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Pharmaceutics, Volume 16, Issue 4 (April 2024) – 110 articles

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17 pages, 4360 KiB  
Article
Drug Release from Lipid Microparticles—Insights into Drug Incorporation and the Influence of Physiological Factors
by Eliza Wolska and Karolina Sadowska
Pharmaceutics 2024, 16(4), 545; https://doi.org/10.3390/pharmaceutics16040545 (registering DOI) - 15 Apr 2024
Viewed by 130
Abstract
The aim of this study was to assess the impact of physiological factors, namely tear fluid and lysozyme enzyme, as well as surfactant polysorbate, on the release profile from solid lipid microparticles (SLM), in the form of dispersion intended for ocular application. Indomethacin [...] Read more.
The aim of this study was to assess the impact of physiological factors, namely tear fluid and lysozyme enzyme, as well as surfactant polysorbate, on the release profile from solid lipid microparticles (SLM), in the form of dispersion intended for ocular application. Indomethacin (Ind) was used as a model drug substance and a release study was performed by applying the dialysis bag method. Conducting release studies taking into account physiological factors is expected to improve development and screening studies, as well as support the regulatory assessment of this multi-compartment lipid dosage form. The effect of the lysozyme was directly related to its effect on lipid microparticles, as it occurred only in their presence (no effect on the solubility of Ind). Polysorbate also turned out to be an important factor interacting with the SLM surface, which determined the release of Ind from SLM. However, in study models without tear fluid or lysozyme, the release of Ind did not exceed 60% within 96 h. Ultimately, only the simultaneous application of artificial tear fluid, lysozyme, and polysorbate allowed for the release of 100% of Ind through the SLM dispersion. The examination of the residues after the release studies indicated the possibility of releasing 100% of Ind from SLM without complete degradation of the microparticles’ matrix. The incubation of SLM with tear fluid confirmed a similar influence of physiological factors contained in tear fluid on the surface structure of SLM as that observed during the in vitro studies. Full article
(This article belongs to the Special Issue Lipid/Polymer-Based Drug Delivery Systems)
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18 pages, 2771 KiB  
Article
Transcription Factor Binding Site in Promoter Determines the Pattern of Plasmid-Based Transgene Expression In Vivo
by Chunbo Zhang and Dexi Liu
Pharmaceutics 2024, 16(4), 544; https://doi.org/10.3390/pharmaceutics16040544 (registering DOI) - 15 Apr 2024
Viewed by 173
Abstract
Understanding the regulation of transgene expression is critical for the success of plasmid-based gene therapy and vaccine development. In this study, we used two sets of plasmid vectors containing secreted embryonic alkaline phosphatase or the mouse IL-10 gene as a reporter and investigated [...] Read more.
Understanding the regulation of transgene expression is critical for the success of plasmid-based gene therapy and vaccine development. In this study, we used two sets of plasmid vectors containing secreted embryonic alkaline phosphatase or the mouse IL-10 gene as a reporter and investigated the role of promoter elements in regulating transgene expression in vivo. We demonstrated in mice that hydrodynamic transfer of plasmids with the CMV promoter resulted in a high level of reporter gene expression that declined rapidly over time. In contrast, when plasmids with albumin promoters were used, a lower but sustained gene expression pattern was observed. We also found that plasmids containing a shorter CMV promoter sequence with fewer transcription factor binding sites showed a decrease in the peak level of gene expression without changing the overall pattern of reporter gene expression. The replacement of regulatory elements in the CMV promoter with a single regulatory element of the albumin promoter changed the pattern of transient gene expression seen in the CMV promoter to a pattern of sustained gene expression identical to that of a full albumin promoter. ChIP analyses demonstrated an elevated binding of acetylated histones and TATA box-binding protein to the promoter carrying regulatory elements of the albumin promoter. These results suggest that the strength of a promoter is determined by the number of appropriate transcription factor binding sites, while gene expression persistence is determined by the presence of regulatory elements capable of recruiting epigenetic modifying complexes that make the promoter accessible for transcription. This study provides important insights into the mechanisms underlying gene expression regulation in vivo, which can be used to improve plasmid-based gene therapy and vaccine development. Full article
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19 pages, 1407 KiB  
Article
Transport of Non-Steroidal Anti-Inflammatory Drugs across an Oral Mucosa Epithelium In Vitro Model
by Grace C. Lin, Heinz-Peter Friedl, Sarah Grabner, Anna Gerhartl and Winfried Neuhaus
Pharmaceutics 2024, 16(4), 543; https://doi.org/10.3390/pharmaceutics16040543 (registering DOI) - 15 Apr 2024
Viewed by 153
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, [...] Read more.
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell® model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured. Full article
(This article belongs to the Special Issue Transport of Drugs through Biological Barriers—an Asset or Risk)
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14 pages, 3508 KiB  
Article
In Vivo Imaging of Acute Hindlimb Ischaemia in Rat Model: A Pre-Clinical PET Study
by Gergely Farkasinszky, Judit Szabó Péliné, Péter Károlyi, Szilvia Rácz, Noémi Dénes, Tamás Papp, József Király, Zsuzsanna Szabo, István Kertész, Gábor Mező, Gabor Halmos, Zita Képes and György Trencsényi
Pharmaceutics 2024, 16(4), 542; https://doi.org/10.3390/pharmaceutics16040542 (registering DOI) - 15 Apr 2024
Viewed by 209
Abstract
Background: To better understand ischaemia-related molecular alterations, temporal changes in angiogenic Aminopeptidase N (APN/CD13) expression and glucose metabolism were assessed with PET using a rat model of peripheral arterial disease (PAD). Methods: The mechanical occlusion of the base of the left hindlimb triggered [...] Read more.
