptionally hard. To overcome these issues, the use of lipid nanocarriers, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), is a promising strategy. In this study, SLN and NLC were prepared and optimized to facilitate riluzole uptake into the brain for ALS therapy. The lipid nanoparticles were characterized through different techniques, with respect to their physicochemical properties (size, zeta potential (ZP), polydispersity index (PDI)), as well as encapsulation efficiency, morphology, stability, in vitro release, crystallinity, and biocompatibility. Riluzole-loaded nanocarriers exhibited characteristics suitable for brain delivery, including mean diameters between 147.2 and 203.1 nm, low PDI (<0.3), and negative ZP between −22.5 and −27.5 mV. Additionally, they were physically stable over 3 months under storage conditions (5 ℃ and 25 ℃), promoting a slow and sustained release of the drug, which was shown to be inside the core of the lipid matrix. Cytotoxicity assays demonstrated that both SLN and NLC did not significantly affect the viability of an hCMEC/D3 cell monolayer at a riluzole concentration up to 10 μM. The results suggest that the developed nanocarriers could be a viable platform to target riluzole to the central nervous system (CNS). Nevertheless, further in vitro and in vivo studies are needed to validate their therapeutic efficacy and safety.

Nanoparticles Mediated the Diagnosis and Therapy of Glioblastoma: Bypass or Cross the Blood-Brain Barrier.

Glioblastoma is one of the most aggressive central nervous system malignancies with high morbidity and mortality. Current clinical approaches, including surgical resection, radiotherapy, and chemotherapy, are limited by the difficulty of targeting brain lesions accurately, leading to disease recurrence and fatal outcomes. The lack of effective treatments has prompted researchers to continuously explore novel therapeutic strategies. In recent years, nanomedicine has made remarkable progress and expanded its application in brain drug delivery, providing a new treatment for brain tumors. Against this background, this article reviews the application and progress of nanomedicine delivery systems in brain tumors. In this paper, the mechanism of nanomaterials crossing the blood-brain barrier is summarized. Furthermore, the specific application of nanotechnology in glioblastoma is discussed in depth.

Insight into lipid-based nanoplatform-mediated drug and gene delivery in neuro-oncology and their clinical prospects.

Tumors of the Central nervous System (CNS) are a spectrum of neoplasms that range from benign lesions to highly malignant and aggressive lesions. Despite aggressive multimodal treatment approaches, the morbidity and mortality are high with dismal survival outcomes in these malignant tumors. Moreover, the non-specificity of conventional treatments substantiates the rationale for precise therapeutic strategies that selectively target infiltrating tumor cells within the brain, and minimize systemic and collateral damage. With the recent advancement of nanoplatforms for biomaterials applications, lipid-based nanoparticulate systems present an attractive and breakthrough impact on CNS tumor management. Lipid nanoparticles centered immunotherapeutic agents treating malignant CNS tumors could convene the clear need for precise treatment strategies. Immunotherapeutic agents can selectively induce specific immune responses by active or innate immune responses at the local site within the brain. In this review, we discuss the therapeutic applications of lipid-based nanoplatforms for CNS tumors with an emphasis on revolutionary approaches in brain targeting, imaging, and drug and gene delivery with immunotherapy. Lipid-based nanoparticle platforms represent one of the most promising colloidal carriers for chemotherapeutic, and immunotherapeutic drugs. Their current application in oncology especially in brain tumors has brought about a paradigm shift in cancer treatment by improving the antitumor activity of several agents that could be used to selectively target brain tumors. Subsequently, the lab-to-clinic transformation and challenges towards translational feasibility of lipid-based nanoplatforms for drug and gene/immunotherapy delivery in the context of CNS tumor management is addressed.

Recent Approaches of Intranasal to Brain Drug Delivery System

While the intranasal administration of drugs to the brain has been gaining both research attention and regulatory success over the past several years, key fundamental and translational challenges remain to fully leveraging the promise of this drug delivery pathway for improving the treatment of various neurological and psychiatric illnesses. In response, this review highlights the current state of understanding of the nose-to-brain drug delivery pathway and how both biological and clinical barriers to drug transport using the pathway can been addressed, as illustrated by demonstrations of how currently approved intranasal sprays leverage these pathways to enable the design of successful therapies. Moving forward, aiming to better exploit the understanding of this fundamental pathway, we also outline the development of nanoparticle systems that show improvement in delivering approved drugs to the brain and how engineered nanoparticle formulations could aid in breakthroughs in terms of delivering emerging drugs and therapeutics while avoiding systemic adverse effects.

