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Pharmaceutics, Volume 17, Issue 1 (January 2025) – 138 articles

Cover Story (view full-size image): This study explores the synergistic effects of mechanical high-intensity focused ultrasound (M-HIFU) and dendritic cell (DC) vaccines in targeting OLFM4-expressing tumors. OLFM4, associated with cancer stem cells (CSCs), promotes immune evasion and tumor progression. M-HIFU induces immunogenic cell death, releasing tumor antigens and enhancing immune responses, while DC vaccines loaded with OLFM4 amplify anti-tumor immunity. Combination therapy involving both has shown significant tumor suppression, reduced metastasis, and improved immune memory. Further, intratumoral DC administration alongside M-HIFU was particularly effective. This approach highlights a promising strategy for enhancing cancer immunotherapy through tumor microenvironment modulation. View this paper
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23 pages, 4442 KiB  
Article
Biotechnological Phytocomplex of Zanthoxylum piperitum (L.) DC. Enhances Collagen Biosynthesis In Vitro and Improves Skin Elasticity In Vivo
by Giovanna Rigillo, Giovanna Pressi, Oriana Bertaiola, Chiara Guarnerio, Matilde Merlin, Roberto Zambonin, Stefano Pandolfo, Angela Golosio, Francesca Masin, Fabio Tascedda, Marco Biagi and Giulia Baini
Pharmaceutics 2025, 17(1), 138; https://doi.org/10.3390/pharmaceutics17010138 - 20 Jan 2025
Viewed by 1012
Abstract
Background: Zanthoxylum piperitum (L.) DC., commonly known as Japanese pepper, is a deciduous shrub native to East Asia. Its berries are widely used as a spice, known for imparting a distinctive, tingly numbing sensation. Biologically, Z. piperitum has antimicrobial, antioxidant, and anti-inflammatory [...] Read more.
Background: Zanthoxylum piperitum (L.) DC., commonly known as Japanese pepper, is a deciduous shrub native to East Asia. Its berries are widely used as a spice, known for imparting a distinctive, tingly numbing sensation. Biologically, Z. piperitum has antimicrobial, antioxidant, and anti-inflammatory properties, and it is studied for its potential benefits in pain relief and digestive health. This study proposed a novel biotechnological Z. piperitum phytocomplex (ZPP) obtained by plant cell culture for skin health, specifically targeting collagen synthesis, extracellular matrix stability, and resilience against cellular stress. Given the bioactivity of Z. piperitum, we aimed to analyze its efficacy as a sustainable alternative for skin-supportive applications in cosmetics and supplements. Methods: ZPP was produced through stable plant cell cultures, yielding a lignan-rich (3.02% w/w) phytocomplex. Human fibroblasts (HFFs) were treated with varying ZPP concentrations to assess cellular viability, collagen metabolism, and ECM-related enzyme activities, both under normal and cell stress conditions. The in vivo assessment was performed by measuring biophysical skin parameters such as hydration, elasticity, and roughness in female volunteers for a period of six weeks. Results: In vitro, ZPP exhibited non-cytotoxicity at all concentrations tested. Under hyperosmotic stress, ZPP reduced cellular damage, suggesting enhanced resilience. ZPP upregulated lysyl oxidase (LOX) protein levels, critical for collagen cross-linking and ECM stability, with protective effects observed under oxidative/inflammatory conditions. Additionally, ZPP selectively inhibited collagenase, attenuating collagen breakdown, though antioxidant activity was modest. In vivo evaluation highlighted improved skin hydration, elasticity, and roughness. Conclusions: ZPP shows promise as a biotechnological agent for skin health, particularly in supporting collagen integrity, ECM stabilization, and cellular resilience under stress. While further studies are needed to explore its full efficacy, especially for aging and environmentally stressed skin, these findings highlight ZPP’s potential as a new ingredient for cosmetic formulations aimed at skin care and the treatment of alterations caused by aging or environmental conditions. Full article
(This article belongs to the Special Issue Skin Care Products for Healthy and Diseased Skin)
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32 pages, 11368 KiB  
Review
A Compendium of Magnetic Nanoparticle Essentials: A Comprehensive Guide for Beginners and Experts
by Carlos O. Amorim
Pharmaceutics 2025, 17(1), 137; https://doi.org/10.3390/pharmaceutics17010137 - 20 Jan 2025
Viewed by 752
Abstract
Magnetic nanoparticles (MNPs) are advanced materials that combine the unique properties of magnetic materials and nanoscale dimensions, enabling a wide range of applications in biomedicine, environmental science, and information technology. This review provides a comprehensive yet accessible introduction to the fundamental principles, characterization [...] Read more.
Magnetic nanoparticles (MNPs) are advanced materials that combine the unique properties of magnetic materials and nanoscale dimensions, enabling a wide range of applications in biomedicine, environmental science, and information technology. This review provides a comprehensive yet accessible introduction to the fundamental principles, characterization techniques, and diverse applications of MNPs, with a focus on their nanoscale magnetic properties, such as superparamagnetism, single-domain behavior, and surface effects. It also delves into their classification and the critical role of parameters like magnetic anisotropy and blocking temperature. Emphasis is placed on routine characterization methods, including X-ray diffraction, electron microscopy, and magnetometry, as well as advanced concepts like magnetic hyperthermia and self-regulated heating. Designed for newcomers and experts alike, this review serves as both an educational guide and a quick-reference resource, ensuring clarity while maintaining scientific rigor. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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62 pages, 3804 KiB  
Review
Nanosuspension Innovations: Expanding Horizons in Drug Delivery Techniques
by Shery Jacob, Fathima Sheik Kather, Sai H. S. Boddu, Mahesh Attimarad and Anroop B. Nair
Pharmaceutics 2025, 17(1), 136; https://doi.org/10.3390/pharmaceutics17010136 - 19 Jan 2025
Viewed by 1001
Abstract
Nanosuspensions (NS), with their submicron particle sizes and unique physicochemical properties, provide a versatile solution for enhancing the administration of medications that are not highly soluble in water or lipids. This review highlights recent advancements, future prospects, and challenges in NS-based drug delivery, [...] Read more.
Nanosuspensions (NS), with their submicron particle sizes and unique physicochemical properties, provide a versatile solution for enhancing the administration of medications that are not highly soluble in water or lipids. This review highlights recent advancements, future prospects, and challenges in NS-based drug delivery, particularly for oral, ocular, transdermal, pulmonary, and parenteral routes. The conversion of oral NS into powders, pellets, granules, tablets, and capsules, and their incorporation into film dosage forms to address stability concerns is thoroughly reviewed. This article summarizes key stabilizers, polymers, surfactants, and excipients used in NS formulations, along with ongoing clinical trials and recent patents. Furthermore, a comprehensive analysis of various methods for NS preparation is provided. This article also explores various in vitro and in vivo characterization techniques, as well as scale-down technologies and bottom-up methods for NS preparation. Selected examples of commercial NS drug products are discussed. Rapid advances in the field of NS could resolve issues related to permeability-limited absorption and hepatic first-pass metabolism, offering promise for medications based on proteins and peptides. The evolution of novel stabilizers is essential to overcome the current limitations in NS formulations, enhancing their stability, bioavailability, targeting ability, and safety profile, which ultimately accelerates their clinical application and commercialization. Full article
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14 pages, 915 KiB  
Article
Monitoring M-Protein, Therapeutic Antibodies, and Polyclonal Antibodies in a Multiparametric Mass Spectrometry Assay Provides Insight into Therapy Response Kinetics in Patients with Multiple Myeloma
by Charissa Wijnands, Peter G. A. Karel, Jolein Gloerich, Gad Armony, Anastasia Tzasta, Corrie M. de Kat Angelino, Luciano Di Stefano, Vincent Bonifay, Theo M. Luider, Martijn M. VanDuijn, Sandra J. Croockewit, Elizabeth A. de Kort, Daan A. R. Castelijn, Claudia A. M. Stege, Hans J. C. T. Wessels, Alain J. van Gool, Niels W. C. J. van de Donk and Joannes F. M. Jacobs
Pharmaceutics 2025, 17(1), 135; https://doi.org/10.3390/pharmaceutics17010135 - 19 Jan 2025
Viewed by 1091
Abstract
Background/Objectives: Multiple Myeloma (MM) is a hematologic malignancy caused by clonally expanded plasma cells that produce a monoclonal immunoglobulin (M-protein), a personalized biomarker. Recently, we developed an ultra-sensitive mass spectrometry method to quantify minimal residual disease (MS-MRD) by targeting unique M-protein peptides. Therapeutic [...] Read more.