Background: To better understand ischaemia-related molecular alterations, temporal changes in angiogenic Aminopeptidase N (APN/CD13) expression and glucose metabolism were assessed with PET using a rat model of peripheral arterial disease (PAD). Methods: The mechanical occlusion of the base of the left hindlimb triggered using a tourniquet was applied to establish the ischaemia/reperfusion injury model in Fischer-344 rats. 2-[18F]FDG and [68Ga]Ga-NOTA-c(NGR) PET imaging performed 1, 3, 5, 7, and 10 days post-ischaemia induction was followed by Western blotting and immunohistochemical staining for APN/CD13 in ischaemic and control muscle tissue extracts. Results: Due to a cellular adaptation to hypoxia, a gradual increase in [68Ga]Ga-NOTA-c(NGR) and 2-[18F]FDG uptake was observed from post-intervention day 1 to 7 in the ischaemic hindlimbs, which was followed by a drop on day 10. Conforming pronounced angiogenic recovery, the NGR accretion of the ischaemic extremities differed significantly from the controls 5, 7, and 10 days after ischaemia induction (p ≤ 0.05), which correlated with the Western blot and immunohistochemical results. No remarkable radioactivity was depicted between the normally perfused hindlimbs of either the ischaemic or the control groups. Conclusions: The PET-based longitudinal assessment of angiogenesis-associated APN/CD13 expression and glucose metabolism during ischaemia may continue to broaden our knowledge on the pathophysiology of PAD. Full article
(This article belongs to the Section Clinical Pharmaceutics)
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39 pages, 1216 KiB  
Review
Aptamers for the Delivery of Plant-Based Compounds: A Review
by Joana Gamboa, Pedro Lourenço, Carla Cruz and Eugenia Gallardo
Pharmaceutics 2024, 16(4), 541; https://doi.org/10.3390/pharmaceutics16040541 (registering DOI) - 14 Apr 2024
Viewed by 454
Abstract
Natural compounds have a high potential for the treatment of various conditions, including infections, inflammatory diseases, and cancer. However, they usually present poor pharmacokinetics, low specificity, and even toxicity, which limits their use. Therefore, targeted drug delivery systems, typically composed of a carrier [...] Read more.
Natural compounds have a high potential for the treatment of various conditions, including infections, inflammatory diseases, and cancer. However, they usually present poor pharmacokinetics, low specificity, and even toxicity, which limits their use. Therefore, targeted drug delivery systems, typically composed of a carrier and a targeting ligand, can enhance natural product selectivity and effectiveness. Notably, aptamers—short RNA or single-stranded DNA molecules—have gained attention as promising ligands in targeted drug delivery since they are simple to synthesize and modify, and they present high tissue permeability, stability, and a wide array of available targets. The combination of natural products, namely plant-based compounds, with a drug delivery system utilizing aptamers as targeting agents represents an emerging strategy that has the potential to broaden its applications. This review discusses the potential of aptamers as targeting agents in the delivery of natural compounds, as well as new trends and developments in their utilization in the field of medicine. Full article
(This article belongs to the Special Issue Novel Technological Approaches for Targeted Drug Delivery Systems)
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34 pages, 627 KiB  
Review
Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies
by Ahmad Khalid Madadi and Moon-Jun Sohn
Pharmaceutics 2024, 16(4), 540; https://doi.org/10.3390/pharmaceutics16040540 (registering DOI) - 14 Apr 2024
Viewed by 445
Abstract
Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood–brain barrier (BBB), which significantly restricts the [...] Read more.
Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood–brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood–brain barrier and the complex pathophysiology of TBM. Full article
(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy)
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22 pages, 4338 KiB  
Article
Non-Invasive Delivery of Negatively Charged Nanobodies by Anodal Iontophoresis: When Electroosmosis Dominates Electromigration
by Phedra Firdaws Sahraoui, Oscar Vadas and Yogeshvar N. Kalia
Pharmaceutics 2024, 16(4), 539; https://doi.org/10.3390/pharmaceutics16040539 (registering DOI) - 13 Apr 2024
Viewed by 231
Abstract
Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged [...] Read more.
Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged M7D12H nanobody and a series of negatively charged variants with single amino acid substitutions. Surprisingly, M7D12H and its variants were only delivered transdermally by anodal iontophoresis. In contrast, transdermal permeation after cathodal iontophoresis and passive diffusion was <LOQ. The anodal iontophoretic delivery of these negatively charged proteins was achieved because electroosmosis was the dominant electrotransport mechanism. Cutaneous deposition after the anodal iontophoresis of M7D12HWT (wild type), and the R54E and K65E variants, was statistically superior to that after cathodal iontophoresis (6.07 ± 2.11, 9.22 ± 0.80, and 14.45 ± 3.45 μg/cm2, versus 1.12 ± 0.30, 0.72 ± 0.27, and 0.46 ± 0.07 µg/cm2, respectively). This was not the case for S102E, where cutaneous deposition after anodal and cathodal iontophoresis was 11.89 ± 0.87 and 8.33 ± 2.62 µg/cm2, respectively; thus, a single amino acid substitution appeared to be sufficient to impact the iontophoretic transport of a 17.5 kDa protein. Visualization studies using immunofluorescent labeling showed that skin transport of M7D12HWT was achieved via the intercellular and follicular routes. Full article
(This article belongs to the Special Issue Transdermal Delivery: Challenges and Opportunities)
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22 pages, 6322 KiB  
Article
In Situ Preparation of Tannic Acid-Modified Poly(N-isopropylacrylamide) Hydrogel Coatings for Boosting Cell Response
by Jufei Xu, Xiangzhe Liu, Pengpeng Liang, Hailong Yuan and Tianyou Yang
Pharmaceutics 2024, 16(4), 538; https://doi.org/10.3390/pharmaceutics16040538 (registering DOI) - 13 Apr 2024
Viewed by 175
Abstract
The improvement of the capability of poly(N-isopropylacrylamide) (PNIPAAm) hydrogel coating in cell adhesion and detachment is critical to efficiently prepare cell sheets applied in cellular therapies and tissue engineering. To enhance cell response on the surface, the amine group-modified PNIPAAm (PNIPAAm-APTES) [...] Read more.
The improvement of the capability of poly(N-isopropylacrylamide) (PNIPAAm) hydrogel coating in cell adhesion and detachment is critical to efficiently prepare cell sheets applied in cellular therapies and tissue engineering. To enhance cell response on the surface, the amine group-modified PNIPAAm (PNIPAAm-APTES) nanohydrogels were synthesized and deposited spontaneously on tannic acid (TA)-modified polyethylene (PE) plates. Subsequently, TA was introduced onto PNIPAAm-APTES nanohydrogels to fabricate coatings composed of TA-modified PNIPAAm-APTES (PNIPAAm-APTES-TA). Characterization techniques, including TEM, SEM, XPS, and UV-Vis spectroscopy, confirmed the effective deposition of hydrogels of PNIPAAm as well as the morphologies, content of chemical bonding-TA, and stability of various coatings. Importantly, the porous hydrogel coatings exhibited superhydrophilicity at 20 °C and thermo-responsive behavior. The fluorescence measurement demonstrated that the coating’s stability effectively regulated protein behavior, influencing cell response. Notably, cell response tests revealed that even without precise control over the chain length/thickness of PNIPAAm during synthesis, the coatings enhanced cell adhesion and detachment, facilitating efficient cell culture. This work represented a novel and facile approach to preparing bioactive PNIPAAm for cell culture. Full article
(This article belongs to the Special Issue Novel Drug Delivery Systems of Phytomedicines)
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18 pages, 4092 KiB  
Article
First Generic Teriparatide: Structural and Biological Sameness to Its Reference Medicinal Product
by Jimena Fernández-Carneado, Mariona Vallès-Miret, Sílvia Arrastia-Casado, Ana Almazán-Moga, Maria J. Macias, Pau Martin-Malpartida, Marta Vilaseca, Mireia Díaz-Lobo, Mayte Vazquez, Rosa M. Sanahuja, Gemma Gambús and Berta Ponsati
Pharmaceutics 2024, 16(4), 537; https://doi.org/10.3390/pharmaceutics16040537 (registering DOI) - 13 Apr 2024
Viewed by 204
Abstract
Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential [...] Read more.
Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility–mass spectrometry (IM–MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP. Full article
(This article belongs to the Section Biologics and Biosimilars)
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20 pages, 2693 KiB  
Article
A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer
by Nora D. Mineva, Stefania Pianetti, Sonia G. Das, Srimathi Srinivasan, Nicolas M. Billiald and Gail E. Sonenshein
Pharmaceutics 2024, 16(4), 536; https://doi.org/10.3390/pharmaceutics16040536 (registering DOI) - 13 Apr 2024
Viewed by 185
Abstract
New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and [...] Read more.
New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange–mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment. Full article
(This article belongs to the Special Issue Advances in Anticancer Agent, 2nd Edition)
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17 pages, 872 KiB  
Review
Delivery of DNA-Based Therapeutics for Treatment of Chronic Diseases
by Carleigh Sussman, Rachel A. Liberatore and Marek M. Drozdz
Pharmaceutics 2024, 16(4), 535; https://doi.org/10.3390/pharmaceutics16040535 (registering DOI) - 13 Apr 2024
Viewed by 157
Abstract
Gene therapy and its role in the medical field have evolved drastically in recent decades. Studies aim to define DNA-based medicine as well as encourage innovation and the further development of novel approaches. Gene therapy has been established as an alternative approach to [...] Read more.
Gene therapy and its role in the medical field have evolved drastically in recent decades. Studies aim to define DNA-based medicine as well as encourage innovation and the further development of novel approaches. Gene therapy has been established as an alternative approach to treat a variety of diseases. Its range of mechanistic applicability is wide; gene therapy has the capacity to address the symptoms of disease, the body’s ability to fight disease, and in some cases has the ability to cure disease, making it a more attractive intervention than some traditional approaches to treatment (i.e., medicine and surgery). Such versatility also suggests gene therapy has the potential to address a greater number of indications than conventional treatments. Many DNA-based therapies have shown promise in clinical trials, and several have been approved for use in humans. Whereas current treatment regimens for chronic disease often require frequent dosing, DNA-based therapies can produce robust and durable expression of therapeutic genes with fewer treatments. This benefit encourages the application of DNA-based gene therapy to manage chronic diseases, an area where improving efficiency of current treatments is urgent. Here, we provide an overview of two DNA-based gene therapies as well as their delivery methods: adeno associated virus (AAV)-based gene therapy and plasmid DNA (pDNA)-based gene therapy. We will focus on how these therapies have already been utilized to improve treatment of chronic disease, as well as how current literature supports the expansion of these therapies to treat additional chronic indications in the future. Full article
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19 pages, 4137 KiB  
Article
Investigation of Photodynamic Therapy Promoted by Cherenkov Light Activated Photosensitizers—New Aspects and Revelations
by Lisa Hübinger, Kerstin Wetzig, Roswitha Runge, Holger Hartmann, Falk Tillner, Katja Tietze, Marc Pretze, David Kästner, Robert Freudenberg, Claudia Brogsitter and Jörg Kotzerke
Pharmaceutics 2024, 16(4), 534; https://doi.org/10.3390/pharmaceutics16040534 (registering DOI) - 13 Apr 2024
Viewed by 163
Abstract
This work investigates the proposed enhanced efficacy of photodynamic therapy (PDT) by activating photosensitizers (PSs) with Cherenkov light (CL). The approaches of Yoon et al. to test the effect of CL with external radiation were taken up and refined. The results were used [...] Read more.
This work investigates the proposed enhanced efficacy of photodynamic therapy (PDT) by activating photosensitizers (PSs) with Cherenkov light (CL). The approaches of Yoon et al. to test the effect of CL with external radiation were taken up and refined. The results were used to transfer the applied scheme from external radiation therapy to radionuclide therapy in nuclear medicine. Here, the CL for the activation of the PSs (psoralen and trioxsalen) is generated by the ionizing radiation from rhenium-188 (a high-energy beta-emitter, Re-188). In vitro cell survival studies were performed on FaDu, B16 and 4T1 cells. A characterization of the PSs (absorbance measurement and gel electrophoresis) and the CL produced by Re-188 (luminescence measurement) was performed as well as a comparison of clonogenic assays with and without PSs. The methods of Yoon et al. were reproduced with a beam line at our facility to validate their results. In our studies with different concentrations of PS and considering the negative controls without PS, the statements of Yoon et al. regarding the positive effect of CL could not be confirmed. There are slight differences in survival fractions, but they are not significant when considering the differences in the controls. Gel electrophoresis showed a dominance of trioxsalen over psoralen in conclusion of single and double strand breaks in plasmid DNA, suggesting a superiority of trioxsalen as a PS (when irradiated with UVA). In addition, absorption measurements showed that these PSs do not need to be shielded from ambient light during the experiment. An observational test setup for a PDT nuclear medicine approach was found. The CL spectrum of Re-188 was measured. Fluctuating inconclusive results from clonogenic assays were found. Full article
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19 pages, 2263 KiB  
Article
Molecular Ballet: Investigating the Complex Interaction between Self-Assembling Dendrimers and Human Serum Albumin via Computational and Experimental Methods
by Gabriele Cavalieri, Domenico Marson, Nicoletta Giurgevich, Rachele Valeri, Fulvia Felluga, Erik Laurini and Sabrina Pricl
Pharmaceutics 2024, 16(4), 533; https://doi.org/10.3390/pharmaceutics16040533 - 12 Apr 2024
Viewed by 205
Abstract
Dendrimers, intricate macromolecules with highly branched nanostructures, offer unique attributes including precise control over size, shape, and functionality, making them promising candidates for a wide range of biomedical applications. The exploration of their interaction with biological environments, particularly human serum albumin (HSA), holds [...] Read more.