P.064 Enhancing the neuroprotective properties of edaravone using glutathione nanogel as a promising carrier for brain drug delivery in transient global ischemia in a rodent model

Background: Edaravone (EDV) is an antioxidant that scavengs ROS, which is known to associate with pathophysiology of ischemic stroke. Low stability and bioavailability are major EDV drawbacks. Decorating nanogel surface with glutathione to target brain tissue was performed to optimize drug delivery. Methods: Nano vehicle characterization was assessed with FT-IR and HNMR. Images from the surface of nano vehicle was captured by AFM and TEM instruments. After development of mPEG-b-PLGA EDV nano particles, their effect on biochemical factors including malondialdehyde and protein carbonyl level was measured on Wistar rats under global ischemia. The level of GSH and FRAP were also measured. Results: The Size (199 nm, hydrodynamic diameter) and zeta potential (-25 mV) of optimum formulation was assessed and the calibration curve in deionized water was created at 244 nm. In-vitro drug release profile depicted a sustained release process. EDV and glutathione presence in one vehicle simultaneously, resulted in elevated spatial memory and learning along with cognitive function. In addition, significantly lower MDA and PCO, and higher level of neural GSH and FRAP were observed. Conclusions: The developed mPEG-b-PLGA EDV nanogel can be a suited vehicle for brain drug delivery of EDV, while managing to minimize the biochemical and pathophysiological alterations in ischemic-like disorder.

Potential Role of Carbon Nanomaterials in the Treatment of Malignant Brain Gliomas.

Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to the considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis of these in patients is still very unfavorable. The limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors, are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood-brain barrier, which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood-brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, a penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, a large surface area, and easy modification with molecules, which render them as suitable candidates for deliver drugs. In this review, we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas and discuss the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain.

FerryCalin: an engineered lipocalin protein directed against the transferrin receptor with potential for brain drug delivery.

The transferrin receptor (TfR) mediates transcytosis across the blood-brain barrier (BBB), which offers a promising approach for the non-invasive delivery of therapeutics into the brain parenchyma. Employing the recombinant homodimeric murine TfR ectodomain, prepared in a biochemically functional state, we have selected a cognate Anticalin via phage display and bacterial cell surface display from a random library based on the human lipocalin 2 (Lcn2). After affinity maturation, several engineered lipocalin were identified that bind murine TfR in a non-competitive manner with the natural ligand (transferrin•Fe3+), among those an Anticalin - dubbed FerryCalin - exhibiting a dissociation constant (KD) of 3.8 nM. Epitope analysis using the SPOT technique revealed a sequential epitope in a surface region of TfR remote from the transferrin-binding site. Due to their fast konrate and short complex half-life, as evidenced by real-time surface plasmon resonance (SPR) measurements, FerryCalin, or one of its related mutants, shows characteristics as a potential vehicle for the brain delivery of biopharmaceuticals.

Aptamer Nanoconstructs Crossing Human Blood-Brain Barrier Discovered via Microphysiological System-Based SELEX Technology.

Blood-brain barrier (BBB) remains one of the critical challenges in developing neurological therapeutics. Short single-stranded DNA/RNA nucleotides forming a three-dimensional structure, called aptamers, have received increasing attention as BBB shuttles for efficient brain drug delivery owing to their practical advantages over Trojan horse antibodies or peptides. Aptamers are typically obtained by combinatorial chemical technology, termed Systemic Evolution of Ligands by EXponential Enrichment (SELEX), against purified targets, living cells, or animal models. However, identifying reliable BBB-penetrating aptamers that perform efficiently under human physiological conditions has been challenging because of the poor physiological relevance in the conventional SELEX process. Here, we report a human BBB shuttle aptamer (hBS) identified using a human microphysiological system (MPS)-based SELEX (MPS-SELEX) method. A two-channel MPS lined with human brain microvascular endothelial cells (BMECs) interfaced with astrocytes and pericytes, recapitulating high-level barrier function of in vivo BBB, was exploited as a screening platform. The MPS-SELEX procedure enabled robust function-based screening of the hBS candidates, which was not achievable in traditional in vitro BBB models. The identified aptamer (hBS01) through five-round of MPS-SELEX exhibited high capability to transport protein cargoes across the human BBB via clathrin-mediated endocytosis and enhanced uptake efficiency in BMECs and brain cells. The enhanced targeting specificity of hBS01 was further validated both in vitro and in vivo, confirming its powerful brain accumulation efficiency. These findings demonstrate that MPS-SELEX has potential in the discovery of aptamers with high target specificity that can be widely utilized to boost the development of drug delivery strategies.

ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery.

The drug efflux transporters ABCB1 and ABCG2 at the blood-brain barrier limit the delivery of drugs into the brain. Strategies to overcome ABCB1/ABCG2 have been largely unsuccessful, which poses a tremendous clinical problem to successfully treat central nervous system (CNS) diseases. Understanding basic transporter biology, including intracellular regulation mechanisms that control these transporters, is critical to solving this clinical problem.In this comprehensive review, we summarize current knowledge on signaling pathways that regulate ABCB1/ABCG2 at the blood-brain barrier. In Section I, we give a historical overview on blood-brain barrier research and introduce the role that ABCB1 and ABCG2 play in this context. In Section II, we summarize the most important strategies that have been tested to overcome the ABCB1/ABCG2 efflux system at the blood-brain barrier. In Section III, the main component of this review, we provide detailed information on the signaling pathways that have been identified to control ABCB1/ABCG2 at the blood-brain barrier and their potential clinical relevance. This is followed by Section IV, where we explain the clinical implications of ABCB1/ABCG2 regulation in the context of CNS disease. Lastly, in Section V, we conclude by highlighting examples of how transporter regulation could be targeted for therapeutic purposes in the clinic. SIGNIFICANCE STATEMENT: The ABCB1/ABCG2 drug efflux system at the blood-brain barrier poses a significant problem to successful drug delivery to the brain. The article reviews signaling pathways that regulate blood-brain barrier ABCB1/ABCG2 and could potentially be targeted for therapeutic purposes.

Transcranial application of magnetic pulses for improving brain drug delivery efficiency via intranasal injection of magnetic nanoparticles.

As the blood-brain barrier (BBB) hinders efficient drug delivery to the brain, drug delivery via the intranasal pathway, bypassing the BBB, has received considerable attention. However, intranasal administration still has anatomical and physiological limitations, necessitating further solutions to enhance effectiveness. In this study, we used transcranial magnetic stimulation (TMS) on fluorescent magnetic nanoparticles (MNPs) of different sizes (50, 100, and 300 nm) to facilitate MNP's transportation and delivery to the brain parenchyma. To validate this concept, anesthetized rats were intranasally injected with the MNPs, and TMS was applied to the center of the head. As the result, a two-fold increase in brain MNP delivery was achieved using TMS compared with passive intranasal administration. In addition, histological analysis that was performed to investigate the safety revealed no gross or microscopic damages to major organs caused by the nanoparticles. While future studies should establish the delivery conditions in humans, we expect an easy clinical translation in terms of device safety, similar to the use of conventional TMS. The strategy reported herein is the first critical step towards effective drug transportation to the brain.