Background/Objectives: Multiple Myeloma (MM) is a hematologic malignancy caused by clonally expanded plasma cells that produce a monoclonal immunoglobulin (M-protein), a personalized biomarker. Recently, we developed an ultra-sensitive mass spectrometry method to quantify minimal residual disease (MS-MRD) by targeting unique M-protein peptides. Therapeutic antibodies (t-Abs), key in MM treatment, often lead to deep and long-lasting responses. However, t-Abs can significantly decrease the total polyclonal immunoglobulin (Ig) levels which require supplemental IgG infusion. Here, we demonstrate the simultaneous monitoring of M-proteins, t-Abs, and polyclonal Ig-titers using an untargeted mass spectrometry assay, offering a comprehensive view of therapy response. Methods: Sera collected between 2013 and 2024 from four patients and cerebrospinal fluid (CSF) from one patient who received various t-Abs were analyzed with MS-MRD. M-protein sequences were obtained with a multi-enzyme de novo protein sequencing approach. Unique peptides for M-proteins and t-Abs were selected based on linearity, sensitivity, and slope coefficient in serial dilutions. Ig constant regions were monitored using isotype-specific peptides. Results: The MS-MRD multiplex analysis provided detailed information on drug concentrations and therapy response kinetics. For example, in two patients with refractory disease over five lines of therapy, the MS-MRD analysis showed that the deepest responses were achieved with bispecific t-Ab (teclistamab) treatment. M-protein and t-Ab were also detectable in the CSF of one patient with MS-MRD. Conclusions: This proof-of-concept study shows that the multiplex monitoring of the M-protein, any t-Ab combination, and all Ig-isotypes within one mass spectrometry run is feasible and provides unique insight into therapy response kinetics. Full article
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30 pages, 2847 KiB  
Review
Resveratrol—A Promising Therapeutic Agent with Problematic Properties
by Lyubomira Radeva and Krassimira Yoncheva
Pharmaceutics 2025, 17(1), 134; https://doi.org/10.3390/pharmaceutics17010134 - 19 Jan 2025
Viewed by 1255
Abstract
Resveratrol is a natural polyphenol (stilbenoid), which can be found in grape skin, red wine, blueberries, peanuts and others. The biological properties of resveratrol, in particular antioxidant, anti-inflammatory, anticancer, estrogenic, vasorelaxant and cardioprotective activity, are the main reason for its importance in medicine [...] Read more.
Resveratrol is a natural polyphenol (stilbenoid), which can be found in grape skin, red wine, blueberries, peanuts and others. The biological properties of resveratrol, in particular antioxidant, anti-inflammatory, anticancer, estrogenic, vasorelaxant and cardioprotective activity, are the main reason for its importance in medicine and pharmacy. Despite all of its advantages, however, there are many problems related to this polyphenolic substance, such as low stability, water insolubility, poor bioavailability and fast metabolism. For this reason, scientists are currently searching for different approaches to dealing with these problematic properties and improving the therapeutic usage of resveratrol. This review summarizes the mechanisms of the biological effects of resveratrol, determined in vitro and in vivo, and the main limitations of the drug. The article emphasizes new approaches for the improvement of resveratrol delivery, in particular nanoencapsulation, formation of nanocrystals, prodrugs and structure analogues. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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20 pages, 5619 KiB  
Article
Alginate Hydrogel Beads with a Leakproof Gold Shell for Ultrasound-Triggered Release
by Marcus Flowers, Alex Paulsen, Claire R. W. Kaiser, Adam B. Tuma, Hubert H. Lim, Brenda M. Ogle and Chun Wang
Pharmaceutics 2025, 17(1), 133; https://doi.org/10.3390/pharmaceutics17010133 - 19 Jan 2025
Viewed by 491
Abstract
Background/Objectives: Focused ultrasound has advantages as an external stimulus for drug delivery as it is non-invasive, has high precision and can penetrate deep into tissues. Here, we report a gold-plated alginate (ALG) hydrogel system that retains highly water-soluble small-molecule fluorescein for sharp off/on [...] Read more.
Background/Objectives: Focused ultrasound has advantages as an external stimulus for drug delivery as it is non-invasive, has high precision and can penetrate deep into tissues. Here, we report a gold-plated alginate (ALG) hydrogel system that retains highly water-soluble small-molecule fluorescein for sharp off/on release after ultrasound exposure. Methods: The ALG is crosslinked into beads with calcium chloride and layered with a polycation to adjust the surface charge for the adsorption of catalytic platinum nanoparticles (Pt NPs). The coated bead is subject to electroless plating, forming a gold shell. Ultrasound is applied to the gold-plated ALG beads and the release of fluorescein with or without ultrasound stimulation is quantified. Results: Polyethylenimine (PEI), not poly-L-lysine (PLL), is able to facilitate Pt NP adsorption. Gold shell thickness is proportional to the duration of electroless plating and can be controlled. Gold-plated ALG beads are impermeable to the fluorescein cargo and have nearly zero leakage. Exposure to focused ultrasound initiated the release of fluorescein with full release achieved after 72 h. Conclusions: The gold-plated ALG hydrogel is a new material platform that can retain highly water-soluble molecules with a sharp off/on release initiated by focused ultrasound. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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21 pages, 2408 KiB  
Article
Chitosan Nanoparticles for Enhanced Immune Response and Delivery of Multi-Epitope Helicobacter pylori Vaccines in a BALB/c Mouse Model
by Rita Amaral, Tomás Concha, Jorge Vítor, António J. Almeida, Cecília Calado and Lídia M. Gonçalves
Pharmaceutics 2025, 17(1), 132; https://doi.org/10.3390/pharmaceutics17010132 - 18 Jan 2025
Viewed by 582
Abstract
Background/Objectives: Helicobacter pylori is the leading cause of chronic gastritis, peptic ulcer, gastric adenocarcinoma, and mucosal-associated lymphoma. Due to the emerging problems with antibiotic treatment against H. pylori in clinical practice, H. pylori vaccination has gained more interest. Oral immunization is considered [...] Read more.