Dendrimers, intricate macromolecules with highly branched nanostructures, offer unique attributes including precise control over size, shape, and functionality, making them promising candidates for a wide range of biomedical applications. The exploration of their interaction with biological environments, particularly human serum albumin (HSA), holds significant importance for biomedical utilization. In this study, the interaction between HSA and a recently developed self-assembling amphiphilic dendrimer (AD) was investigated using various experimental techniques. Fluorescence spectroscopy and isothermal titration calorimetry revealed moderate interactions between the protein and the AD nanomicelles (NMs), primarily attributed to favorable enthalpic contributions arising from electrostatic interactions and hydrogen bonding. Structural analysis indicated minimal changes in HSA upon complexation with the AD NMs, which was further supported by computational simulations demonstrating stable interactions at the atomistic level. These findings provide valuable insights into the binding mechanisms and thermodynamic parameters governing HSA/AD NM interactions, thereby contributing to the understanding of their potential biomedical applications. Full article
19 pages, 1312 KiB  
Article
68Ga-DOTA-D-Alanine-BoroPro Radiotracer for Imaging of the Fibroblast Activation Protein in Malignant and Non-Malignant Diseases
by Diana Trujillo-Benítez, Myrna Luna-Gutiérrez, José G. Aguirre-De Paz, Pedro Cruz-Nova, Gerardo Bravo-Villegas, Joel E. Vargas-Ahumada, Paola Vallejo-Armenta, Enrique Morales-Avila, Nallely Jiménez-Mancilla, Rigoberto Oros-Pantoja, Clara Santos-Cuevas, Erika Azorín-Vega, Blanca Ocampo-García and Guillermina Ferro-Flores
Pharmaceutics 2024, 16(4), 532; https://doi.org/10.3390/pharmaceutics16040532 - 12 Apr 2024
Viewed by 187
Abstract
Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2’,2’’,2’’’-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) [...] Read more.
Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2’,2’’,2’’’-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) as a novel radiotracer for PET imaging and evaluate its usefulness for FAP expression in malignant and non-malignant tissues. The coupling of p-SCN-benzene DOTA with HYNIC-iFAP was used for the chemical synthesis and further labeling with 68Ga. Radiochemical purity was verified by radio-HPLC. The specificity of 68Ga-iFAP was evaluated in HCT116 cells, in which FAP expression was verified by immunofluorescence and Western blot. Biodistribution and biokinetic studies were performed in murine models. 68Ga-iFAP uptake at the myocardial level was assessed in mice with induced infarction. First-in-human images of 68Ga-iFAP in healthy subjects and patients with myocardial infarction, glioblastoma, prostate cancer, and breast cancer were also obtained. DOTA-D-Alanine BoroPro was prepared with a chemical purity of 98% and was characterized by UPLC mass spectroscopy, FT-IR, and UV-vis. The 68Ga-iFAP was obtained with a radiochemical purity of >95%. In vitro and in vivo studies demonstrated 68Ga-iFAP-specific recognition for FAP, rapid renal elimination, and adequate visualization of the glioblastoma, breast tumor, prostate cancer, and myocardial infarction sites. The results of this research justify further dosimetry and clinical trials to establish the specificity and sensitivity of 68Ga-iFAP PET for FAP expression imaging. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
32 pages, 9317 KiB  
Review
Cell Membrane-Coated Biomimetic Nanoparticles in Cancer Treatment
by Shu Zhang, Xiaojuan Zhang, Huan Gao, Xiaoqin Zhang, Lidan Sun, Yueyan Huang, Jie Zhang and Baoyue Ding
Pharmaceutics 2024, 16(4), 531; https://doi.org/10.3390/pharmaceutics16040531 - 12 Apr 2024
Viewed by 188
Abstract
Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point [...] Read more.
Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point of research and development, due to their exceptional traits, including precise targeting, low toxicity, and good biocompatibility. This review outlines the categorization and advantages of cell membrane bionic nano-delivery systems, provides an introduction to preparation methods, and assesses their applications in cancer treatment, including chemotherapy, gene therapy, immunotherapy, photodynamic therapy, photothermal therapy, and combination therapy. Notably, the review delves into the challenges in the application of various cell membrane bionic nano-delivery systems and identifies opportunities for future advancement. Embracing cell membrane-coated biomimetic nanoparticles presents a novel and unparalleled avenue for personalized tumor therapy. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
20 pages, 3649 KiB  
Article
Technological Functionalisation of Microencapsulated Genistein and Daidzein Delivery Systems Soluble in the Stomach and Intestines
by Jurga Andreja Kazlauskaite, Inga Matulyte, Mindaugas Marksa and Jurga Bernatoniene
Pharmaceutics 2024, 16(4), 530; https://doi.org/10.3390/pharmaceutics16040530 - 12 Apr 2024
Viewed by 149
Abstract
Encapsulating antioxidant-rich plant extracts, such as those found in red clover, within microcapsules helps protect them from degradation, thus improving stability, shelf life, and effectiveness. This study aimed to develop a microencapsulation delivery system using chitosan and alginate for microcapsules that dissolve in [...] Read more.
Encapsulating antioxidant-rich plant extracts, such as those found in red clover, within microcapsules helps protect them from degradation, thus improving stability, shelf life, and effectiveness. This study aimed to develop a microencapsulation delivery system using chitosan and alginate for microcapsules that dissolve in both the stomach and intestines, with the use of natural and synthetic emulsifiers. The microcapsules were formed using the extrusion method and employing alginate or chitosan as shell-forming material. In this study, all selected emulsifiers formed Pickering (β-CD) and traditional (white mustard extract, polysorbate 80) stable emulsions. Alginate-based emulsions resulted in microemulsions, while chitosan-based emulsions formed macroemulsions, distinguishable by oil droplet size. Although chitosan formulations with higher red clover extract (C1) concentrations showed potential, they exhibited slightly reduced firmness compared to other formulations (C2). Additionally, both alginate and chitosan formulations containing β-CD released bioactive compounds more effectively. The combined use of alginate and chitosan microcapsules in a single pill offers an innovative way to ensure dual solubility in both stomach and intestinal environments, increasing versatility for biomedical and pharmaceutical applications. Full article
(This article belongs to the Special Issue Natural Product Pharmaceuticals)
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15 pages, 3654 KiB  
Article
An Integrative Study of Scrophularia takesimensis Nakai in an Ovalbumin-Induced Murine Model of Asthma: The Effect on T Helper 2 Cell Activation
by Yun-Soo Seo, Jun-Ho Song, Hyo Seon Kim, Hyeon Hwa Nam, Sungyu Yang, Goya Choi, Sung-Wook Chae, Jeongmin Lee, Bokyung Jung, Joong-Sun Kim and Inkyu Park
Pharmaceutics 2024, 16(4), 529; https://doi.org/10.3390/pharmaceutics16040529 - 12 Apr 2024
Viewed by 238
Abstract
Scrophularia have traditionally been used as herbal medicines to treat neuritis, sore throats, and laryngitis. In particular, S. takesimensis, a Korean endemic species with restricted distribution on Ulleung Island, holds significant resource and genetic value. However, its pharmacological properties have not been [...] Read more.
