Pharmaceutics

41 pages, 16493 KiB

Open AccessArticle

Anxiolytic and Antidepressant Effects of Organic Polysulfide, Dimethyl Trisulfide Are Partly Mediated by the Transient Receptor Potential Ankyrin 1 Ion Channel in Mice

by Kitti Göntér, Viktória Kormos, Erika Pintér and Gábor Pozsgai

Pharmaceutics 2025, 17(6), 781; https://doi.org/10.3390/pharmaceutics17060781 (registering DOI) - 14 Jun 2025

Abstract

Background/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has [...] Read more.

Background/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model involving three-week exposure, we examined the impact of DMTS on depression-like behaviour and anxiety and identified the involved brain regions. Methods: Our methods involved testing both Trpa1-wild-type and gene-knockout mice under CUMS conditions and DMTS treatment. DMTS was administered intraperitoneally at a dose of 30 mg/kg on days 16 and 20 of the 21-day CUMS protocol—in hourly injections seven times to ensure sustained exposure. Various behavioural assessments—including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests—were performed to evaluate anxiety and depression-like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB (FBJ murine osteosarcoma viral oncogene homolog B) immunohistochemistry was utilised to assess chronic neuronal activation in stress-relevant brain areas. Results: Results showed that CUMS induces depression-like behaviour, with the response being modulated by the TRPA1 status and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Conclusions: Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1-mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety. Full article

(This article belongs to the Section Drug Targeting and Design)

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16 pages, 1431 KiB

Open AccessArticle

Cenostigma bracteosum Hydroethanolic Extract: Chemical Profile, Antibacterial Activity, Cytotoxicity, and Gel Formulation Development

by Addison R. Almeida, Francisco A. S. D. Pinheiro, Marília G. M. Fideles, Roberto B. L. Cunha, Vitor P. P. Confessor, Kátia N. Matsui, Weslley S. Paiva, Hugo A. O. Rocha, Gislene Ganade, Laila S. Espindola, Waldenice A. Morais and Leandro S. Ferreira

Pharmaceutics 2025, 17(6), 780; https://doi.org/10.3390/pharmaceutics17060780 (registering DOI) - 14 Jun 2025

Abstract

Background:Cenostigma bracteosum (Tul.) Gagnon & G.P. Lewis (Fabaceae), popularly known as “catingueira”, is a plant widely distributed in the Caatinga biome, which comprises 11% of the Brazilian territory. While this species is of interest given local knowledge, formal reports are lacking in [...] Read more.

Background:Cenostigma bracteosum (Tul.) Gagnon & G.P. Lewis (Fabaceae), popularly known as “catingueira”, is a plant widely distributed in the Caatinga biome, which comprises 11% of the Brazilian territory. While this species is of interest given local knowledge, formal reports are lacking in the literature, warranting targeted investigation. This study aimed to prepare and characterize a hydroethanolic extract of C. bracteosum leaves, prepare carbopol gels containing the extract, and evaluate their cytotoxicity and antibacterial activity against Staphylococcus aureus and Escherichia coli. Methods: The initial extract was prepared in an ultrasonic bath using ethanol/water (70:30, v/v). The extract (1 mg/mL) was analyzed by liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS). Carbopol-based gels containing 1% and 3% of C. bracteosum extract were prepared and characterized in terms of pH, conductivity, spreadability, and rheology. The cytotoxicity was determined by the MTT method using MC3T3-E1 pre-osteoblast cells and L929-CCL1 fibroblast cells. The antibacterial activity of the extract and gels was evaluated using the agar diffusion method against S. aureus and E. coli. Results: The C. bracteosum leaves extract demonstrated antibacterial activity against S. aureus and E. coli, were not cytotoxic for the assessed cells at concentrations up to 100 μg/mL, and its analysis by UHPLC-MS/MS allowed the annotation of 18 metabolites, mainly of the phenolic acid and flavonoids glycoside classes, together with a biflavonoid. The prepared gels remained stable over the 30-day post-production analysis period. Conclusions: These findings provide a better understanding of the chemical diversity of the secondary metabolites of a common Caatinga biome species—C. bracteosum—specifically present in leaves hydroethanolic extract and gel formulation adapted for skin application with activity against S. aureus. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Antimicrobial Activity of Bioactive Compounds in Drug Formulations)

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59 pages, 3492 KiB

Open AccessReview

Surfactant-Enabled Nanocarriers in Breast Cancer Therapy: Targeted Delivery and Multidrug Resistance Reversal

by Ashirwad Jadhav and Karuppiah Nagaraj

Pharmaceutics 2025, 17(6), 779; https://doi.org/10.3390/pharmaceutics17060779 (registering DOI) - 13 Jun 2025

Abstract

Breast cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. Its treatment is complicated by molecular heterogeneity and the frequent development of multidrug resistance (MDR). Conventional drug delivery approaches are often limited by poor aqueous solubility, rapid systemic clearance, [...] Read more.