Background/Objectives: Helicobacter pylori is the leading cause of chronic gastritis, peptic ulcer, gastric adenocarcinoma, and mucosal-associated lymphoma. Due to the emerging problems with antibiotic treatment against H. pylori in clinical practice, H. pylori vaccination has gained more interest. Oral immunization is considered a promising approach for preventing initial colonization of this bacterium in the gastrointestinal tract, establishing a first line of defense at gastric mucosal surfaces. Chitosan nanoparticles can be exploited effectively for oral vaccine delivery due to their stability, simplicity of target accessibility, and beneficial mucoadhesive and immunogenic properties. Methods: In this study, new multi-epitope pDNA- and recombinant protein-based vaccines incorporating multiple H. pylori antigens were produced and encapsulated in chitosan nanoparticles for oral and intramuscular administration. The induced immune response was assessed through the levels of antigen-specific IgGs, secreted mucosal SIgA, and cytokines (IL-2, IL-10, and IFN-γ) in immunized BALB/C mice. Results: Intramuscular administration of both pDNA and recombinant protein-based vaccines efficiently stimulated the production of specific IgG2a and IgG1, which was supported by cytokines levels. Oral immunizations with either pDNA or recombinant protein vaccines revealed high SIgA levels, suggesting effective gastric mucosal immunization, contrasting with intramuscular immunizations, which did not induce SIgA. Conclusions: These findings indicate that both pDNA and recombinant protein vaccines encapsulated into chitosan nanoparticles are promising candidates for eradicating H. pylori and mitigating associated gastric diseases in humans. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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21 pages, 5046 KiB  
Article
Spermine Significantly Increases the Transfection Efficiency of Cationic Polymeric Gene Vectors
by Yue Lv, Jiaoqin Xue, Pengfei Cui and Lin Qiu
Pharmaceutics 2025, 17(1), 131; https://doi.org/10.3390/pharmaceutics17010131 - 17 Jan 2025
Viewed by 551
Abstract
Background/Objectives: Non-viral vectors have gained recognition for their ability to enhance the safety of gene delivery processes. Among these, polyethyleneimine (PEI) stands out as the most widely utilized cationic polymer due to its accessibility. Traditional methods of modifying PEI, such as ligand conjugation, [...] Read more.
Background/Objectives: Non-viral vectors have gained recognition for their ability to enhance the safety of gene delivery processes. Among these, polyethyleneimine (PEI) stands out as the most widely utilized cationic polymer due to its accessibility. Traditional methods of modifying PEI, such as ligand conjugation, chemical derivatization, and cross-linking, are associated with intricate preparation procedures, limited transfection efficiency, and suboptimal biocompatibility. Methods: In this investigation, enhanced transfection efficiency was achieved through the straightforward physical blending of PEI carriers with spermine. Results: Transfection assays explored the maximal enhancement potential conferred by spermine, alongside further methodological refinements aimed at optimizing transfection efficacy, showcasing a potential increase of up to 40.7%. Through the comparison of different addition sequences of spermine, the optimal complex PEI/Spermine/DNA for transfection efficiency was selected. Characterization of PEI/Spermine/DNA revealed that, compared to PEI/DNA, its particle size increased to approximately 150 nm. Molecular dynamics simulation results revealed that spermine can enhance the interaction between PEI and DNA, thereby forming a system with lower energy and greater stability. Mechanistic inquiries studies also disclosed that spermine augments the endosomal escape capability of PEI carriers without altering pathways involved in the cellular uptake of gene nanoparticles, thereby facilitating heightened gene expression. Conclusions: PEI-Sper emerges as a promising non-viral vector for gene delivery, distinguished by its simplicity in preparation, cost-effectiveness, and superior transfection efficiency. Full article
(This article belongs to the Section Gene and Cell Therapy)
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20 pages, 5063 KiB  
Article
Polymer-Free Electrospinning of β-Cyclodextrin–Oligolactide for Magnolol and Honokiol Pharmaceutical Formulations
by Diana-Andreea Blaj, Catalina A. Peptu, Mihaela Balan-Porcarasu, Cristian Peptu, Cristina Gabriela Tuchilus and Lacramioara Ochiuz
Pharmaceutics 2025, 17(1), 130; https://doi.org/10.3390/pharmaceutics17010130 - 17 Jan 2025
Viewed by 565
Abstract
Background: Magnolol (MG) and honokiol (HK) are bioactive compounds extracted from Magnolia obovata and Magnolia Officinalis trees with significant pharmacological properties, including antioxidant and antibacterial activity. However, their poor water solubility and low bioavailability limit the therapeutic potential. Methods: To address these limitations, [...] Read more.
Background: Magnolol (MG) and honokiol (HK) are bioactive compounds extracted from Magnolia obovata and Magnolia Officinalis trees with significant pharmacological properties, including antioxidant and antibacterial activity. However, their poor water solubility and low bioavailability limit the therapeutic potential. Methods: To address these limitations, this study aims to develop MG and HK formulations by co-electrospinning using custom-synthesized β-cyclodextrin–oligolactide (β-CDLA) derivatives. MALDI MS and NMR were employed for the structural assessment of the β-CDLA derivatives. This polymer-free electrospinning technique utilizes the high solubility of β-CDLA to incorporate MG and HK into fibrous webs. The morphology of the resulting fibers is established by SEM and further characterized using FTIR and NMR spectroscopy to confirm the successful incorporation of MG and HK. The antioxidant activity was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, while the antimicrobial activity was evaluated against several standard microorganisms (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans). Results: The MG and HK electrospun formulations were prepared using highly concentrated feed solutions in dimethylformamide (180% w/v). The resulting β-CDLA fibers, with diameters above 400 nm and an active compound content of 7% wt., exhibited enhanced long-term antioxidant activity and improved antimicrobial efficacy, including notable activity against Escherichia coli. Conclusions: This study demonstrates the potential of MG and HK-loaded β-CDLA fibrous formulations as delivery systems with prolonged antioxidant activity and notable antibacterial efficacy, providing a promising platform for biomedical applications. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Pharmaceutical Applications)
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12 pages, 1987 KiB  
Article
Prilling as an Effective Tool for Manufacturing Submicrometric and Nanometric PLGA Particles for Controlled Drug Delivery to Wounds: Stability and Curcumin Release
by Chiara De Soricellis, Chiara Amante, Paola Russo, Rita Patrizia Aquino and Pasquale Del Gaudio
Pharmaceutics 2025, 17(1), 129; https://doi.org/10.3390/pharmaceutics17010129 - 17 Jan 2025
Viewed by 626
Abstract
Background/Objectives: This study investigates for the first time the use of the prilling technique in combination with solvent evaporation to produce nano- and submicrometric PLGA particles to deliver properly an active pharmaceutical ingredient. Curcumin (CCM), a hydrophobic compound classified under BCS (Biopharmaceutics Classification [...] Read more.
Background/Objectives: This study investigates for the first time the use of the prilling technique in combination with solvent evaporation to produce nano- and submicrometric PLGA particles to deliver properly an active pharmaceutical ingredient. Curcumin (CCM), a hydrophobic compound classified under BCS (Biopharmaceutics Classification System) class IV, was selected as the model drug. Methods: Key process parameters, including polymer concentration, solvent type, nozzle size, and surfactant levels, were optimized to obtain stable particles with a narrow size distribution determined by DLS analysis. Results: Particles mean diameter (d50) 316 and 452 nm, depending on drug-loaded cargo as Curcumin-loaded PLGA nanoparticles demonstrated high encapsulation efficiency, assessed via HPLC analysis, stability, and controlled release profiles. In vitro studies revealed a faster release for lower drug loadings (90% release in 6 h) compared to sustained release over 7 days for higher-loaded nanoparticles, attributed to polymer degradation and drug-polymer interactions on the surface of the particles, as confirmed by FTIR analyses. Conclusions: These findings underline the potential of this scalable technique for biomedical applications, offering a versatile platform for designing drug delivery systems with tailored release characteristics. Full article
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48 pages, 3257 KiB  
Review
Evolution of Alzheimer’s Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy
by Emma Ortiz-Islas, Pedro Montes, Citlali Ekaterina Rodríguez-Pérez, Elizabeth Ruiz-Sánchez, Talía Sánchez-Barbosa, Diego Pichardo-Rojas, Cecilia Zavala-Tecuapetla, Karla Carvajal-Aguilera and Victoria Campos-Peña
Pharmaceutics 2025, 17(1), 128; https://doi.org/10.3390/pharmaceutics17010128 - 17 Jan 2025
Viewed by 1104
Abstract
Alzheimer’s disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently [...] Read more.