Brain‐X: A new interdisciplinary journal for advancing neuroscience research

Despite significant advancements in brain research, the intricacies of the brain remain a mystery. The Human Brain Project (HBP) is an international research initiative modeled1-3 after the Human Genome Project (HGP), launched in both the United States and Europe,4, 5 that aims to unravel the complex structure and function of the human brain. HBP takes an interdisciplinary approach, incorporating fields such as biology, medicine, informatics, chemistry, materials, and physics. Such an approach is necessary for furthering our understanding of the brain and advancing neuroscience as a field. However, there is currently no professional journal that focuses specifically on interdisciplinary approaches to brain and neuroscience research. To fill this gap, we are proud to announce the launch of Brain-X. The “X” in the name represents the intersection of brain and neuroscience with a strong emphasis on interdisciplinary research. This international publication will showcase the latest discoveries and technological breakthroughs, providing novel insights into all aspects of brain, neuroscience, and neurology. Brain-X is dedicated to promoting interdisciplinarity and welcomes contributions from diverse fields. In particular, the journal strongly encourages studies that utilize mathematics, physics, chemistry, engineering, materials science, or information science to tackle issues in brain and neuroscience research across various disciplines. As a peer-reviewed and open-access journal, Brain-X partners with Wiley to enhance the visibility of interdisciplinary research in this field. The journal publishes a range of article types, including original research articles, data articles, methods articles, reviews, perspectives, research letters, commentaries, and correspondences. Brain-X will comprehensively cover a broad range of topics, including but not limited to aging and brain, brain-computer interface, brain injury and rehabilitation, brain-inspired computing and artificial intelligence (AI), brain-inspired 3D printing, brain rhythm and disease, brain-gut axis, cellular and molecular neuroscience, cerebral organoids, chemical neuroscience, clinical neurology, computational neuroscience, crosstalk between brain and other organs, nanoparticles for brain drug delivery, and nerve regeneration materials. The editorial board of Brain-X comprises influential scientists from around the world who enthusiastically encourage contributions from researchers. The journal guarantees a rapid review process with fair and prompt decisions. Upon acceptance, high-quality support from the editorial team ensures that the manuscript reaches its full potential in brain and neuroscience research. Brain-X aims to serve as a platform for students, scientists, and clinicians to share their discoveries and perspectives on brain, neuroscience, and neurology. The journal is committed to providing valuable and helpful information to the community in a timely and innovative manner. Kunlin Jin: Writing – original draft; Writing – review & editing. The author declares no conflicts of interest.

Intracranial nanomedicine-gel with deep brain-penetration for glioblastoma therapy.

Glioblastoma Multiforme (GBM) is one of the challenging tumors to treat as it recurs, almost 100%, even after surgery, radiation, and chemotherapy. In many cases, recurrence happens within 2-3cm depth of the resected tumor margin, indicating the inefficacy of current anti-glioma drugs to penetrate deep into the brain tissue. Here, we report an injectable nanoparticle-gel system, capable of providing deep brain penetration of drug up to 4cm, releasing in a sustained manner up to >15days. The system consists of ∼222nm sized PLGA nanoparticles (NP-222) loaded with an anti-glioma drug, Carmustine (BCNU), and coated with a thick layer of polyethylene glycol (PEG). Upon release of the drug from PLGA core, it will interact with the outer PEG-layer leading to the formation of PEG-BCNU nanocomplexes of size ∼33nm (BCNU-NC-33), which could penetrate >4cm deep into the brain tissue compared to the free drug (< 5mm). In vitro drug release showed sustained release of drug for 15days by BCNU-NP gel, and enhanced cytotoxicity by BCNU-NC-33 drug-nanocomplexes in glioma cell lines. Ex vivo goat-brain phantom studies showed drug diffusion up to 4cm in tissue and in vivo brain-diffusion studies showed almost complete coverage within the rat brain (∼1.2cm), with ∼55% drug retained in the tissue by day-15, compared to only ∼5% for free BCNU. Rat orthotopic glioma studies showed excellent anti-tumor efficacy by BCNU-NP gel compared to free drug, indicating the potential of the gel-system for anti-glioma therapy. In effect, we demonstrate a unique method of sustained release of drug in the brain using larger PLGA nanoparticles acting as a reservoir while deep-penetration of the released drug was achieved by in situ formation of drug-nanocomplexes of size <50nm which is less than the native pore size of brain tissue (> 100nm). This method will have a major impact on a challenging field of brain drug delivery.

Enhancing the Neuroprotection Potential of Edaravone in Transient Global Ischemia Treatment with Glutathione- (GSH-) Conjugated Poly(methacrylic acid) Nanogel as a Promising Carrier for Targeted Brain Drug Delivery.

Ischemic stroke is the most common among various stroke types and the second leading cause of death, worldwide. Edaravone (EDV) is one of the cardinal antioxidants that is capable of scavenging reactive oxygen species, especially hydroxyl molecules, and has been already used for ischemic stroke treatment. However, poor water solubility, low stability, and bioavailability in aqueous media are major EDV drawbacks. Thus, to overcome the aforementioned drawbacks, nanogel was exploited as a drug carrier of EDV. Furthermore, decorating the nanogel surface with glutathione as targeting ligands would potentiate the therapeutic efficacy. Nanovehicle characterization was assessed with various analytical techniques. Size (199 nm, hydrodynamic diameter) and zeta potential (-25 mV) of optimum formulation were assessed. The outcome demonstrated a diameter of around 100 nm, sphere shape, and homogenous morphology. Encapsulation efficiency and drug loading were determined to be 99.9% and 37.5%, respectively. In vitro drug release profile depicted a sustained release process. EDV and glutathione presence in one vehicle simultaneously made the possibility of antioxidant effects on the brain in specific doses, which resulted in elevated spatial memory and learning along with cognitive function in Wistar rats. In addition, significantly lower MDA and PCO and higher levels of neural GSH and antioxidant levels were observed, while histopathological improvement was approved. The developed nanogel can be a suited vehicle for drug delivery of EDV to the brain and improve ischemia-induced oxidative stress cell damage.