Breast cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. Its treatment is complicated by molecular heterogeneity and the frequent development of multidrug resistance (MDR). Conventional drug delivery approaches are often limited by poor aqueous solubility, rapid systemic clearance, non-specific biodistribution, and off-target toxicity. This review will critically explore the possibility of surfactant-based drug delivery systems (DDSs) in addressing the constraints of standard breast cancer treatments. It focuses on the mechanisms by which surfactants promote solubility, facilitate cellular uptake, and overcome drug resistance, while also analyzing current therapeutic success and future directions. A thorough review of preclinical and clinical investigations was undertaken, focusing on important surfactant-based DDSs such as polymeric micelles, nanoemulsions, liposomes, and self-emulsifying systems (SEDDSs). Mechanistic insights into surfactant functions, such as membrane permeabilization and efflux pump inhibition, were studied alongside delivery systems incorporating ligands and co-loaded medicines. Pluronic^® micelles, TPGS-based systems, biosurfactant-stabilized nanoparticles, and lipid-based carrier surfactant platforms improve medication solubility, stability, and delivery. Genexol^® are examples of formulations demonstrating effective use and FDA translational potential. These systems now incorporate stimuli-responsive release mechanisms—such as pH, temperature, redox, immuno- and photodynamic treatment—artificial intelligence treatment design, and tailored treatment advancement, and responsive tailoring. Surfactant-enabled DDSs can improve breast cancer care. Innovative approaches for personalized oncology treatment are countered by the enduring challenges of toxicity, regulatory hurdles, and diminished scalability. Full article

(This article belongs to the Special Issue Natural Nanoparticle for Cancer Diagnosis and Treatment, 2nd Edition)

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16 pages, 3483 KiB

Open AccessArticle

Design and Activity Evaluation of Berberine-Loaded Dual pH and Enzyme-Sensitive Colon-Targeting Microparticles

by Jingqi Sun, Xinlong Chai, Xiwen Zeng, Qingwei Wang, Yanwen Ling, Lihong Wang and Jin Su

Pharmaceutics 2025, 17(6), 778; https://doi.org/10.3390/pharmaceutics17060778 (registering DOI) - 13 Jun 2025

Abstract

Ulcerative colitis (UC) is a multifactorial disorder, and conventional oral berberine (BBR) suffers from poor colonic targeting. This study aimed to develop a colon-targeted microparticle system (BBR-ES MPs) based on chitosan (CS) and Eudragit S-100 to enhance BBR delivery efficiency and therapeutic efficacy [...] Read more.

Ulcerative colitis (UC) is a multifactorial disorder, and conventional oral berberine (BBR) suffers from poor colonic targeting. This study aimed to develop a colon-targeted microparticle system (BBR-ES MPs) based on chitosan (CS) and Eudragit S-100 to enhance BBR delivery efficiency and therapeutic efficacy in UC. Methods: BBR-CS nanocarriers were prepared via ionotropic gelation and coated with Eudragit S-100 to form pH/enzyme dual-responsive MPs. Colon-targeting performance was validated through in vitro release assays. SPF-grade male KM mice (Ethics Approval No.: JMSU-2021090301) with dextran sulfate sodium (DSS)-induced UC were divided into normal, model, BBR, and BBR-ES MPs groups. Therapeutic outcomes were evaluated by monitoring body weight, disease activity index (DAI), colon length, histopathology, inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10), and myeloperoxidase (MPO) activity via ELISA. Gut microbiota diversity was analyzed using 16S rRNA sequencing. Results: BBR-ES MP treatment significantly reduced DAI scores (p < 0.01), restored colon length, downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α; p < 0.05), and upregulated anti-inflammatory IL-10. Microbiota analysis revealed that the Bacteroidetes/Firmicutes ratio, which decreased in the model group, was restored post-treatment, with alpha/beta diversity approaching normal levels. BBR-ES MPs outperformed free BBR at equivalent doses. Conclusion: BBR-ES MPs achieved colon-targeted drug delivery via pH/enzyme dual-responsive mechanisms, effectively alleviating UC inflammation and modulating gut dysbiosis, offering a safe and precise therapeutic strategy for UC management. Full article

(This article belongs to the Section Drug Targeting and Design)

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27 pages, 1992 KiB

Open AccessReview

Revolutionizing Diabetes Management Through Nanotechnology-Driven Smart Systems

by Aayush Kaushal, Aanchal Musafir, Gourav Sharma, Shital Rani, Rajat Kumar Singh, Akhilesh Kumar, Sanjay Kumar Bhadada, Ravi Pratap Barnwal and Gurpal Singh

Pharmaceutics 2025, 17(6), 777; https://doi.org/10.3390/pharmaceutics17060777 (registering DOI) - 13 Jun 2025

Abstract

Diabetes is a global health challenge, and while current treatments offer relief, they often fall short in achieving optimal control and long-term outcomes. Nanotechnology offers a groundbreaking approach to diabetes management by leveraging materials at the nanoscale to improve drug delivery, glucose monitoring, [...] Read more.