Alzheimer’s disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer’s disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions. Full article
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15 pages, 1664 KiB  
Article
Nanoparticle-in-Hydrogel Delivery System for the Sequential Release of Two Drugs
by Demian van Straten, Jaime Fernández Bimbo, Wim E. Hennink, Tina Vermonden and Raymond M. Schiffelers
Pharmaceutics 2025, 17(1), 127; https://doi.org/10.3390/pharmaceutics17010127 - 17 Jan 2025
Viewed by 761
Abstract
Background/Objectives: Glioblastoma is the most common and lethal primary brain tumor. Patients often suffer from tumor- and treatment induced vasogenic edema, with devastating neurological consequences. Intracranial edema is effectively treated with dexamethasone. However, systemic dexamethasone requires large doses to surpass the blood brain [...] Read more.
Background/Objectives: Glioblastoma is the most common and lethal primary brain tumor. Patients often suffer from tumor- and treatment induced vasogenic edema, with devastating neurological consequences. Intracranial edema is effectively treated with dexamethasone. However, systemic dexamethasone requires large doses to surpass the blood brain barrier in therapeutic quantities, which is associated with significant side effects. The aim of this study was to investigate a biodegradable, dextran-hydroxyethyl methacrylate (dex-HEMA) based hydrogel, containing polymeric micelles loaded with dexamethasone and liposomes encapsulating dexamethasone phosphate for localized and prolonged delivery. Methods: Poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide (mPEG-b-p(HPMA-Bz)) micelles were loaded with dexamethasone and characterized. The dexamethasone micelles, together with dexamethasone phosphate liposomes, were dispersed in an aqueous dex-HEMA solution followed by radical polymerization using a photoinitiator in combination with light. The kinetics and mechanisms of drug release from this hydrogel were determined. Results: The diameter of the nanoparticles was larger than the mesh size of the hydrogel, rendering them immobilized in the polymer network. The micelles immediately released free dexamethasone from the hydrogel for two weeks. The dexamethasone phosphate loaded in the liposomes was not released until the gel degraded and intact liposomes were released, starting after 15 days. The different modes of release result in a biphasic and sequential release profile of dexamethasone followed by dexamethasone phosphate liposomes. Conclusions: The results show that this hydrogel system loaded with both dexamethasone polymeric micelles and dexamethasone phosphate loaded liposomes has potential as a local delivery platform for the sequential release of dexamethasone and dexamethasone phosphate, for the intracranial treatment of glioblastoma associated edema. Full article
(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)
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2 pages, 452 KiB  
Correction
Correction: Razzaq et al. Development of Cephradine-Loaded Gelatin/Polyvinyl Alcohol Electrospun Nanofibers for Effective Diabetic Wound Healing: In-Vitro and In-Vivo Assessments. Pharmaceutics 2021, 13, 349
by Anam Razzaq, Zaheer Ullah Khan, Aasim Saeed, Kiramat Ali Shah, Naveed Ullah Khan, Bouzid Menaa, Haroon Iqbal and Farid Menaa
Pharmaceutics 2025, 17(1), 126; https://doi.org/10.3390/pharmaceutics17010126 - 17 Jan 2025
Viewed by 346
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)
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14 pages, 1503 KiB  
Article
Synergistic Antifungal Activity of Terbinafine in Combination with Light-Activated Gelatin–Silver Nanoparticles Against Candida albicans Strains
by Atif Ullah, Fawad Ali, Farman Ullah, Sajid Khan Sadozai, Saeed Ahmed Khan, Sajid Hussain, Abdulwahed Fahad Alrefaei and Sajid Ali
Pharmaceutics 2025, 17(1), 125; https://doi.org/10.3390/pharmaceutics17010125 - 17 Jan 2025
Viewed by 576
Abstract
The development of resistance to traditional antifungal therapies has necessitated the exploration of alternative treatment strategies to effectively manage fungal infections, particularly those induced by Candida albicans (C. albicans). This research investigates the possibility of integrating silver nanoparticles (AgNPs) with Terbinafine [...] Read more.
The development of resistance to traditional antifungal therapies has necessitated the exploration of alternative treatment strategies to effectively manage fungal infections, particularly those induced by Candida albicans (C. albicans). This research investigates the possibility of integrating silver nanoparticles (AgNPs) with Terbinafine to improve antifungal effectiveness. Terbinafine, while potent, faces challenges with specific fungal strains, highlighting the need for strategies to enhance its treatment efficacy. Silver nanoparticles were produced through a light-activated, gelatin-based method, resulting in particle sizes ranging from 56.8 nm to 66.2 nm, confirmed by dynamic light scattering and scanning electron microscopy. Stability studies indicated that AgNPs produced with 30 mg of silver nitrate (AgNO₃) exhibited the greatest stability over 60 days across different temperature conditions. The analysis through UV-visible spectrophotometry revealed a notable shift in the absorption spectra as AgNO₃ concentrations increased, which was associated with a strengthening of plasmon resonance. The effectiveness of the AgNPs and Terbinafine combination was assessed against three strains of C. albicans (ATCC 10231, ATCC 90028, and ATCC 18804). Terbinafine demonstrated strong antifungal properties with minimum inhibitory concentrations (MIC) values ranging from 2–4 µg/mL, whereas AgNPs on their own displayed moderate effectiveness. The integrated formulation notably enhanced effectiveness, especially against strain ATCC 90028, revealing a synergistic effect (FIFi = 0.369). These results were complemented by the findings of the time-to-kill assay, where the same strain showed a 3.2 log₁₀ CFU/mL decrease in viable cell count. The process by which AgNPs boost activity entails the disruption of the fungal cell membrane and its internal components, probably as a result of silver ion release and the generation of free radicals. The results indicate that the combination of Terbinafine and AgNPs may act as a powerful alternative for addressing resistant fungal infections, presenting an encouraging direction for future antifungal treatments. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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14 pages, 2787 KiB  
Review
What Is the Optimal Geometry of Dissolving Microneedle Arrays? A Literature Review
by Maira Visscher, Henderik W. Frijlink and Wouter L. J. Hinrichs
Pharmaceutics 2025, 17(1), 124; https://doi.org/10.3390/pharmaceutics17010124 - 17 Jan 2025
Viewed by 557
Abstract
The application of dissolving microneedle arrays (DMNAs) is an emerging trend in drug and vaccine delivery as an alternative for hypodermic needles or other less convenient drug administration methods. The major benefits include, amongst others, that no trained healthcare personnel is required and [...] Read more.
The application of dissolving microneedle arrays (DMNAs) is an emerging trend in drug and vaccine delivery as an alternative for hypodermic needles or other less convenient drug administration methods. The major benefits include, amongst others, that no trained healthcare personnel is required and that the recipient experiences hardly any pain during administration. However, for a successful drug or vaccine delivery from the DMNA, the microneedles should be inserted intact into the skin. A successful penetration into the upper skin layers may be challenging because of the elastic nature of the skin; therefore, a minimum insertion force is required to overcome the total resistance force of the skin. In addition, the microneedles need to stay intact, which requires a certain mechanical strength, and be able to resist the required insertion force. In addition to the type of material with which the DMNAs are produced, the geometry of the DMNAs will also have a profound effect, not only on the mechanical strength but also on the number of insertions and penetration depth into the skin. In this review, the effects of shape, aspect ratio, length, width of the base, tip diameter and angle, and spacing of DMNAs on the aforementioned effect parameters were evaluated to answer the following question: ‘What is the optimal geometry of dissolving microneedle arrays?’. Full article
(This article belongs to the Special Issue Emerging Trends in Skin Delivery Systems)
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22 pages, 8473 KiB  
Article
Bilosomal Co-Encapsulated Tamoxifen and Propranolol for Potentiated Anti-Breast Cancer Efficacy: In Vitro and In Vivo Investigation
by Toka T. Elebyary, Amal A. Sultan, Sally E. Abu-Risha, Gamal M. El Maghraby and Manna Amin
Pharmaceutics 2025, 17(1), 123; https://doi.org/10.3390/pharmaceutics17010123 - 17 Jan 2025
Viewed by 487
Abstract
Background/Objectives: Tamoxifen (TAM) is an anti-breast cancer drug suffering from acquired resistance development, prompting cancer relapse. Propranolol (PRO)’s repurposing for cancer therapy has gained interest. This work aimed to investigate combined TAM/PRO therapy for potentiating the anti-breast cancer activity of TAM. The [...] Read more.
