Brain Theranostics: Focus on Drug Delivery and Outcomes

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 9232

Special Issue Editor

Assistant Professor, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
Interests: neurodevelopmental biology; neurodegenerative disorders; drug delivery; bioimaging; toxicology; biomarker discovery

Special Issue Information

Dear Colleagues,

Brain theranostics is an emerging research field, integrating “therapeutics” and “diagnostics”. The theranostics approach provides new modalities to improve the diagnostic specificity of brain diseases and to develop and investigate the efficacy of newly developed or repurposed therapeutic compounds, and of targeted and controlled drug delivery schemes. Such a promising field involves concepts associated with the design of probes to image brain diseases, the development of non-invasive bioimaging modalities with high sensitivity and specificity to track biomarkers, the identification of disease-associated mechanisms, and the engineering of delivery platforms such as nanoformulations and extracellular vesicles to improve delivery across the blood–brain barrier (BBB) for effective treatment outcomes.  

The objective of this Special Issue is to invite leading experts in the fields of neurodegenerative diseases, neurodevelopmental disorders, neurobehavioral biology, drug-induced neurotoxicity, bioimaging and nanomedicine to discuss their most recent discoveries, and to share their vision for future development in associated topics. Spontaneous submissions are welcome. Both original unpublished research articles and reviews will be considered.

Topics include, but are not limited to:

  1. New techniques to improve the blood–brain barrier (BBB) penetration of theranostic molecules;
  2. Sensitive bioimaging modalities for the detection of brain diseases and/or therapeutic efficacy;
  3. Nanomedicine for the therapy of brain diseases;
  4. New developments for controlled or targeted drug delivery to the brain;
  5. Neurodevelopmental neurotoxicity following in utero exposure to therapeutic drugs and new approaches to improve outcomes;
  6. Neurobehavioral assessments defining brain diseases and therapeutic outcomes;
  7. Novel mechanisms underlying brain diseases.

Dr. Aditya N. Bade
Guest Editor

Manuscript Submission Information

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Keywords

  • brain
  • neurodegenerative diseases
  • therapeutics
  • diagnostics
  • nanomedicine
  • MRI/SPECT/PET
  • blood–brain barrier
  • neurotoxicity
  • behavioral tests

Published Papers (5 papers)