Diabetes is a global health challenge, and while current treatments offer relief, they often fall short in achieving optimal control and long-term outcomes. Nanotechnology offers a groundbreaking approach to diabetes management by leveraging materials at the nanoscale to improve drug delivery, glucose monitoring, and therapeutic precision. Early advancements focused on enhancing insulin delivery through smart nanosystems such as tiny capsules that gradually release insulin, helping prevent dangerous drops in blood sugar. Simultaneously, the development of nanosensors has revolutionised glucose monitoring, offering real-time, continuous data that empowers individuals to manage their condition more effectively. Beyond insulin delivery and monitoring, nanotechnology enables targeted drug delivery systems that allow therapeutic agents to reach specific tissues, boosting efficacy while minimising side effects. Tools like microneedles, carbon nanomaterials, and quantum dots have made treatment less invasive and more patient-friendly. The integration of artificial intelligence (AI) with nanotechnology marks a new frontier in personalised care. AI algorithms can analyse individual patient data to adjust insulin doses and predict glucose fluctuations, paving the way for more responsive, customised treatment plans. As these technologies advance, safety remains a key concern. Rigorous research is underway to ensure the biocompatibility and long-term safety of these novel materials. The future of diabetes care lies in the convergence of nanotechnology and AI, offering personalised, data-driven strategies that address the limitations of conventional approaches. This review explores current progress, persistent challenges, and the transformative potential of nanotechnology in reshaping diabetes diagnosis and treatment and improving patient quality of life. Full article

(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application)

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28 pages, 5945 KiB

Open AccessArticle

Liposomal Encapsulation of Carob (Ceratonia siliqua L.) Pulp Extract: Design, Characterization, and Controlled Release Assessment

by Aleksandra A. Jovanović, Dragana Dekanski, Milena D. Milošević, Ninoslav Mitić, Aleksandar Rašković, Nikola Martić and Andrea Pirković

Pharmaceutics 2025, 17(6), 776; https://doi.org/10.3390/pharmaceutics17060776 (registering DOI) - 13 Jun 2025

Abstract

Background: Carob (Ceratonia siliqua L.) pulp flour is primarily used in the food industry. As a rich source of bioactive compounds, particularly polyphenols, it holds promise for pharmaceutical formulation research and development. Objectives: This study focused on developing liposomal particles loaded with [...] Read more.

Background: Carob (Ceratonia siliqua L.) pulp flour is primarily used in the food industry. As a rich source of bioactive compounds, particularly polyphenols, it holds promise for pharmaceutical formulation research and development. Objectives: This study focused on developing liposomal particles loaded with carob pulp extract using the proliposome method, followed by modifications through UV irradiation and sonication. Methods: The resulting liposomes were analyzed for encapsulation efficiency, vesicle size, polydispersity index (PDI), mobility, zeta potential, viscosity, surface tension, density, antioxidant activity, FT-IR spectra, and release kinetics under simulated gastrointestinal conditions. In addition, nanoparticle tracking analysis and transmission electron microscopy (TEM) were used for liposomal characterization. Results: The findings revealed a high encapsulation efficiency across all samples (>70%). The particle size and PDI measurements confirmed the presence of a multilamellar and uniform liposomal system before post-processing modifications. The medium value of zeta potential suggested a moderately electrostatically stabilized liposomal suspension. The sonicated liposomes demonstrated a higher concentration of vesicles in comparison to non-treated and UV-irradiated samples. TEM analysis revealed purified liposomal vesicles with preserved structural integrity. Encapsulation, as well as UV irradiation and sonication of liposomes, did not diminish the extract’s anti-DPPH activity. However, the ABTS radical scavenging potential of the pure extract was significantly lower compared to its encapsulated counterparts. UV irradiation and sonication notably reduced the anti-ABTS capacity of the extract-liposome system. Monitoring the release of bioactive compounds demonstrated controlled delivery from liposomal particles under simulated gastrointestinal conditions. Conclusions: Overall, liposomal formulations of carob pulp extract exhibit significant potential for further development as a functional food ingredient or for use in the prevention and treatment of various diseases. Full article

(This article belongs to the Special Issue Advanced Liposomes for Drug Delivery, 2nd Edition)

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29 pages, 2344 KiB

Open AccessReview

Intranasal Drug Delivery Technology in the Treatment of Central Nervous System Diseases: Challenges, Advances, and Future Research Directions

by Xunxun Wu, Ranqing Zang, Yiting Qiu, Yufang Zhang, Junbin Peng, Zhiyun Cheng, Site Wei, Meiyan Liu and Yong Diao

Pharmaceutics 2025, 17(6), 775; https://doi.org/10.3390/pharmaceutics17060775 (registering DOI) - 13 Jun 2025

Abstract

As population aging becomes an increasingly critical global issue, the incidence of central nervous system (CNS) diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke, has risen sharply. However, the blood–brain barrier (BBB) presents a significant obstacle to the effective treatment of [...] Read more.

As population aging becomes an increasingly critical global issue, the incidence of central nervous system (CNS) diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke, has risen sharply. However, the blood–brain barrier (BBB) presents a significant obstacle to the effective treatment of these CNS disorders, limiting the ability of therapeutic agents to reach the brain. In this context, intranasal drug delivery, which bypasses the BBB, has attracted considerable attention in recent years. By utilizing pathways such as the olfactory and trigeminal nerves, intranasal drug delivery facilitates the rapid transport of drugs to the brain, thereby enhancing both the bioavailability and targeting efficiency of the drugs. This review provides an overview of the molecular mechanisms underlying intranasal drug delivery, its advancements in the treatment of CNS diseases, strategies to improve delivery efficiency, and a discussion of the challenges and potential future directions in this field. The aim of this paper is to offer valuable insights and guidance for researchers and clinicians working in the area of CNS disease treatment. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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32 pages, 6157 KiB

Open AccessArticle

mPEG-PCL Nanoparticles to Improve Oral Bioavailability of Acalabrutinib: Effect of Polymer Lipophilicity and Hydrophilicity on Physicochemical Properties and In Vivo Performance in Rats

by Swagata Sinha, Punna Rao Ravi, Sahadevan Rajesh Rashmi and Łukasz Szeleszczuk

Pharmaceutics 2025, 17(6), 774; https://doi.org/10.3390/pharmaceutics17060774 - 13 Jun 2025

Abstract

Background/Objectives: This research focuses on the development and optimization of polymer–lipid hybrid nanoparticles (PLHNs) using two grades of mPEG-PCL co-polymers in combination with DPPC and lecithin to address the biopharmaceutical challenges of acalabrutinib (ACP), a selective treatment for different hematological malignancies. Methods: [...] Read more.