Background/Objectives: Tamoxifen (TAM) is an anti-breast cancer drug suffering from acquired resistance development, prompting cancer relapse. Propranolol (PRO)’s repurposing for cancer therapy has gained interest. This work aimed to investigate combined TAM/PRO therapy for potentiating the anti-breast cancer activity of TAM. The work probed bilosomes versus standard noisome for simultaneous oral and intratumor delivery of TAM and PRO. Methods: Bilosomes comprising Span60, cholesterol, and increasing concentrations of bile salts were prepared together with bile salts containing free standard niosomes. The vesicular size and morphology were characterized. The entrapment and release efficiencies of TAM and PRO from the tailored vesicles were determined. The in vivo investigations of anti-tumor activity of TAM with or without PRO employed the solid Ehrlich carcinoma model. Results: The vesicles of all fabricated dispersions were spherical and negatively charged, with a size ranging from 104 to 182 nm. The entrapment efficiency depended on the nature of the drug, recording values ranging from 87.5% to 97.8% for TAM and from 31.0% to 46.8% for PRO. Incorporation of bile salts into vesicles increased TAM and PRO release compared to standard niosomes. Oral administration of combined TAM/PRO bilosomes showed a significant reduction in tumor growth volume compared to that recorded following naked drug administration. Histopathological investigations reflected a significant decline in tumor giant cells and mitotic figures, implying the in vivo capability of the TAM/PRO combination to interfere with cancer cell proliferation and persistence. Conclusions: The overall results demonstrated the impact of repurposed PRO to enhance the anti-breast cancer activity of TAM when both were co-encapsulated into bilosomes. Full article
(This article belongs to the Special Issue Lipid-Based Nanoparticles for Drug Delivery in Cancer)
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15 pages, 3782 KiB  
Article
Development of Spray-Dried Micelles, Liposomes, and Solid Lipid Nanoparticles for Enhanced Stability
by Shradha Dattani, Xiaoling Li, Charina Lampa, Amanda Barriscale, Behzad Damadzadeh, David Lechuga-Ballesteros and Bhaskara R. Jasti
Pharmaceutics 2025, 17(1), 122; https://doi.org/10.3390/pharmaceutics17010122 - 17 Jan 2025
Viewed by 664
Abstract
Objectives: Micelles, liposomes, and solid lipid nanoparticles (SLNs) are promising drug delivery vehicles; however, poor aqueous stability requires post-processing drying methods for maintaining long-term stability. The objective of this study was to compare the potential of lipid-based micelles, liposomes, and SLNs for producing [...] Read more.
Objectives: Micelles, liposomes, and solid lipid nanoparticles (SLNs) are promising drug delivery vehicles; however, poor aqueous stability requires post-processing drying methods for maintaining long-term stability. The objective of this study was to compare the potential of lipid-based micelles, liposomes, and SLNs for producing stable re-dispersible spray-dried powders with trehalose or a combination of trehalose and L-leucine. This study provides novel insights into the implementation of spray drying as a technique to enhance long-term stability for these lipid-based nanocarriers. Methods: Aqueous dispersions of LDV-targeted micelles, liposomes, and SLNs loaded with paclitaxel (PTX) were converted into re-dispersible powders using spray drying. The physicochemical properties of the nanocarriers were determined via scanning electron microscopy (SEM), Karl Fischer titration, differential scanning calorimetry (DSC), and dynamic light scattering (DLS). Short-term stability of all nanocarrier formulations was compared by measuring particle size, polydispersity index (PDI), and paclitaxel retention over 7 days at room temperature and at 4 °C. Results: Paclitaxel-loaded micelles, liposomes, and SLN formulations were successfully converted into well-dispersed spray-dried powders with acceptable yields (71.5 to 83.5%), low moisture content (<2%), and high transition temperatures (95.1 to 100.8 °C). SEM images revealed differences in morphology, where nanocarriers spray-dried with trehalose or a combination of trehalose and L-leucine produced smooth or corrugated particle surfaces, respectively. Reconstituted spray-dried nanocarriers maintained their nanosize and paclitaxel content over 7 days at 4 °C. Conclusions: The results of this study demonstrate the potential for the development of spray-dried lipid-based nanocarriers for long-term stability. Full article
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52 pages, 8840 KiB  
Review
Advances in Drug Targeting, Drug Delivery, and Nanotechnology Applications: Therapeutic Significance in Cancer Treatment
by Fatih Ciftci, Ali Can Özarslan, İmran Cagri Kantarci, Aslihan Yelkenci, Ozlem Tavukcuoglu and Mansour Ghorbanpour
Pharmaceutics 2025, 17(1), 121; https://doi.org/10.3390/pharmaceutics17010121 - 16 Jan 2025
Viewed by 989
Abstract
In the 21st century, thanks to advances in biotechnology and developing pharmaceutical technology, significant progress is being made in effective drug design. Drug targeting aims to ensure that the drug acts only in the pathological area; it is defined as the ability to [...] Read more.
In the 21st century, thanks to advances in biotechnology and developing pharmaceutical technology, significant progress is being made in effective drug design. Drug targeting aims to ensure that the drug acts only in the pathological area; it is defined as the ability to accumulate selectively and quantitatively in the target tissue or organ, regardless of the chemical structure of the active drug substance and the method of administration. With drug targeting, conventional, biotechnological and gene-derived drugs target the body’s organs, tissues, and cells that can be selectively transported to specific regions. These systems serve as drug carriers and regulate the timing of release. Despite having many advantageous features, these systems have limitations in thoroughly treating complex diseases such as cancer. Therefore, combining these systems with nanoparticle technologies is imperative to treat cancer at both local and systemic levels effectively. The nanocarrier-based drug delivery method involves encapsulating target-specific drug molecules into polymeric or vesicular systems. Various drug delivery systems (DDS) were investigated and discussed in this review article. The first part discussed active and passive delivery systems, hydrogels, thermoplastics, microdevices and transdermal-based drug delivery systems. The second part discussed drug carrier systems in nanobiotechnology (carbon nanotubes, nanoparticles, coated, pegylated, solid lipid nanoparticles and smart polymeric nanogels). In the third part, drug targeting advantages were discussed, and finally, market research of commercial drugs used in cancer nanotechnological approaches was included. Full article
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17 pages, 15496 KiB  
Article
A Finite Element Method for Modeling Diffusion and Drug Release from Nanocellulose/Nanoporous Silicon Composites
by Paulo Zúñiga, Marcelo Aravena, Silvia Ponce and Jacobo Hernandez-Montelongo
Pharmaceutics 2025, 17(1), 120; https://doi.org/10.3390/pharmaceutics17010120 - 16 Jan 2025
Viewed by 621
Abstract
Background and Objective: A previous study investigated the in vitro release of methylene blue (MB), a widely used cationic dye in biomedical applications, from nanocellulose/nanoporous silicon (NC/nPSi) composites under conditions simulating body fluids. The results showed that MB release rates varied significantly [...] Read more.