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Research

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17 pages, 3724 KiB  
Article
Accelerated Neuroimmune Dysfunction in Aged HIV-1-Infected Humanized Mice
Pharmaceuticals 2024, 17(2), 149; https://doi.org/10.3390/ph17020149 - 23 Jan 2024
Viewed by 973
Abstract
Disordered immunity, aging, human immunodeficiency virus type one (HIV-1) infection, and responses to antiretroviral therapy are linked. However, how each factor is linked with the other(s) remains incompletely understood. It has been reported that accelerated aging, advanced HIV-1 infection, inflammation, and host genetic [...] Read more.
Disordered immunity, aging, human immunodeficiency virus type one (HIV-1) infection, and responses to antiretroviral therapy are linked. However, how each factor is linked with the other(s) remains incompletely understood. It has been reported that accelerated aging, advanced HIV-1 infection, inflammation, and host genetic factors are associated with host cellular, mitochondrial, and metabolic alterations. However, the underlying mechanism remains elusive. With these questions in mind, we used chronically HIV-1-infected CD34-NSG humanized mice (hu-mice) to model older people living with HIV and uncover associations between HIV-1 infection and aging. Adult humanized mice were infected with HIV-1 at the age of 20 weeks and maintained for another 40 weeks before sacrifice. Animal brains were collected and subjected to transcriptomics, qPCR, and immunofluorescence assays to uncover immune disease-based biomarkers. CD4+ T cell decline was associated with viral level and age. Upregulated C1QA, CD163, and CXCL16 and downregulated LMNA and CLU were identified as age-associated genes tied to HIV-1 infection. Ingenuity pathway analysis affirmed links to innate immune activation, pyroptosis signaling, neuroinflammation, mitochondrial dysfunction, cellular senescence, and neuronal dysfunction. In summary, CD34-NSG humanized mice are identified as a valuable model for studying HIV-1-associated aging. Biomarkers of immune senescence and neuronal signaling are both age- and virus-associated. By exploring the underlying biological mechanisms that are linked to these biomarkers, interventions for next generation HIV-1-infected patients can be realized. Full article
(This article belongs to the Special Issue Brain Theranostics: Focus on Drug Delivery and Outcomes)
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29 pages, 3584 KiB  
Article
Lyophilized Nasal Inserts of Atomoxetine HCl Solid Lipid Nanoparticles for Brain Targeting as a Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): A Pharmacokinetics Study on Rats
Pharmaceuticals 2023, 16(2), 326; https://doi.org/10.3390/ph16020326 - 20 Feb 2023
Cited by 5 | Viewed by 2288
Abstract
The study aims to investigate the ability of lyophilized nasal inserts of nanosized atomoxetine HCl solid lipid nanoparticles (ATM-SLNs) to transport atomoxetine (ATM) directly to the brain and overcome the first-pass metabolism. In this case, 16 formulae of (ATM-SLNs) were prepared using hot [...] Read more.
The study aims to investigate the ability of lyophilized nasal inserts of nanosized atomoxetine HCl solid lipid nanoparticles (ATM-SLNs) to transport atomoxetine (ATM) directly to the brain and overcome the first-pass metabolism. In this case, 16 formulae of (ATM-SLNs) were prepared using hot melt emulsification, stirring and ultrasonication method technique. A full factorial design was established with 24 trials by optimization of four variables; lipid type (Compritol 888 ATO or stearic acid) (X1), lipid to drug ratio [(1:2) or (2:1)] (X2), span 60: Pluronic f127 ratio [(1:3) or (3:1)] (X3) and probe sonication time (five or ten minutes) (X4). The prepared SLNs were characterized for entrapment efficiency (EE%), in-vitro drug release after 30 min (Q30min), particle size (PS), zeta potential (ZP) and polydispersity index (PDI). Design Expert® software was used to select the optimum two formulae. The morphological examination for the optimum two formulae was carried out using a transmission electron microscope (TEM). Furthermore, eight lyophilized nasal inserts were prepared by using a 23 full factorial design by optimization of three variables: type of (ATM-SLNs) formula (X1), type of polymer (NOVEON AA1 or HPMC K100m) (X2) and concentration of polymer (X3). They were evaluated for nasal inserts’ physicochemical properties. The two optimum inserts were selected by Design Expert® software. The two optimum insets with the highest desirability values were (S4 and S8). They were subjected to DSC thermal stability study and in-vivo study on rats. They were compared with atomoxetine oral solution, atomoxetine (3 mg/kg, intraperitoneal injection) and the pure atomoxetine solution loaded in lyophilized insert. (ATM-SLNs) showed EE% range of (41.14 mg ± 1.8% to 90.6 mg ± 2.8%), (Q30min%) of (27.11 ± 5.9% to 91.08 ± 0.15%), ZP of (−8.52 ± 0.75 to −28.4 ± 0.212% mV), PS of (320.9 ± 110.81% nm to 936.7 ± 229.6% nm) and PDI of (0.222 ± 0.132% to 0.658 ± 0.03%). Additionally, the two optimum (ATM-SLNs) formulae chosen, i.e., F7 and F9 showed spherical morphology. Nasal inserts had assay of drug content of (82.5 ± 2.5% to 103.94 ± 3.94%), Q15min% of (89.9 ± 6.4% to 100%) and Muco-adhesion strength of (3510.5 ± 140.21 to 9319.5 ± 39.425). DSC results of S4 and S8 showed compatibility of (ATM) with the other excipients. S8 and S4 also showed higher trans-nasal permeation to the brain with brain targeting efficiency of (211.3% and 177.42%, respectively) and drug transport percentages of (52.7% and 43.64%, respectively). To conclude, lyophilized nasal inserts of (ATM-SLNs) enhanced (ATM) trans-nasal drug targeting permeation and brain targeting efficiency. Full article
(This article belongs to the Special Issue Brain Theranostics: Focus on Drug Delivery and Outcomes)
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17 pages, 1733 KiB  
Article
Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment
Pharmaceuticals 2022, 15(9), 1083; https://doi.org/10.3390/ph15091083 - 30 Aug 2022
Cited by 2 | Viewed by 1821
Abstract
A liposphere system for intranasal delivery of quetiapine fumarate (QTF) was created to assess the potential for enhanced drug delivery. We investigated the effects of particle size, entrapment effectiveness, poly dispersibility index, and pluronic incorporation percentage on these variables. The optimal formula was [...] Read more.
A liposphere system for intranasal delivery of quetiapine fumarate (QTF) was created to assess the potential for enhanced drug delivery. We investigated the effects of particle size, entrapment effectiveness, poly dispersibility index, and pluronic incorporation percentage on these variables. The optimal formula was examined using a TEM, and investigations into DSC, XRD, and FTIR were made. Optimized liposphere formulation in vitro dissolution investigation with a mean diameter of 294.4 ± 18.2 nm revealed about 80% drug release in 6 h. The intranasal injection of QTF-loaded lipospheres showed a shorter Tmax compared to that of intranasal and oral suspension, per the findings of an in vivo tissue distribution investigation in Wistar mice. Lipospheres were able to achieve higher drug transport efficiency (DTE %) and direct nose-to-brain drug transfer (DTP %). A potentially effective method for delivering QTF to specific brain regions is the liposphere system. Full article
(This article belongs to the Special Issue Brain Theranostics: Focus on Drug Delivery and Outcomes)
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Review