Background/Objectives: This research focuses on the development and optimization of polymer–lipid hybrid nanoparticles (PLHNs) using two grades of mPEG-PCL co-polymers in combination with DPPC and lecithin to address the biopharmaceutical challenges of acalabrutinib (ACP), a selective treatment for different hematological malignancies. Methods: Variations in the mPEG-to-ε-caprolactone ratio influenced both the molecular weight (Mw) of the synthesized co-polymers and their aqueous phase affinity. The ACP-loaded PLHNs (ACP-PLHNs) were optimized using a circumscribed central composite design. The in vivo studies were performed in Wistar rats. Results: The lipophilic mPEG-PCL (Mw = 9817.67 Da) resulted in PLHNs with a particle size of 155.91 nm and 40.08% drug loading, while the hydrophilic mPEG-PCL (Mw = 23,615.84 Da) yielded PLHNs with a relatively larger size (223.46 nm) and relatively higher drug loading (46.59%). The drug release profiles were polymer-grade dependent: lipophilic ACP-PLHNs (lACP-PLHNs) sustained release up to 30 h in pH 7.2 buffer, while hydrophilic ACP-PLHNs (hACP-PLHNs) completed release within 24 h. Stability studies showed greater stability for lACP-PLHNs, likely due to reduced molecular rearrangement from the chemically stable lipophilic co-polymer. Conclusions: Oral administration of both formulations exhibited a 2-fold (p < 0.001) improvement in the C_max and AUC_0-tlast and a 3.9-fold (p < 0.001) increase in the relatively oral bioavailability compared to the conventional ACP suspension in male wistar rats. Full article

(This article belongs to the Special Issue Recent Advances on Molecular Modeling in Pharmaceutics)

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23 pages, 3048 KiB

Open AccessArticle

Ivy Leaf Dry Extract EA 575^® Is a Potent Immunomodulator Acting on Dendritic Cells

by Miodrag Čolić, Sergej Tomić, Marina Bekić, Anđela Dubovina, Hanns Häberlein, André Rademaekers, Srđan Mašić and Dejan Bokonjić

Pharmaceutics 2025, 17(6), 773; https://doi.org/10.3390/pharmaceutics17060773 - 12 Jun 2025

Abstract

Background/Objectives: Ivy leaf extract has been shown to alleviate bronchial infection symptoms through various mechanisms, including anti-inflammatory effects. However, its impact on adaptive immunity, particularly dendritic cell (DC)/T-cell interactions, remains unexplored. This study investigated the immunomodulatory potential of ivy leaf extract (EA [...] Read more.

Background/Objectives: Ivy leaf extract has been shown to alleviate bronchial infection symptoms through various mechanisms, including anti-inflammatory effects. However, its impact on adaptive immunity, particularly dendritic cell (DC)/T-cell interactions, remains unexplored. This study investigated the immunomodulatory potential of ivy leaf extract (EA 575^®) using human monocyte-derived DCs (MoDCs). Methods: Immature MoDCs (imMoDCs) were differentiated with IL-4/GM-CSF and matured with LPS/IFN-γ (mMoDCs). MoDCs, treated with EA 575^® during differentiation, were co-cultured with purified T cells. Results: EA 575^® (non-cytotoxic up to 100 µg/mL) inhibited MoDC differentiation and maturation by reducing the expression of CD1a, CD83, CD40, CD86, HLA-DR, Dectin-1, CD206, CD209, HIF-1α, and proinflammatory cytokines (IL-12, IL-23, IL-27, IL-1β, IL-6, TNF-α). EA 575^®-treated mMoDCs suppressed allogeneic T-cell proliferation and reduced Th1 (IFN-γ), Th17 (IL-17A, IL-22), Th9 (IL-9), Th21 (IL-21), TNF-α, and IL-6 responses. Effects were dose-dependent, with higher concentrations (100 µg/mL) showing stronger inhibition. At lower concentrations (20 µg/mL), EA 575^® increased Th2 (IL-4, IL-5) and IL-10 responses, and the frequencies of CD4+ T cells with Treg properties, such as CD25hiFoxp3+, Tr1 (IL-10+Foxp3−), and IL-35+ Foxp3+ cells. Immunoregulatory mechanisms mediated by EA 575^®-treated mMoDCs correlated with the upregulation of tolerogenic markers (PD-L1, ILT3, ILT4, IDO1) on mMoDCs and the increased frequency of exhausted CD4+ T cells (PD-1+CD69+) and cytotoxic T cells (Granzyme B+PD-1+). Conclusions: EA 575^® induces tolerogenic DCs with significant anti-inflammatory and immunoregulatory properties, a previously undescribed phenomenon. Lower concentrations primarily enhance immunoregulatory responses, while higher concentrations exert more pronounced anti-inflammatory effects. Full article