Background and Objective: A previous study investigated the in vitro release of methylene blue (MB), a widely used cationic dye in biomedical applications, from nanocellulose/nanoporous silicon (NC/nPSi) composites under conditions simulating body fluids. The results showed that MB release rates varied significantly with the nPSi concentration in the composite, highlighting its potential for controlled drug delivery. To further analyze the relationship between diffusion dynamics and the MB concentration, this study developed a finite element (FE) method to solve Fick’s equations governing the drug delivery system. Methods: Release profiles of MB from NC/nPSi composites with varying nPSi concentrations (0%, 0.1%, 0.5%, and 1.0%) were experimentally measured in triplicate using phosphate-buffered saline (PBS) at 37 °C, pH 7.4, and 100 rpm. Mathematical models incorporating linear and quadratic dependencies of the diffusion coefficient on the MB concentration were developed and tested using the FE method. Model parameters were refined by minimizing the error between simulated and experimental MB release profiles. Results: The proposed FE method closely matched experimental data, validating its accuracy and robustness in simulating the diffusion and release processes. Conclusions: This study emphasizes the significant impact of the nPSi concentration on enhancing release control and highlights the importance of material composition in designing drug delivery systems. The findings suggest that the FE method can be effectively applied to model other complex systems, paving the way for advancements in precision drug delivery and broader biomedical applications. Full article
(This article belongs to the Special Issue Mathematical Modeling in Drug Delivery)
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37 pages, 67526 KiB  
Article
Stable Gastric Pentadecapeptide BPC 157 as Therapy After Surgical Detachment of the Quadriceps Muscle from Its Attachments for Muscle-to-Bone Reattachment in Rats
by Danijel Matek, Irena Matek, Eva Staresinic, Mladen Japjec, Ivan Bojanic, Alenka Boban Blagaic, Lidija Beketic Oreskovic, Ivana Oreskovic, Tihomil Ziger, Tomislav Novinscak, Ivan Krezic, Sanja Strbe, Martin Drinkovic, Filip Brkic, Jelena Popic, Anita Skrtic, Sven Seiwerth, Mario Staresinic, Predrag Sikiric and Ivica Brizic
Pharmaceutics 2025, 17(1), 119; https://doi.org/10.3390/pharmaceutics17010119 - 16 Jan 2025
Viewed by 618
Abstract
Background: This is a novel rat study using native peptide therapy, focused on reversing quadriceps muscle-to-bone detachment to reattachment and stable gastric pentadecapeptide BPC 157 per-oral therapy for shared muscle healing and function restoration. Methods: Pharmacotherapy recovering various muscle, tendon, ligament, and bone [...] Read more.
Background: This is a novel rat study using native peptide therapy, focused on reversing quadriceps muscle-to-bone detachment to reattachment and stable gastric pentadecapeptide BPC 157 per-oral therapy for shared muscle healing and function restoration. Methods: Pharmacotherapy recovering various muscle, tendon, ligament, and bone lesions, and severed junctions (i.e., myotendinous junction), per-oral in particular (BPC 157/kg/day 10 µg, 10 ng), provides muscle-to-bone reattachment after quadriceps muscle detachment, both complete (rectus muscle) and partial (vastus muscles). Results: Immediately post-injury, and at 1, 2, 3, 5, 7, 14, 21, 28, 60, and 90 days post-injury, quadriceps muscle-to-bone detachment showed definitive healing failure (impaired walking and permanent knee flexure). Contrarily, macro/microscopic, ultrasonic, magnetic resonance, biomechanical, and functional assessments revealed that BPC 157 therapy recovering effects for all time points were consistent. All parameters of the walking pattern fully improved, and soon after detachment and therapy application, muscle approached the bone, leaving a minimal gap (on ultrasonic assessment), and leg contracture was annihilated. The healing process occurs immediately after detachment from both sides: the muscle and the bone. The reattachment fibers from the ends of the muscle could be traced into the new bone formed at the surface (note, at day 3 post-detachment, increased mesenchymal cells occurred with periosteum reactivation). Consequently, at 3 months, the form was stable, and the balance between the muscle and bone was the following: well-organized bone, newly formed as more cortical bone providing a narrower bone marrow space, and the muscle and mature fibers were oriented parallel to the bone axis and were in close contact with bone. Conclusions: Therefore, to achieve quadriceps muscle-to-bone reattachment, the BPC 157 therapy reversing course acts from the beginning, resolving an otherwise insurmountable deleterious course. Full article
(This article belongs to the Topic Peptoids and Peptide Based Drugs)
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16 pages, 288 KiB  
Review
Water-Soluble Vitamins: Hypo- and Hypervitaminosis in Pediatric Population
by Roberto Paparella, Fabiola Panvino, Lucia Leonardi, Ida Pucarelli, Michela Menghi, Ginevra Micangeli, Francesca Tarani, Marcello Niceta, Debora Rasio, Rouzha Pancheva, Marco Fiore and Luigi Tarani
Pharmaceutics 2025, 17(1), 118; https://doi.org/10.3390/pharmaceutics17010118 - 16 Jan 2025
Viewed by 607
Abstract
Background/Objectives: Water-soluble vitamins, comprising the B-complex vitamins and vitamin C, are essential for normal growth, cellular metabolism, and immune function in pediatric populations. Due to limited storage in the body, these vitamins require consistent intake to prevent deficiencies. Pediatric populations, particularly infants and [...] Read more.
Background/Objectives: Water-soluble vitamins, comprising the B-complex vitamins and vitamin C, are essential for normal growth, cellular metabolism, and immune function in pediatric populations. Due to limited storage in the body, these vitamins require consistent intake to prevent deficiencies. Pediatric populations, particularly infants and young children, face a heightened risk of both deficiency and, in rare cases, toxicity due to varying dietary intake and increased developmental needs. This review explores the clinical importance of water-soluble vitamins, focusing on hypo- and hypervitaminosis in children. Methods: A narrative review of the recent literature on the sources, recommended intakes, deficiency symptoms, and potential toxicities associated with each water-soluble vitamin was conducted. Results: Deficiencies in water-soluble vitamins can lead to diverse clinical outcomes, such as neurological, hematological, and immune-related symptoms, depending on the specific vitamin involved. Pediatric populations with increased nutritional needs, such as those experiencing rapid growth or with malabsorption conditions, are particularly vulnerable to vitamin insufficiencies. Conversely, although uncommon, excessive intake of certain water-soluble vitamins may cause mild toxicity, primarily gastrointestinal or neurological. Conclusions: Monitoring water-soluble vitamin levels and providing tailored nutritional support are critical to prevent the adverse effects of hypo- and hypervitaminosis in children. Further research is needed to refine pediatric nutritional guidelines and address the specific needs of young patients, supporting optimal health outcomes. Full article
(This article belongs to the Section Clinical Pharmaceutics)
51 pages, 16764 KiB  
Review
Synthesis of Arginase Inhibitors: An Overview
by Maria Cristina Molaro, Chiara Battisegola, Marica Erminia Schiano, Mariacristina Failla, Maria Grazia Rimoli, Loretta Lazzarato, Konstantin Chegaev and Federica Sodano
Pharmaceutics 2025, 17(1), 117; https://doi.org/10.3390/pharmaceutics17010117 - 16 Jan 2025
Viewed by 581
Abstract
Arginase (ARG) is a binuclear manganese-containing metalloenzyme that can convert L-arginine to L-ornithine and urea and plays a key role in the urea cycle. It also mediates different cellular functions and processes such as proliferation, senescence, apoptosis, autophagy, and inflammatory responses in various [...] Read more.