Scrophularia have traditionally been used as herbal medicines to treat neuritis, sore throats, and laryngitis. In particular, S. takesimensis, a Korean endemic species with restricted distribution on Ulleung Island, holds significant resource and genetic value. However, its pharmacological properties have not been thoroughly evaluated. Thus, we provide detailed morphological characteristics and genomic information for S. takesimensis in this study. Moreover, its pharmacological activity was evaluated in an ovalbumin-induced asthma rat model, using extracts of S. takesimensis roots (100 or 200 mg/kg). The distinguishing features of S. takesimensis from related species include the presence or absence of stem wings, leaf shape, and habitat. The chloroplast (cp) genome of this species is 152,420 bp long and exhibits a conserved quadripartite structure. A total of 114 genes were identified, which included 80 protein-coding genes, 30 transfer RNA (tRNA) genes, and 4 ribosomal RNA (rRNA) genes. The gene order, content, and orientation of the S. takesimensis cp genome was highly conserved and consistent with the general structure observed in S. buergeriana and S. ningpoensis cp genomes. Confirming the anti-inflammatory effects of S. takesimensis extract (STE) using an established mouse model of ovalbumin-induced asthma, we observed reduced asthmatic phenotypes, including inflammatory cell infiltration, mucus production, and suppression of T helper 2 (Th2) cell. Furthermore, STE treatment reduced Th2 cell activation and differentiation. This study underscores the medicinal value of S. takesimensis. The importance of preserving S. takesimensis was revealed and crucial insights were provided for further research on its utilization as a medicinal resource. Full article
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24 pages, 3499 KiB  
Review
Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy
by Nikolaos Kokkorakis, Marios Zouridakis and Maria Gaitanou
Pharmaceutics 2024, 16(4), 528; https://doi.org/10.3390/pharmaceutics16040528 - 11 Apr 2024
Viewed by 228
Abstract
During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising [...] Read more.
During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising pharmacological target in cancer since it is overexpressed in many tumors, and its overexpression is correlated with patients’ poor prognosis. Mirk/Dyrk1B acts as a negative cell cycle regulator, maintaining the survival of quiescent cancer cells and conferring their resistance to chemotherapies. Many studies have demonstrated the valuable therapeutic effect of Mirk/Dyrk1B inhibitors in cancer cell lines, mouse xenografts, and patient-derived 3D-organoids, providing a perspective for entering clinical trials. Since the majority of Mirk/Dyrk1B inhibitors target the highly conserved ATP-binding site, they exhibit off-target effects with other kinases, especially with the highly similar Dyrk1A. In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy, 2nd Edition)
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13 pages, 2931 KiB  
Article
Iron Oxide Nanoparticles: Selectively Targeting Melanoma Cells In Vitro by Inducing DNA Damage via H2AX Phosphorylation and Hindering Proliferation through ERK Dephosphorylation
by Danai E. Prokopiou, Anastasia Chillà, Francesca Margheri, Gabriella Fibbi, Anna Laurenzana and Eleni K. Efthimiadou
Pharmaceutics 2024, 16(4), 527; https://doi.org/10.3390/pharmaceutics16040527 - 11 Apr 2024
Viewed by 179
Abstract
This study investigates the distinctive characteristics of iron oxide magnetic nanoparticles (mNPs) and their potential application in cancer therapy, focusing on melanoma. Three types of mNPs, pre-validated for safety, underwent molecular analysis to uncover the activated signaling pathways in melanoma cells. Using the [...] Read more.
This study investigates the distinctive characteristics of iron oxide magnetic nanoparticles (mNPs) and their potential application in cancer therapy, focusing on melanoma. Three types of mNPs, pre-validated for safety, underwent molecular analysis to uncover the activated signaling pathways in melanoma cells. Using the Western blot technique, the study revealed that mNPs induce cytotoxicity, hinder proliferation through ERK1/2 dephosphorylation, and prompt proapoptotic effects, including DNA damage by inducing H2AX phosphorylation. Additionally, in vitro magnetic hyperthermia notably enhanced cellular damage in melanoma cells. Moreover, the quantification of intracellular iron levels through Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis unveils the precise dosage required to induce cellular damage effectively. These compelling findings not only shed light on the therapeutic potential of mNPs in melanoma treatment but also open exciting avenues for future research, heralding a new era in the development of targeted and effective cancer therapies. Indeed, by discerning the effective dose, our approach becomes instrumental in optimizing the therapeutic utilization of iron oxide magnetic nanoparticles, enabling the induction of precisely targeted and controlled cellular responses. Full article
(This article belongs to the Special Issue Magnetic Nanoparticles: Tools for Drug Delivery, Therapy and Imaging)
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26 pages, 4877 KiB  
Article
Prebiotic Systems Containing Anthocyanin-Rich Pomegranate Flower Extracts with Antioxidant and Antidiabetic Effects
by Anna Gościniak, Natalia Rosiak, Daria Szymanowska, Andrzej Miklaszewski and Judyta Cielecka-Piontek
Pharmaceutics 2024, 16(4), 526; https://doi.org/10.3390/pharmaceutics16040526 - 10 Apr 2024
Viewed by 258
Abstract
Pomegranate flower extract, rich in anthocyanins, demonstrates beneficial health-promoting properties such as an anti-diabetic and antioxidant effect, among others. However, the potential health-promoting properties may be hindered by the low stability of anthocyanins. Therefore, the aim of our study was to assess whether [...] Read more.