(This article belongs to the Section Gene and Cell Therapy)

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27 pages, 6437 KiB

Open AccessArticle

A Natural Latex-Based Smart Dressing for Curcumin Delivery Combined with LED Phototherapy in Diabetic Foot Ulcers: A Pilot Clinical Study

by Thamis Fernandes Santana Gomes, Natália Carvalho Guimarães, Ludmilla Pinto Guiotti Cintra Abreu, Gabriella de Oliveira Silva, Vitória Regina Pereira da Silva, Franciéle de Matos da Silva, Fabiane Hiratsuka Veiga-Souza, Paulo Eduardo Narcizo de Souza, Mário Fabrício Fleury Rosa, Graziella Anselmo Joanitti, Suélia de Siqueira Rodrigues Fleury Rosa and Marcella Lemos Brettas Carneiro

Pharmaceutics 2025, 17(6), 772; https://doi.org/10.3390/pharmaceutics17060772 - 12 Jun 2025

Abstract

Background: Diabetic foot ulcers (DFUs) affect 25% of diabetes patients, with high risks of amputation (70%), recurrence (65% within 3–5 years), and mortality (50–70% at 5-years). Current treatments are limited by persistent inflammation, oxidative stress, and cost barriers. This study evaluates a [...] Read more.

Background: Diabetic foot ulcers (DFUs) affect 25% of diabetes patients, with high risks of amputation (70%), recurrence (65% within 3–5 years), and mortality (50–70% at 5-years). Current treatments are limited by persistent inflammation, oxidative stress, and cost barriers. This study evaluates a bioactive dressing combining a natural latex-based (NLB) biomembrane (Hevea brasiliensis) with curcumin-loaded liposomes, exhibiting angiogenic and antimicrobial properties, and red LED (light-emitting diode) phototherapy (635–640 nm) to address these challenges. Methods: A pilot clinical trial randomized 15 DFU participants into three groups: Control (CG, n = 5, standard care); Experimental Group 1 (EG1, n = 5, NLB + LED, daily treatment); and Experimental Group 2 (EG2, n = 5, NLB-curcumin liposomes + LED, daily treatment). Outcomes included wound closure, inflammatory/oxidative markers, and therapy feasibility. Assessments at D0, D22, and D45 included hematological/biochemical profiling, reactive oxygen species (ROS), and wound area measures. Results: On day 45, GE2 showed an average ulcer contraction of 89.8%, while CG showed 32.8%, and GE1 showed 9.7%. Systemic ROS and biomarkers (C-reactive protein, leukocytes) showed no significant changes (p > 0.05), though transient inflammatory spikes occurred. The combined therapy (EG2) accelerated healing without direct biomarker correlations. Conclusions: These findings highlight the potential of this combined therapy as an accessible, cost-effective DFU treatment, warranting larger studies to optimize home-based protocols and elucidate mechanisms. Full article

(This article belongs to the Special Issue Advances in Drug Delivery Systems for the Treatment of Chronic Wound Healing)

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21 pages, 3205 KiB

Open AccessArticle

Click on Click: Click-Flavone Glycosides Encapsulated in Click-Functionalised Polymersomes for Glioblastoma Therapy

by Nuno M. Saraiva, Ana Alves, Ana Isabel Barbosa, Andreia Marinho, Salette Reis, Marta Correia-da-Silva and Paulo C. Costa

Pharmaceutics 2025, 17(6), 771; https://doi.org/10.3390/pharmaceutics17060771 - 12 Jun 2025

Abstract

In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and alkyne groups and therefore, the 3,7-dihydroxyflavone (1) was first [...] Read more.

In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and alkyne groups and therefore, the 3,7-dihydroxyflavone (1) was first converted in 3,7-(prop-2-yn-yloxy)flavone (2) and acetobromo-α-D-glucose (3) was converted into 2,3,4,6-tetra-O-acetyl-β-glucopyranosyl azide (4). Subsequently, a click reaction was performed via copper-catalysed cycloaddition (CuAAC) between 2 and 4, as well as between 2 and 2-acetamido-3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl (AG931) and, 2 and commercial 2-azidoethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl (AG358), resulting in three distinct disubstituted flavone glycosides (5a–5c). Biological assays performed on L929 fibroblast cell lines and human glioblastoma astrocytoma U-251 cell lines indicated cytocompatibility with fibroblasts and reduced metabolic activity of GBM cells in the presence of compound 5b and 5c. To enhance therapeutic effect, improve local drug delivery, and overcome solubility issues of these high molecular weight compounds, the synthesised compounds were encapsulated in polymeric particles (polymersomes, PMs) composed of polylactic acid-polyethylene glycol (PEG-PLA) functionalized, once more by click chemistry, with 0.1 mol% transferrin mimetic (T7—HRPYIAH) peptide. The PMs were prepared by solvent displacement and exhibited stability over 100 days, encapsulation efficiency of 39–93%, and mean size diameters of 120–180 nm. The toxicity assays of the PMs on the U-251 cell line showed a significant decrease in metabolic activity, supporting the potential of this delivery system against GBM. Among the PMs tested, the flavone 5c-based PM demonstrated the highest efficacy. Full article

(This article belongs to the Special Issue Nano-Based Technology for Glioblastoma)

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18 pages, 5213 KiB

Open AccessArticle

Lung Delivery of Lactose-Free Microparticles Loaded with Azithromycin for the Treatment of Bacterial Infections

by Gracia Molina, Dolores R. Serrano, María Auxiliadora Dea-Ayuela, Carmina Rodriguez, Elena González-Burgos and Brayan J. Anaya

Pharmaceutics 2025, 17(6), 770; https://doi.org/10.3390/pharmaceutics17060770 - 11 Jun 2025

Abstract

Background/Objectives: Respiratory bacterial infections remain a significant global health challenge, with effective drug delivery to the lungs being crucial for successful treatment. This study aimed to develop a lactose-free dry powder inhaler (DPI) formulation containing azithromycin (AZM) microparticles for enhanced pulmonary delivery. Methods: [...] Read more.