Arginase (ARG) is a binuclear manganese-containing metalloenzyme that can convert L-arginine to L-ornithine and urea and plays a key role in the urea cycle. It also mediates different cellular functions and processes such as proliferation, senescence, apoptosis, autophagy, and inflammatory responses in various cell types. In mammals, there are two isoenzymes, ARG-1 and ARG-2; they are functionally similar, but their coding genes, tissue distribution, subcellular localization, and molecular regulation are distinct. In recent decades, the abnormal expression of ARG-1 or ARG-2 has been reported to be increasingly linked to a variety of diseases, including cardiovascular disease, inflammatory bowel disease, Alzheimer’s disease, and cancer. Therefore, considering the current relevance of this topic and the need to address the growing demand for new and more potent ARG inhibitors in the context of various diseases, this review was conceived. We will provide an overview of all classes of ARG inhibitors developed so far including compounds of synthetic, natural, and semisynthetic origin. For the first time, the synthesis protocol and optimized reaction conditions of each molecule, including those reported in patent applications, will be described. For each molecule, its inhibitory activity in terms of IC50 towards ARG-1 and ARG-2 will be reported specifying the type of assay conducted. Full article
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24 pages, 12125 KiB  
Article
Amphotericin B Encapsulation in Polymeric Nanoparticles: Toxicity Insights via Cells and Zebrafish Embryo Testing
by Magno Maciel-Magalhães, Renata Jurema Medeiros, Nayara Cecília do Couto Guedes, Thais Morais de Brito, Gabriele Fátima de Souza, Beatriz Rodrigues Canabarro, Fausto Klabund Ferraris, Fábio Coelho Amendoeira, Helvécio Vinicius Antunes Rocha, Beatriz Ferreira de Carvalho Patricio and Isabella Fernandes Delgado
Pharmaceutics 2025, 17(1), 116; https://doi.org/10.3390/pharmaceutics17010116 - 16 Jan 2025
Viewed by 777
Abstract
Background: Amphotericin B (AmB) is a commonly utilized antifungal agent, which is also recommended for the treatment of certain neglected tropical diseases, including leishmaniasis. However, its clinical application is constrained because of its poor oral bioavailability and adverse effects, prompting the investigation of [...] Read more.
Background: Amphotericin B (AmB) is a commonly utilized antifungal agent, which is also recommended for the treatment of certain neglected tropical diseases, including leishmaniasis. However, its clinical application is constrained because of its poor oral bioavailability and adverse effects, prompting the investigation of alternative drug delivery systems. Polymeric nanoparticles (PNPs) have gained attention as a potential drug delivery vehicle, providing advantages such as sustained release and enhanced bioavailability, and could have potential as AmB carriers. However, concerns persist regarding nanomaterials’ toxicity, requiring more studies. Zebrafish (Danio rerio) embryos were used as a valuable model for toxicity testing, especially because of their genetic similarity to humans and standardized developmental assessments. Methods: In this study, we produced and characterized AmB loaded and non-loaded PNPs by nanoprecipitation, dynamic light scattering, transmission electron microscopy, atomic force microscopy and spectroscopy. Afterwards, we verified their toxicity through in vitro MTT assays in three cell lines (HEK293, HepG2, and J774 A1) and in vivo tests with zebrafish embryos. Results: In both trials, it was noted that nanoencapsulation of the drug led to increased toxicity when compared to non-encapsulated AmB, possibly indicating that they penetrated the embryo’s chorion. Nevertheless, it was demonstrated that the polymers used are safe and they are not the cause of toxicity, neither are the nanostructures per se. Conclusions: Therefore, it is believed that the objective of improving the bioavailability of AmB may have been achieved, and the observed toxicity was probably linked to AmB’s ability to destabilize cell membranes. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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18 pages, 2786 KiB  
Article
Revisiting the Metabolism of Donepezil in Rats Using Non-Targeted Metabolomics and Molecular Networking
by Eun-Ji Park, Eui-Hyeon Kim, Ki-Young Kim, Ji-Hyeon Jeon, Im-Sook Song, So-Young Park and Kwang-Hyeon Liu
Pharmaceutics 2025, 17(1), 115; https://doi.org/10.3390/pharmaceutics17010115 - 15 Jan 2025
Viewed by 571
Abstract
Background/Objectives: Although donepezil, a reversible acetylcholinesterase inhibitor, has been in use since 1996, its metabolic characteristics remain poorly characterized. Therefore, this study aims to investigate the in vivo metabolism of donepezil using liquid chromatography–high-resolution mass spectrometry (LC-HRMS) based on a molecular networking [...] Read more.
Background/Objectives: Although donepezil, a reversible acetylcholinesterase inhibitor, has been in use since 1996, its metabolic characteristics remain poorly characterized. Therefore, this study aims to investigate the in vivo metabolism of donepezil using liquid chromatography–high-resolution mass spectrometry (LC-HRMS) based on a molecular networking (MN) approach integrated with a non-targeted metabolomics approach. Methods: After the oral administration of donepezil (30 mg/kg) in rats, urine, feces, and liver samples were collected for LC-HRMS analysis. Chromatographic and spectrometric data were processed through MN and multivariate data analysis to identify the in vivo metabolites of donepezil. Results: A total of 50 metabolites were characterized, including 23 newly identified metabolites. Donepezil was biotransformed by O-demethylation, N-debenzylation, and hydroxylation, and these metabolites are further conjugated with glucuronic acid and sulfurous acid. N-Desbenzyldonepezil (M4), didesmethyldonepezil (M5), and N-desbenzyldonepezil (M4) were identified as the most abundant metabolites in urine, feces, and liver samples, respectively. Conclusions: The metabolic characteristics of donepezil in rats were comparable to those in humans, indicating that a rat is a reliable model for studying donepezil metabolism. This study indicates that a MN approach combined with a metabolomics approach is a reliable tool to identify unknown metabolites of drugs and drug candidates. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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42 pages, 7869 KiB  
Review
Curcumin-Based Nanoparticles: Advancements and Challenges in Tumor Therapy
by Hicham Wahnou, Riad El Kebbaj, Bertrand Liagre, Vincent Sol, Youness Limami and Raphaël Emmanuel Duval
Pharmaceutics 2025, 17(1), 114; https://doi.org/10.3390/pharmaceutics17010114 - 15 Jan 2025
Viewed by 884
Abstract
Curcumin, a bioactive compound derived from the rhizome of Curcuma longa L., has garnered significant attention for its potent anticancer properties. Despite its promising therapeutic potential, its poor bioavailability, rapid metabolism, and low water solubility hinder curcumin’s clinical application. Nanotechnology offers a viable [...] Read more.
Curcumin, a bioactive compound derived from the rhizome of Curcuma longa L., has garnered significant attention for its potent anticancer properties. Despite its promising therapeutic potential, its poor bioavailability, rapid metabolism, and low water solubility hinder curcumin’s clinical application. Nanotechnology offers a viable solution to these challenges by enabling the development of curcumin-based nanoparticles (CNPs) that enhance its bioavailability and therapeutic efficacy. This review provides a comprehensive overview of the recent advancements in the design and synthesis of CNPs for cancer therapy. We discuss various NP formulations, including polymeric, lipid-based, and inorganic nanoparticles, highlighting their role in improving curcumin’s pharmacokinetic and pharmacodynamic profiles. The mechanisms by which CNPs exert anticancer effects, such as inducing apoptosis, inhibiting cell proliferation, and modulating signaling pathways, are explored in details. Furthermore, we examine the preclinical and clinical studies that have demonstrated the efficacy of CNPs in treating different types of tumors, including breast, colorectal, and pancreatic cancers. Finally, the review addresses the current challenges and future perspectives in the clinical translation of CNPs, emphasizing the need for further research to optimize their design for targeted delivery and to enhance their therapeutic outcomes. By synthesizing the latest research, this review underscores the potential of CNPs as a promising avenue for advancing cancer therapy. Full article
(This article belongs to the Special Issue Advances in Anticancer Agent, 2nd Edition)
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11 pages, 697 KiB  
Systematic Review
Investigations of Long-Acting Formulations in Children, Adolescents, and Pregnant Women: A Systematic Review
by Lynn Bertagnolli, Zhengyi Deng, Melissa Davy-Rothwell, Elaine J. Abrams, Charles Flexner and Ethel D. Weld
Pharmaceutics 2025, 17(1), 113; https://doi.org/10.3390/pharmaceutics17010113 - 15 Jan 2025
Viewed by 635
Abstract
Background/Objectives: Long-acting and extended-release drug delivery strategies have greatly improved treatment for a variety of medical conditions. Special populations, specifically infants, children, young people, and pregnant and postpartum women, could greatly benefit from access to these strategies but are often excluded from clinical [...] Read more.