Pomegranate flower extract, rich in anthocyanins, demonstrates beneficial health-promoting properties such as an anti-diabetic and antioxidant effect, among others. However, the potential health-promoting properties may be hindered by the low stability of anthocyanins. Therefore, the aim of our study was to assess whether stabilizing carriers, namely HP-γ-cyclodextrin (HP-γ-CD), α-cyclodextrin (α-CD), Methyl-β-cyclodextrin (Me-β-CD), Inulin (Inu) and Arabic gum (AGu) affect the antioxidant and antidiabetic activity of lyophilized pomegranate flower extract, how they influence stability, release profile, and whether the systems exhibit prebiotic activity. Interactions between pomegranate flower extract and these factors were analyzed using FT-IR. The structures were examined through microscopic imaging while for the prepared prebiotic systems, antidiabetic activity was determined and confirmed by the inhibition of α-amylase and α-glucosidase; antioxidant activity was expressed by DPPH and CUPRAC assays. The content of pelargonidin-3,5-glucoside in these systems was assessed using the HPLC method. The release profiles of pelargonidin-3,5-glucoside were examined in a medium at pH = 6.8 and pH = 1.2, and the stability was assessed after subjecting the systems to high temperatures (T = 90 °C). The prebiotic potential was evaluated for 10 prebiotic bacterial strains (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus brevis Lactobacillus rhamnosus gg, Lactobacillus reuteri, Pediococcus pentosaceus, Lactococcus lactis, Lactobacillus fermentum lf, Streptococcus thermophilus). As a result of the conducted research, better functionalities of the obtained systems containing Pomegranate flower extract were proven in terms of prebiotic and antidiabetic effects. The obtained delivery systems for pelargonidin-3,5-glucoside allow for better use of its health-promoting effects. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Plant Extracts, 2nd Edition)
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23 pages, 5615 KiB  
Article
The Antimicrobial Potency of Mesoporous Silica Nanoparticles Loaded with Melissa officinalis Extract
by Gabriela Petrișor, Ludmila Motelica, Roxana Doina Trușcǎ, Andreea-Luiza Mȋrț, Gabriel Vasilievici, Justinian-Andrei Tomescu, Cristina Manea, Andreea Ștefania Dumbravǎ, Viorica Maria Corbu, Irina Gheorghe-Barbu, Denisa Ficai, Ovidiu-Cristian Oprea, Bogdan-Ștefan Vasile, Anton Ficai and Anca Daniela Raiciu
Pharmaceutics 2024, 16(4), 525; https://doi.org/10.3390/pharmaceutics16040525 - 10 Apr 2024
Viewed by 262
Abstract
Melissa officinalis is an important medicinal plant that is used and studied intensively due to its numerous pharmacological effects. This plant has numerous active compounds with biomedical potential; some are volatile, while others are sensitive to heat or oxygen. Therefore, to increase stability [...] Read more.
Melissa officinalis is an important medicinal plant that is used and studied intensively due to its numerous pharmacological effects. This plant has numerous active compounds with biomedical potential; some are volatile, while others are sensitive to heat or oxygen. Therefore, to increase stability and prolong biological activities, the natural extract can be loaded into various nanostructured systems. In this study, different loading systems were obtained from mesoporous silica, like Mobile Composition of Matter family (MCM) with a hexagonal (MCM-41) or cubic (MCM-48) pore structure, simple or functionalized with amino groups (using 3-aminopropyl) such as triethoxysilane (APTES). Thus, the four materials were characterized from morphological and structural points of view by scanning electron microscopy, a BET analysis with adsorption–desorption isotherms, Fourier-transform infrared spectroscopy (FTIR) and a thermogravimetric analysis coupled with differential scanning calorimetry. Natural extract from Melissa officinalis was concentrated and analyzed by High-Performance Liquid Chromatography to identify the polyphenolic compounds. The obtained materials were tested against Gram-negative bacteria and yeasts and against both reference strains and clinical strains belonging to Gram-positive bacteria that were previously isolated from intra-hospital infections. The highest antimicrobial efficiency was found against Gram-positive and fungal strains. Good activity was also recorded against methicillin-resistant S. aureus, the Melissa officinalis extract inhibiting the production of various virulence factors. Full article
(This article belongs to the Special Issue Where Are We Now and Where Is Antimicrobial Therapy Headed?)
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27 pages, 547 KiB  
Review
Progress in the Use of Hydrogels for Antioxidant Delivery in Skin Wounds
by Lidia Maeso, Pablo Edmundo Antezana, Ailen Gala Hvozda Arana, Pablo Andrés Evelson, Gorka Orive and Martín Federico Desimone
Pharmaceutics 2024, 16(4), 524; https://doi.org/10.3390/pharmaceutics16040524 - 10 Apr 2024
Viewed by 316
Abstract
The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved [...] Read more.
The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved in delayed wound healing is oxidative injury, which is triggered by the overproduction of reactive oxygen species. Oxidative stress has been implicated in the pathogenesis of chronic wounds, where it is known to impair wound healing by causing damage to cellular components, delaying the inflammatory phase of healing, and inhibiting the formation of new blood vessels. Thereby, the treatment of chronic wounds requires a multidisciplinary approach that addresses the underlying causes of the wound, provides optimal wound care, and promotes wound healing. Among the promising approaches to taking care of chronic wounds, antioxidants are gaining interest since they offer multiple benefits related to skin health. Therefore, in this review, we will highlight the latest advances in the use of natural polymers with antioxidants to generate tissue regeneration microenvironments for skin wound healing. Full article
(This article belongs to the Special Issue Biopolymer Materials for Wound Healing, 2nd Edition)
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10 pages, 706 KiB  
Communication
Therapeutic Aqueous Humor Concentrations of Latanoprost Attained in Rats by Administration in a Very-High-Molecular-Weight Hyaluronic Acid Eye Drop
by Kazunari Higa, Reona Kimoto, Takashi Kojima, Murat Dogru, Wolfgang G. K. Müller-Lierheim and Jun Shimazaki
Pharmaceutics 2024, 16(4), 523; https://doi.org/10.3390/pharmaceutics16040523 - 09 Apr 2024
Viewed by 237
Abstract
The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA [...] Read more.
The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA (LPvHiHA), commercial LP (cLP), and diluted LP (dLP)) and after instilling the eye drops, the aqueous humor (AH) was collected at 0.5, 1, 2, 4, and 6 h to measure the LP concentration using an enzyme-linked immunosorbent assay (ELISA). Although the LP concentration in the LPvHiHA eye drop formulation was 3.57 times lower than in the commercial eye drops used (cLP), the LP concentration in the AH following LPvHiHA administration reached a value close to that of cLP. The cLP was diluted to the same concentration of LP as in the LPvHiHA eye drops for the dLP group, but the LP concentration in the AH of these animals was lower than that of the LPvHiHA rats at all time points. The higher LP concentration in the AH of the LPvHiHA rats suggests that vHiHA may aid the transport of LP across the ocular surface epithelium. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery)
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14 pages, 2287 KiB  
Article
Interaction of γ-Polyglutamic Acid/Polyethyleneimine/Plasmid DNA Ternary Complexes with Serum Components Plays a Crucial Role in Transfection in Mice
by Tomotaka Ko, Shintaro Fumoto, Tomoaki Kurosaki, Moe Nakashima, Hirotaka Miyamoto, Hitoshi Sasaki and Koyo Nishida
Pharmaceutics 2024, 16(4), 522; https://doi.org/10.3390/pharmaceutics16040522 - 09 Apr 2024
Viewed by 269
Abstract
Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such [...] Read more.
Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such as γ-polyglutamic acid (γ-PGA), can prevent cytotoxicity and hemagglutination. However, the role of interactions between these complexes and serum components in in vivo gene transfer remains unclear. In this study, we analyzed the contribution of serum components to in vivo gene transfer using PEI/plasmid DNA binary complexes and γ-PGA/PEI/plasmid DNA ternary complexes. In binary complexes, heat-labile components in the serum greatly contribute to the hepatic and splenic gene expression of the luciferase gene. In contrast, serum albumin and salts affected the hepatic and splenic gene expression in the ternary complexes. Changes in physicochemical characteristics, such as increased particle size and decreased absolute values of ζ-potential, might be involved in the enhanced gene expression. These findings would contribute to a better understanding of in vivo non-viral gene transfer using polymers, such as PEI and γ-PGA. Full article
(This article belongs to the Section Gene and Cell Therapy)
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13 pages, 12405 KiB  
Article
Comparative Cytotoxicity of Menthol and Eucalyptol: An In Vitro Study on Human Gingival Fibroblasts
by Clara Puig-Herreros, José Luis Sanz, David García-Bernal, Francisco Javier Rodríguez-Lozano, Laura Murcia, Leopoldo Forner, James Ghilotti, Ricardo E. Oñate-Sánchez and Sergio López-García
Pharmaceutics 2024, 16(4), 521; https://doi.org/10.3390/pharmaceutics16040521 - 09 Apr 2024
Viewed by 294
Abstract
The aim of this study was to assess the influence of eucalyptol and menthol on the cell viability, migration, and reactive oxygen species production of human gingival fibroblasts (GFs) in vitro. Three different concentrations of eucalyptol and menthol were prepared following ISO 10993-5 [...] Read more.
The aim of this study was to assess the influence of eucalyptol and menthol on the cell viability, migration, and reactive oxygen species production of human gingival fibroblasts (GFs) in vitro. Three different concentrations of eucalyptol and menthol were prepared following ISO 10993-5 guidelines (1, 5, and 10 mM). GFs were isolated from extracted teeth from healthy donors. The following parameters were assessed: cell viability via MTT, Annexin-V-FITC and 7-AAD staining, and IC50 assays; cell migration via horizontal scratch wound assay; and cell oxidative stress via reactive oxygen species assay. Data were analyzed using one-way ANOVA and Tukey’s post hoc test. Statistical significance was established at p < 0.05. Eucalyptol and Menthol exhibited high cytotoxicity on gingival fibroblasts, as evidenced by cytotoxicity assays. Eucalyptol showed lower levels of cytotoxicity than menthol, compared to the control group. The cytotoxicity of the tested substances increased in a concentration-dependent manner. The same occurred in a time-dependent manner, although even 10 min of exposure to the tested substances showed a high cytotoxicity to the GFs. Commercially available products for oral application with these substances in their composition should be tested for cytotoxicity before their use. Full article
(This article belongs to the Section Biopharmaceutics)
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21 pages, 8669 KiB  
Article
Cardioprotective and Hepatoprotective Potential of Silymarin in Paracetamol-Induced Oxidative Stress
by Bogdan Okiljević, Nikola Martić, Srđan Govedarica, Bojana Andrejić Višnjić, Milana Bosanac, Jovan Baljak, Branimir Pavlić, Isidora Milanović and Aleksandar Rašković
Pharmaceutics 2024, 16(4), 520; https://doi.org/10.3390/pharmaceutics16040520 - 09 Apr 2024
Viewed by 426
Abstract
Silymarin, derived from Silybum marianum, has been used in traditional medicine for various ailments. In this study, the cardioprotective and hepatoprotective effects of silymarin against paracetamol-induced oxidative stress were examined in 28 male Swiss Webster mice, divided into four groups and treated [...] Read more.
Silymarin, derived from Silybum marianum, has been used in traditional medicine for various ailments. In this study, the cardioprotective and hepatoprotective effects of silymarin against paracetamol-induced oxidative stress were examined in 28 male Swiss Webster mice, divided into four groups and treated for 7 days (via the oral route) with (a) saline 1 mL/kg (control group), (b) saline 1 mL/kg + single dose of paracetamol 110 mg/kg on the 7th day; (c) silymarin 50 mg/kg; and (d) silymarin 50 mg/kg + single dose of paracetamol 110 mg/kg on the 7th day. In vitro and in vivo antioxidant activity together with liver enzyme activity were evaluated. Histopathological and immunohistochemical assessment was performed. Silymarin mitigated paracetamol-induced liver injury by reducing oxidative stress markers such as lipid peroxidation and restoring antioxidant enzyme activity. Silymarin treatment resulted in a significant decrease in liver enzyme levels. Reduced necrosis and inflammatory infiltrate in liver tissues of silymarin-treated groups were detected as well. Immunohistochemical analysis demonstrated reduced expression of inflammatory markers (COX2, iNOS) and oxidative stress marker (SOD2) in the liver tissues of the silymarin-treated groups. Similar trends were observed in cardiac tissue. These results suggest that silymarin exerts potent hepatoprotective and cardioprotective effects against paracetamol-induced oxidative stress, making it a promising therapeutic agent for liver and heart diseases associated with oxidative damage. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Plant Extracts, 2nd Edition)
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16 pages, 582 KiB  
Review
Intranasal Therapy in Palliative Care
by Anna Ingielewicz and Robert K. Szymczak
Pharmaceutics 2024, 16(4), 519; https://doi.org/10.3390/pharmaceutics16040519 - 09 Apr 2024
Viewed by 294
Abstract
In recent years, the use of the intranasal route has been actively explored as a possible drug delivery method in the palliative patient population. There are reports demonstrating the effectiveness of nasally administered medications that are routinely used in patients at the end [...] Read more.