Background/Objectives: Respiratory bacterial infections remain a significant global health challenge, with effective drug delivery to the lungs being crucial for successful treatment. This study aimed to develop a lactose-free dry powder inhaler (DPI) formulation containing azithromycin (AZM) microparticles for enhanced pulmonary delivery. Methods: Using a quality-by-design approach, an optimized formulation (4% AZM, 20% leucine, and 76% mannitol) was achieved. Results: The formulation demonstrated excellent aerodynamic properties with a mass median aerodynamic diameter (MMAD) of 2.72 μm ± 0.01 μm and fine particle fraction (FPF) (<5 μm) of 65.42% ± 5.12%. AZM-loaded microparticles exhibited enhanced efficacy against Pseudomonas aeruginosa with a two-fold reduction in the minimum bactericidal concentration (7.81 μg/mL vs. 15.62 μg/mL) compared to unprocessed AZM, while maintaining activity against Streptococcus pneumoniae. AZM microparticles demonstrated good biocompatibility with red blood cells and bronchial epithelial cells at therapeutic concentrations. Conclusions: These findings establish a promising lactose-free antibiotic formulation for targeted pulmonary delivery with enhanced antimicrobial efficacy. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)

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18 pages, 2967 KiB

Open AccessArticle

Adenoviruses Encapsulated in PEGylated DOTAP-Folate Liposomes Are Protected from the Pre-Existing Humoral Immune Response

by Abraham T. Phung, Jaimin R. Shah, Tao Dong, Omonigho Aisagbonhi, William C. Trogler, Andrew C. Kummel and Sarah L. Blair

Pharmaceutics 2025, 17(6), 769; https://doi.org/10.3390/pharmaceutics17060769 - 11 Jun 2025

Abstract

Background/Objectives: While adenovirus (Ad) therapies have been proven to be effective in local administration, systemic Ad treatments have shown limited success due to pre-existing antibodies in the human blood that neutralize the virus. We developed a liposome coating procedure that protects the [...] Read more.

Background/Objectives: While adenovirus (Ad) therapies have been proven to be effective in local administration, systemic Ad treatments have shown limited success due to pre-existing antibodies in the human blood that neutralize the virus. We developed a liposome coating procedure that protects the Ad from pre-existing neutralizing antibodies in human blood. To assess the in vivo stability of the liposomes, the present study used a novel in vivo method to quantitatively assess the protective capabilities of liposome-encapsulated Ad (DfAd) from neutralizing antibodies. Methods: The assay systemically administers DfAd with a green fluorescent protein transgene (DfAd-GFP) into pre-immunized mice and allows it to circulate in the presence of neutralizing antibodies; the infected blood is extracted and used to transduce HEK293 cells, which emits fluorescence in the presence of protected, un-neutralized Ad. Results: The PEGylated liposome formulation provides 12× protection in vivo relative to unencapsulated Ads. In vitro optimization of the liposome coating reveals a strong correlation between the structural stability of liposomes and protection against anti-Ad neutralizing antibodies, where DSPE-PEG2000-carboxylic acid (DSPE-PEG2000-CA) is a critical component for liposome stability and increasing protection against antibody neutralization of the encapsulated Ad. Conclusions: The findings in the present study confirm that the DfAd liposome can protect against neutralizing antibodies in blood circulation. The novel in vivo assay for liposome protection against neutralizing antibodies and in vitro experiments in the present study provide new tools and insights toward designing liposome–Ad complexes for the systemic treatment of cancer. Full article

(This article belongs to the Special Issue Application of Nanostructured Lipid Carriers in Antibacterial and Anticancer)

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40 pages, 2483 KiB

Open AccessReview

Biological and Biosimilar Medicines in Contemporary Pharmacotherapy for Metabolic Syndrome

by Wiktoria Górecka, Daria Berezovska, Monika Mrozińska, Grażyna Nowicka and Monika E. Czerwińska

Pharmaceutics 2025, 17(6), 768; https://doi.org/10.3390/pharmaceutics17060768 - 11 Jun 2025

Abstract

The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly [...] Read more.