Background/Objectives: Long-acting and extended-release drug delivery strategies have greatly improved treatment for a variety of medical conditions. Special populations, specifically infants, children, young people, and pregnant and postpartum women, could greatly benefit from access to these strategies but are often excluded from clinical trials. We conducted a systematic review of all clinical studies involving the use of a long-acting intramuscular injection or implant in infants, children, young people, and pregnant and postpartum people. Methods: Pubmed, Embase, and Cochrane Library trials were searched. Studies published from 1980 through 2018 were included. After abstract review and duplication removal, full-text articles were obtained for further review, reviewed by two independent reviewers, and disagreements were resolved by a third reviewer. Results: a total of 101 studies of long-acting therapeutics were completed in these populations, and most (80%) of these had a sample size of <100 individuals. Therapeutics for only a small pool of indications were examined in these studies, with 72% of the studies investigating hormonal contraception or other types of hormonal treatments. Only 9.3% of the studies in children and 16.7% of the studies in pregnant people collected any pharmacokinetic (PK) data. Conclusions: Long-acting formulations may behave differently (both pharmacokinetically and pharmacodynamically) in childhood, adolescence, and pregnancy as compared to non-pregnant adulthood. Therefore, it is imperative to increase and improve upon the studies investigating long-acting formulations in order to close the knowledge gap and improve care and treatment in these special populations. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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24 pages, 2695 KiB  
Article
Hybrid Nanocomposite Mini-Tablet to Be Applied into the Post-Extraction Socket: Matching the Potentialities of Resveratrol-Loaded Lipid Nanoparticles and Hydroxyapatite to Promote Alveolar Wound Healing
by Viviana De Caro, Giada Tranchida, Cecilia La Mantia, Bartolomeo Megna, Giuseppe Angellotti and Giulia Di Prima
Pharmaceutics 2025, 17(1), 112; https://doi.org/10.3390/pharmaceutics17010112 - 15 Jan 2025
Viewed by 730
Abstract
Background/Objectives: Following tooth extraction, resveratrol (RSV) can support healing by reducing inflammation and microbial risks, though its poor solubility limits its effectiveness. This study aims to develop a solid nanocomposite by embedding RSV in lipid nanoparticles (mLNP) within a hydrophilic matrix, to [...] Read more.
Background/Objectives: Following tooth extraction, resveratrol (RSV) can support healing by reducing inflammation and microbial risks, though its poor solubility limits its effectiveness. This study aims to develop a solid nanocomposite by embedding RSV in lipid nanoparticles (mLNP) within a hydrophilic matrix, to the scope of improving local delivery and enhancing healing. Hydroxyapatite (HXA), often used as a bone substitute, was added to prevent post-extraction alveolus volume reduction. Methods: The mLNP-RSV dispersion was mixed with seven different polymers in various mLNP/polymer ratios. Following freeze-drying, the powders were redispersed, and the resulting dispersions were tested by DLS experiments. Then, the best two nanocomposites underwent extensive characterization by SEM, XRD, FTIR, Raman spectroscopy, and thermal analysis as well as in vitro partitioning studies aimed at verifying their ability to yield the mLNP-RSV from the hydrophilic matrix to a lipophilic tissue. The characterizations led to identify the best nanocomposite, which was further combined with HXA to obtain hybrid nanocomposites, further evaluated as pharmaceutical powders or in form of mini-tablets. Results: PEG-based nanocomposites emerged as optimal and, following HXA insertion, the resulting powders revealed adequate bulk properties, making them useful as a pharmaceutical intermediate to produce ≈59 mm3 mini-tablets, compliant with the post-extraction socket. Moreover, they were proven ex vivo to be able to promote RSV and GA accumulation into the buccal tissue over time. Conclusions: The here-proposed mini-tablet offers an innovative therapeutic approach for alveolar wound healing promotion as they led to a standardized dose administration, while being handy and stable in terms of physical solid identity as long as it takes to suture the wound. Full article
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23 pages, 406 KiB  
Review
Pulmonary Delivery of Antibiotics to the Lungs: Current State and Future Prospects
by Yahya H. Dallal Bashi, Rachel Mairs, Rand Murtadha and Vicky Kett
Pharmaceutics 2025, 17(1), 111; https://doi.org/10.3390/pharmaceutics17010111 - 15 Jan 2025
Viewed by 1022
Abstract
This paper presents a comprehensive review of the current literature, clinical trials, and products approved for the delivery of antibiotics to the lungs. While there are many literature reports describing potential delivery systems, few of these have translated into marketed products. Key challenges [...] Read more.
This paper presents a comprehensive review of the current literature, clinical trials, and products approved for the delivery of antibiotics to the lungs. While there are many literature reports describing potential delivery systems, few of these have translated into marketed products. Key challenges remaining are the high doses required and, for powder formulations, the ability of the inhaler and powder combination to deliver the dose to the correct portion of the respiratory tract for maximum effect. Side effects, safety concerns, and disappointing clinical trial results remain barriers to regulatory approval. In this review, we describe some possible approaches to address these issues and highlight prospects in this area. Full article
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6 pages, 163 KiB  
Editorial
Nanotechnology-Based Drug Delivery Systems, 2nd Edition
by Andrey N. Kuskov and Ekaterina V. Kukovyakina
Pharmaceutics 2025, 17(1), 110; https://doi.org/10.3390/pharmaceutics17010110 - 15 Jan 2025
Viewed by 687
Abstract
Nanotechnology is a promising and rapidly developing area in the 21st century, which affects various fields of science: physics, chemistry, biology, engineering, microelectronics, and medicine [...] Full article
(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems, 2nd Edition)
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26 pages, 727 KiB  
Review
Targeting Brain Drug Delivery with Macromolecules Through Receptor-Mediated Transcytosis
by Yuanke Li, Ruiying Liu and Zhen Zhao
Pharmaceutics 2025, 17(1), 109; https://doi.org/10.3390/pharmaceutics17010109 - 15 Jan 2025
Viewed by 843
Abstract
Brain diseases pose significant treatment challenges due to the restrictive nature of the blood–brain barrier (BBB). Recent advances in targeting macromolecules offer promising avenues for overcoming these obstacles through receptor-mediated transcytosis (RMT). We summarize the current progress in targeting brain drug delivery with [...] Read more.
Brain diseases pose significant treatment challenges due to the restrictive nature of the blood–brain barrier (BBB). Recent advances in targeting macromolecules offer promising avenues for overcoming these obstacles through receptor-mediated transcytosis (RMT). We summarize the current progress in targeting brain drug delivery with macromolecules for brain diseases. This exploration details the transport mechanisms across the BBB, focusing on RMT and its use of natural ligands for drug delivery. Furthermore, the review examines macromolecular ligands such as antibodies, peptides, and aptamers that leverage RMT for effective BBB traversal. Advancements in macromolecules-based delivery systems for brain diseases are summarized, emphasizing their therapeutic potential and limitations. Finally, emerging RMT strategies, including viral vectors, exosomes, and boron neutron capture therapy, are discussed for their precision in brain-targeted treatments. This comprehensive overview underscores the potential of RMT-based approaches to revolutionize brain disease therapy. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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