In recent years, the use of the intranasal route has been actively explored as a possible drug delivery method in the palliative patient population. There are reports demonstrating the effectiveness of nasally administered medications that are routinely used in patients at the end of life. The subject of this study is the intranasal drug administration among palliative patients. The aim is to summarize currently used intranasal therapies among palliative patients, determine the benefits and difficulties, and identify potential areas for future research. A review of available medical literature published between 2013 and 2023 was performed using online scientific databases. The following descriptors were used when searching for articles: “palliative”, “intranasal”, “nasal”, “end-of-life care”, “intranasal drug delivery” and “nasal drug delivery”. Out of 774 articles, 55 directly related to the topic were finally selected and thoroughly analyzed. Based on the bibliographic analysis, it was shown that drugs administered intranasally may be a good, effective, and convenient form of treatment for patients receiving palliative care, in both children and adults. This topic requires further, high-quality clinical research. Full article
(This article belongs to the Special Issue Nasal Drug Delivery: Challenges and Future Opportunities)
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18 pages, 4039 KiB  
Article
In Vitro Antimicrobial Photodynamic Therapy for Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA) Inhibition Using a Green Light Source
by Karen Roa-Tort, Yael Saavedra, Angélica Villanueva-Martínez, Adriana Ganem-Rondero, Laura Abril Pérez-Carranza, José M. de la Rosa-Vázquez, Gabriel Ugalde-Femat, Omar Molina-Alejandre, Andrea Angela Becerril-Osnaya and Josué D. Rivera-Fernández
Pharmaceutics 2024, 16(4), 518; https://doi.org/10.3390/pharmaceutics16040518 - 09 Apr 2024
Viewed by 430
Abstract
Photodynamic therapy (PDT) has been based on using photosensitizers (PS) and applying light of a specific wavelength. When this technique is used for treating infections, it is known as antimicrobial photodynamic therapy (aPDT). Currently, the use of lighting sources for in vitro studies [...] Read more.
Photodynamic therapy (PDT) has been based on using photosensitizers (PS) and applying light of a specific wavelength. When this technique is used for treating infections, it is known as antimicrobial photodynamic therapy (aPDT). Currently, the use of lighting sources for in vitro studies using aPDT is generally applied in multiwell cell culture plates; however, depending on the lighting arrangement, there are usually errors in the application of the technique because the light from a well can affect the neighboring wells or it may be that not all the wells are used in the same experiment. In addition, one must be awarded high irradiance values, which can cause unwanted photothermal problems in the studies. Thus, this manuscript presents an in vitro antimicrobial photodynamic therapy for a Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA) inhibition study using an arrangement of thermally isolated and independently illuminated green light source systems for eight tubes in vitro aPDT, determining the effect of the following factors: (i) irradiance level, (ii) exposure time, and (iii) Rose Bengal (RB) concentration (used as a PS), registering the Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA) inhibition rates. The results show that in the dark, RB had a poor antimicrobial rate for P. aeruginosa, finding the maximum inhibition (2.7%) at 30 min with an RB concentration of 3 µg/mL. However, by applying light in a correct dosage (time × irradiance) and the adequate RB concentration, the inhibition rate increased by over 37%. In the case of MRSA, there was no significant inhibition with RB in complete darkness and, in contrast, the rate was 100% for those experiments that were irradiated. Full article
(This article belongs to the Special Issue Photodynamic Therapy: Recent Progress and Development)
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16 pages, 991 KiB  
Review
An Overview of the Pharmacokinetics and Pharmacodynamics of Landiolol (an Ultra-Short Acting β1 Selective Antagonist) in Atrial Fibrillation
by Mariana Floria, Alexandru Florinel Oancea, Paula Cristina Morariu, Alexandru Burlacu, Diana Elena Iov, Cristina Petronela Chiriac, Genoveva Livia Baroi, Celina Silvia Stafie, Magdalena Cuciureanu, Viorel Scripcariu and Daniela Maria Tanase
Pharmaceutics 2024, 16(4), 517; https://doi.org/10.3390/pharmaceutics16040517 - 08 Apr 2024
Viewed by 308
Abstract
Landiolol is an ultra-short-acting, selective β1-adrenergic receptor blocker that was originally approved in Japan for the treatment of intraoperative tachyarrhythmias. It has gained attention for its use in the management of tachyarrhythmias and perioperative tachycardia, especially atrial fibrillation for both cardiac and non-cardiac [...] Read more.
Landiolol is an ultra-short-acting, selective β1-adrenergic receptor blocker that was originally approved in Japan for the treatment of intraoperative tachyarrhythmias. It has gained attention for its use in the management of tachyarrhythmias and perioperative tachycardia, especially atrial fibrillation for both cardiac and non-cardiac surgeries. It can be the ideal agent for heart rate control due to its high β1-selectivity, potent negative chronotropic effect, a limited negative inotropic potential, and an ultrashort elimination half-life (around 4 min); moreover, it may have a potential therapeutic effects for sepsis and pediatric patients. Landiolol seems to be superior to other short-acting and selective beta-blockers such as esmolol. This review aims to provide a comprehensive overview of landiolol, a new ultra-short-acting β1 selective antagonist, including its pharmacology, clinical applications, efficacy, safety profile, and future directions in research and clinical data. Full article
(This article belongs to the Special Issue Advances in the Pharmaceutical Treatment of Cardiovascular Disease)
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14 pages, 7480 KiB  
Article
Size Tuning of Mesoporous Silica Adjuvant for One-Shot Vaccination with Long-Term Anti-Tumor Effect
by Xiupeng Wang, Yu Sogo and Xia Li
Pharmaceutics 2024, 16(4), 516; https://doi.org/10.3390/pharmaceutics16040516 - 08 Apr 2024
Viewed by 343
Abstract
Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect [...] Read more.
Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect by one-shot vaccination. This strategy is based on the size-dependent immunostimulation mechanism of mesoporous silica particles. Hollow mesoporous silica (HMS) nanoparticles enhance the antigen uptake with dendritic cells around the immunization site in vivo. In contrast, hierarchically porous silica (HPS) microparticles prolong cancer antigen retention and release in vivo. The size tuning of the mesoporous silica adjuvant prepared by combining both nanoparticles and microparticles demonstrates the immunological properties of both components and has a long-term anti-tumor effect after one-shot vaccination. One-shot vaccination with HMS-HPS-ovalbumin (OVA)-Poly IC (PIC, a TLR3 agonist) increases CD4+ T cell, CD8+ T cell, and CD86+ cell populations in draining lymph nodes even 4 months after vaccination, as well as effector memory CD8+ T cell and tumor-specific tetramer+CD8+ T cell populations in splenocytes. The increases in the numbers of effector memory CD8+ T cells and tumor-specific tetramer+CD8+ T cells indicate that the one-shot vaccination with HMS-HPS-OVA-PIC achieved the longest survival time after a challenge with E.G7-OVA cells among all groups. The size tuning of the mesoporous silica adjuvant shows promise for one-shot vaccination that mimics multiple clinical vaccinations in future cancer immunoadjuvant development. This study may have important implications in the long-term vaccine design of one-shot vaccinations. Full article
(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)
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