Nanosystems for Brain Targeting of Antipsychotic Drugs: An Update on the Most Promising Nanocarriers for Increased Bioavailability and Therapeutic Efficacy

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. Nevertheless, adverse drug reactions jeopardize clinical outcomes, resulting in patient non-compliance. The design formulation strategies for enhancing brain drug delivery has been a major challenge, mainly due to the restrictive properties of the blood-brain barrier. However, recent pharmacokinetic and pharmacodynamic in vivo assays confirmed the advantage of the intranasal route when compared to oral and intravenous administration, as it allows direct nose-to-brain drug transport via neuronal pathways, reducing systemic side effects and maximizing therapeutic outcomes. In addition, the incorporation of antipsychotic drugs into nanosystems such as polymeric nanoparticles, polymeric mixed micelles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanoemulgels, nanosuspensions, niosomes and spanlastics, has proven to be quite promising. The developed nanosystems, having a small and homogeneous particle size (ideal for nose-to-brain delivery), high encapsulation efficiency and good stability, resulted in improved brain bioavailability and therapeutic-like effects in animal models. Hence, although it is essential to continue research in this field, the intranasal delivery of nanosystems for the treatment of schizophrenia, bipolar disorder and other related disorders has proven to be quite promising, opening a path for future therapies with higher efficacy.

Current and Future Nano-Carrier-Based Approaches in the Treatment of Alzheimer's Disease.

It is a very alarming situation for the globe because 55 million humans are estimated to be affected by Alzheimer's disease (AD) worldwide, and still it is increasing at the rapid speed of 10 million cases per year worldwide. This is an urgent reminder for better research and treatment due to the unavailability of a permanent medication for neurodegenerative disorders like AD. The lack of drugs for neurodegenerative disorder treatment is due to the complexity of the structure of the brain, mainly due to blood-brain barrier, because blood-brain drug molecules must enter the brain compartment. There are several novel and conventional formulation approaches that can be employed for the transportation of drug molecules to the target site in the brain, such as oral, intravenous, gene delivery, surgically implanted intraventricular catheter, nasal and liposomal hydrogels, and repurposing old drugs. A drug's lipophilicity influences metabolic activity in addition to membrane permeability because lipophilic substances have a higher affinity for metabolic enzymes. As a result, the higher a drug's lipophilicity is, the higher its permeability and metabolic clearance. AD is currently incurable, and the medicines available merely cure the symptoms or slow the illness's progression. In the next 20 years, the World Health Organization (WHO) predicts that neurodegenerative illnesses affecting motor function will become the second-leading cause of mortality. The current article provides a brief overview of recent advances in brain drug delivery for AD therapy.

High and low permeability of human pluripotent stem cell-derived blood-brain barrier models depend on epithelial or endothelial features.

The search for reliable human blood-brain barrier (BBB) models represents a challenge for the development/testing of strategies aiming to enhance brain delivery of drugs. Human-induced pluripotent stem cells (hiPSCs) have raised hopes in the development of predictive BBB models. Differentiating strategies are thus required to generate endothelial cells (ECs), a major component of the BBB. Several hiPSC-based protocols have reported the generation of in vitro models with significant differences in barrier properties. We studied in depth the properties of iPSCs byproducts from two protocols that have been established to yield these in vitro barrier models. Our analysis/study reveals that iPSCs derivatives endowed with EC features yield high permeability models while the cells that exhibit outstanding barrier properties show principally epithelial cell-like (EpC) features. We found that models containing EpC-like cells express tight junction proteins, transporters/efflux pumps and display a high functional tightness with very low permeability, which are features commonly shared between BBB and epithelial barriers. Our study demonstrates that hiPSC-based BBB models need extensive characterization beforehand and that a reliable human BBB model containing EC-like cells and displaying low permeability is still needed.