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17 pages, 1547 KiB  
Review
Chemotherapy-Mediated Neuronal Aberration
Pharmaceuticals 2023, 16(8), 1165; https://doi.org/10.3390/ph16081165 - 16 Aug 2023
Cited by 1 | Viewed by 1198
Abstract
Chemotherapy is a life-sustaining therapeutic option for cancer patients. Despite the advancement of several modern therapies, such as immunotherapy, gene therapy, etc., chemotherapy remains the first-line therapy for most cancer patients. Along with its anti-cancerous effect, chemotherapy exhibits several detrimental consequences that restrict [...] Read more.
Chemotherapy is a life-sustaining therapeutic option for cancer patients. Despite the advancement of several modern therapies, such as immunotherapy, gene therapy, etc., chemotherapy remains the first-line therapy for most cancer patients. Along with its anti-cancerous effect, chemotherapy exhibits several detrimental consequences that restrict its efficacy and long-term utilization. Moreover, it effectively hampers the quality of life of cancer patients. Cancer patients receiving chemotherapeutic drugs suffer from neurological dysfunction, referred to as chemobrain, that includes cognitive and memory dysfunction and deficits in learning, reasoning, and concentration ability. Chemotherapy exhibits neurotoxicity by damaging the DNA in neurons by interfering with the DNA repair system and antioxidant machinery. In addition, chemotherapy also provokes inflammation by inducing the release of various pro-inflammatory cytokines, including NF-kB, IL-1β, IL-6, and TNF-α. The chemotherapy-mediated inflammation contributes to chemobrain in cancer patients. These inflammatory cytokines modulate several growth signaling pathways and reactive oxygen species homeostasis leading to systemic inflammation in the body. This review is an effort to summarize the available information which discusses the role of chemotherapy-induced inflammation in chemobrain and how it impacts different aspects of therapeutic outcome and the overall quality of life of the patient. Further, this article also discusses the potential of herbal-based remedies to overcome chemotherapy-mediated neuronal toxicity as well as to improve the quality of life of cancer patients. Full article
(This article belongs to the Special Issue Brain Theranostics: Focus on Drug Delivery and Outcomes)
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34 pages, 2060 KiB  
Review
HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment
Pharmaceuticals 2022, 15(12), 1533; https://doi.org/10.3390/ph15121533 - 09 Dec 2022
Cited by 4 | Viewed by 2227
Abstract
Children born to mothers, with or at risk, of human immunodeficiency virus type-1 (HIV-1) infection are on the rise due to affordable access of antiretroviral therapy (ART) to pregnant women or those of childbearing age. Each year, up to 1.3 million HIV-1-infected women [...] Read more.
Children born to mothers, with or at risk, of human immunodeficiency virus type-1 (HIV-1) infection are on the rise due to affordable access of antiretroviral therapy (ART) to pregnant women or those of childbearing age. Each year, up to 1.3 million HIV-1-infected women on ART have given birth with recorded mother-to-child HIV-1 transmission rates of less than 1%. Despite this benefit, the outcomes of children exposed to antiretroviral drugs during pregnancy, especially pre- and post- natal neurodevelopment remain incompletely understood. This is due, in part, to the fact that pregnant women are underrepresented in clinical trials. This is underscored by any potential risks of neural tube defects (NTDs) linked, in measure, to periconceptional usage of dolutegravir (DTG). A potential association between DTG and NTDs was first described in Botswana in 2018. Incidence studies of neurodevelopmental outcomes associated with DTG, and other integrase strand transfer inhibitors (INSTIs) are limited as widespread use of INSTIs has begun only recently in pregnant women. Therefore, any associations between INSTI use during pregnancy, and neurodevelopmental abnormalities remain to be explored. Herein, United States Food and Drug Administration approved ARVs and their use during pregnancy are discussed. We provide updates on INSTI pharmacokinetics and adverse events during pregnancy together with underlying mechanisms which could affect fetal neurodevelopment. Overall, this review seeks to educate both clinical and basic scientists on potential consequences of INSTIs on fetal outcomes as a foundation for future scientific investigations. Full article
(This article belongs to the Special Issue Brain Theranostics: Focus on Drug Delivery and Outcomes)
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