The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly being supplemented by biological and biosimilar agents. This trend is particularly evident in the development and advancement of anti-diabetic and hypolipemic therapies. This review explores advances in the treatment of hypercholesterolemia and hypertriglyceridemia, elevated lipoprotein(a) [Lp(a)], diabetes, and obesity associated with metabolic syndrome. It focuses mainly on biopharmaceuticals such as proteins and nucleotide-based drugs (antisense oligonucleotides, small interfering RNA), but also on dipeptidyl peptidase-4 (DPP-4) inhibitors classified as incretin drugs along with glucagon-like peptide-1 (GLP-1) analogues. Due to the substantial role of SGLT-2 (sodium/glucose cotransporter 2) inhibitors in novel diabetes therapies, especially for managing cardiovascular risk, this group of compounds was also included in this review. Many clinical data in the field of effectiveness of biopharmaceuticals in metabolic disorders are provided. Therefore, in this review, we mainly include a brief history of drug development and approval, first synthesis and structure modifications, which relevantly influence pharmacokinetics, and safety. We provide only brief comparison of biological drugs with metformin and sulphonylureas derivatives. Databases such as PubMed, Scopus, and Google Scholar are searched for the period between 2000 and 2024. Full article

(This article belongs to the Section Biologics and Biosimilars)

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14 pages, 1586 KiB

Open AccessArticle

Stability-Guided Formulation of a Light-Sensitive D-LSD Capsule for Clinical Investigation

by Bernard Do, Luc Mallet, Maxime Annereau, Danielle Libong, Audrey Solgadi, Florence Vorspan, Muriel Paul and Philippe-Henri Secretan

Pharmaceutics 2025, 17(6), 767; https://doi.org/10.3390/pharmaceutics17060767 - 11 Jun 2025

Abstract

Background/Objectives: D-lysergic acid diethylamide (D-LSD) is under investigation as a potential therapeutic strategy for alcohol use disorder (AUD). However, the extreme light sensitivity of D-LSD presents a significant challenge in developing suitable pharmaceutical forms, particularly for clinical trial settings. This study proposes a [...] Read more.

Background/Objectives: D-lysergic acid diethylamide (D-LSD) is under investigation as a potential therapeutic strategy for alcohol use disorder (AUD). However, the extreme light sensitivity of D-LSD presents a significant challenge in developing suitable pharmaceutical forms, particularly for clinical trial settings. This study proposes a liquid-filled capsule formulation designed to provide accurate dosing while protecting D-LSD from photodegradation. Methods: To support formulation development and ensure its suitability as an investigational medicinal product, a multi-tiered analytical strategy was employed. This included liquid chromatography coupled with ion mobility spectrometry and mass spectrometry (LC-IM-MS), along with quantum chemical calculations (density functional theory (DFT) and time dependent-DFT (TD-DFT)), to ensure robust and orthogonal structural characterization of degradation products. Results: Photostress studies demonstrated that while D-LSD in solution rapidly degrades into photoisomers and photooxidative byproducts, the capsule formulation markedly mitigates these transformations under ICH-compliant conditions. Conclusions: These findings highlight the essential role of orthogonal stability profiling in guiding formulation development and demonstrate that this approach may offer a viable, photostable platform for future clinical investigation of D-LSD in the treatment of AUD. Full article

(This article belongs to the Special Issue Pharmaceutical Solid Dosage Forms: Manufacturing, Design, Development, and Biomedical Applications)

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17 pages, 5473 KiB

Open AccessArticle

Sivelestat-Loaded Neutrophil-Membrane-Coated Antioxidative Nanoparticles for Targeted Endothelial Protection in Sepsis

by Juexian Wei, Aijia Zhong, Yuting Zhang, Ehua Deng, Hengzong Mo, Hongyu Zhao, Jiayu Huang, Huaidong Peng, Kaiyin Zhang, Xiaohui Chen, Haifeng Mao, Yixin Chen and Yongcheng Zhu

Pharmaceutics 2025, 17(6), 766; https://doi.org/10.3390/pharmaceutics17060766 - 10 Jun 2025

Abstract

Background/Objectives: This study aims to develop and evaluate neutrophil-membrane-coated nanoparticles (Siv@NMs) encapsulating sivelestat for the treatment of sepsis-induced endothelial injury. Leveraging the intrinsic chemotactic properties of neutrophil membranes, Siv@NMs are engineered to achieve site-specific delivery of sivelestat to damaged endothelia, thereby overcoming [...] Read more.

Background/Objectives: This study aims to develop and evaluate neutrophil-membrane-coated nanoparticles (Siv@NMs) encapsulating sivelestat for the treatment of sepsis-induced endothelial injury. Leveraging the intrinsic chemotactic properties of neutrophil membranes, Siv@NMs are engineered to achieve site-specific delivery of sivelestat to damaged endothelia, thereby overcoming the limitations of conventional therapies in mitigating endothelial dysfunction and multiorgan failure associated with sepsis. Methods: Siv@NMs were synthesized through a combination of ultrasonication and extrusion techniques to encapsulate sivelestat within neutrophil-membrane-derived vesicles. Comprehensive physicochemical characterization included analysis of particle size distribution, zeta potential, and encapsulation efficiency. Stability profiles and controlled release kinetics were systematically evaluated under simulated conditions. In vitro investigations encompassed (1) endothelial cell biocompatibility assessment via cytotoxicity assays, (2) investigation of the targeting efficiency in suppressing endothelial neutrophil extracellular trap generation during inflammation, and (3) ROS-scavenging capacity quantification using flow cytometry with DCFH-DA fluorescent probes. In vivo therapeutic efficacy was validated using a cecal ligation and puncture (CLP) sepsis mouse model, with multiparametric monitoring of endothelial function, inflammatory markers, ROS levels, and survival outcomes. Results: The optimized Siv@NMs exhibited an average particle size of approximately 150 nm, and a zeta potential of −10 mV was achieved. Cellular studies revealed that (1) Siv@NMs selectively bound to inflammatory endothelial cells with minimal cytotoxicity, and (2) Siv@NMs significantly reduced ROS accumulation in endothelial cells subjected to septic stimuli. In vitro experiments demonstrated that Siv@NMs treatment markedly attenuated endothelial injury biomarkers’ expression (ICAM-1 and iNOS), suppressed formation of neutrophil extracellular traps, and improved survival rates compared to treatment with free sivelestat. Conclusions: The neutrophil-membrane-coated nanoparticles loaded with sivelestat present a breakthrough strategy for precision therapy of sepsis-associated endothelial injury. This bioengineered system synergistically combines targeted drug delivery with multimodal therapeutic effects, including ROS mitigation, anti-inflammatory action, and endothelial protection. These findings substantiate the clinical translation potential of Siv@NMs as a next-generation nanotherapeutic for sepsis management. Full article

(This article belongs to the Special Issue ROS-Mediated Nano Drug Delivery for Antitumor Therapy)

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14 pages, 492 KiB

Open AccessArticle

Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog

by Kumar Kulldeep Niloy, Jamie Horn, Nazmul H. Bhuiyan, Khaled A. Shaaban, Suhas S. Bhosale, Thomas E. Prisinzano, Jon S. Thorson, Jurgen Rohr and Markos Leggas

Pharmaceutics 2025, 17(6), 765; https://doi.org/10.3390/pharmaceutics17060765 - 10 Jun 2025

Abstract

Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing [...] Read more.

Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing its further development. Through semisynthetic chemical modifications, we identified mithramycin SA-Trp (MTMSA-Trp) as being a pharmacologically superior congener. To explore their pharmacokinetic (PK) differences, this study examined the plasma PKs and plasma protein binding (PPB) of MTM and MTMSA-Trp in mice, rats, and monkeys. Methods: Protein binding was investigated by rapid equilibrium dialysis in plasma from mice, rats, monkeys, and humans. The pharmacokinetics were investigated at milligram- and microgram-level doses in mice and rats. The pharmacokinetics in monkeys were investigated using the cassette dosing approach at two microgram-level doses. The MTMSA-Trp pharmacokinetic linearity was evaluated in mice at 0.3, 1, 3, and 10 mg/kg doses. All samples were analyzed using LC-MS/MS. Results: Plasma protein binding was higher for MTMSA-Trp (1–4% unbound) than for MTM (10–30% unbound) across species, except in athymic nude mice (1–4% unbound and <1% for mithramycin and MTMSA-Trp, respectively). In mice and rats, MTMSA-Trp had significantly lower clearance than MTM at both milligram and microgram doses; however, the difference in plasma exposure was more pronounced at milligram doses. Consistent with the rodent PK results, cassette microdosing in monkeys showed that the clearance of MTMSA-Trp was lower than that of MTM, but the differences were less pronounced. In the dose proportionality study, MTMSA-Trp showed linear pharmacokinetics at 1, 3, and 10 mg/kg doses. Conclusions: MTMSA-Trp has significantly lower clearance than MTM in rodent models. This is a significant improvement compared to the parent drug, MTM, and warrants further evaluation of PKs in non-rodent models to enable the prediction of MTMSA-Trp PK in humans. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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25 pages, 3318 KiB

Open AccessReview

Solute–Vehicle–Skin Interactions and Their Contribution to Pharmacokinetics of Skin Delivery

by Pronalis Tapfumaneyi, Khanh Phan, Yicheng Huang, Kewaree Sodsri, Sarika Namjoshi, Howard Maibach and Yousuf Mohammed

Pharmaceutics 2025, 17(6), 764; https://doi.org/10.3390/pharmaceutics17060764 - 10 Jun 2025

Abstract

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients [...] Read more.

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients is a delicate balance between the molecular properties of the drug, the skin properties of the patients, and the formulation properties. Understanding this interplay can aid in the development of products applied to the skin. The kinetics of percutaneous absorption and an understanding of the rate-limiting steps involved can facilitate the optimization of these systems and enhance the degree to which skin drug delivery can be achieved. Solute–vehicle, vehicle–skin, and solute–skin interactions contribute notably to product release as well as the rate of absorption and diffusion across skin layers. These interactions alter the degree of permeation by interfering with the skin barrier or solubility and thermodynamic activity of the active pharmaceutical ingredient. This article aims to provide a concise understanding of some of the factors involved in the skin absorption of topical products, i.e., the pharmacokinetics of percutaneous absorption as well as the solute–vehicle–skin interactions that determine the rate of release of products and the degree of drug diffusion across the skin. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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5 pages, 177 KiB

Open AccessEditorial

Editorial for Special Issue ‘Engineering and Characterisation of Novel Nanomedicine Formulations, 2nd Edition’

by Raquel Fernández-García, Francisco Bolás-Fernández and Ana Isabel Fraguas-Sánchez

Pharmaceutics 2025, 17(6), 763; https://doi.org/10.3390/pharmaceutics17060763 - 10 Jun 2025

Abstract

Nanomedicine applies nanotechnology to revolutionise healthcare through the development of systems at the nanoscale (below 1000 nm) to enhance drug delivery [...] Full article

(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations, 2nd Edition)

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