Pharmaceutics

16 pages, 1726 KiB

Open AccessArticle

Cationic Polymer Micelles as Carriers of Bioactive Sesquiterpene Lactones from Inula Helenium L. for Effective Treatment of Bacterial Biofilms

by Rumena Stancheva, Tsvetozara Damyanova, Tsvetelina Paunova-Krasteva, Ralitsa Veleva, Tanya Topouzova-Hristova, Viktoria Ivanova, Antoaneta Trendafilova, Ivaylo Dimitrov, Stanislav Rangelov and Emi Haladjova

Pharmaceutics 2025, 17(6), 800; https://doi.org/10.3390/pharmaceutics17060800 - 19 Jun 2025

Viewed by 551

Abstract

Objectives: Nanosized polymeric micelles (PMs) with an average size of about 80 nm and moderately positive ζ potential, based on an amphiphilic poly(4-methyl-piperazin-1-yl)-propenone)-b-polylactide (PMPP-PLA) block copolymer, were prepared. They were used as platforms for the delivery of bioactive sesquiterpene lactones from Inula helenium [...] Read more.

Objectives: Nanosized polymeric micelles (PMs) with an average size of about 80 nm and moderately positive ζ potential, based on an amphiphilic poly(4-methyl-piperazin-1-yl)-propenone)-b-polylactide (PMPP-PLA) block copolymer, were prepared. They were used as platforms for the delivery of bioactive sesquiterpene lactones from Inula helenium L. root extract. Methods: The PMs were characterized with good encapsulation efficiency as a maximum value of 72% was reached at a polymer-to-extract mass ratio of 10:1. The loaded micelles exhibited good colloidal stability. An in vitro release was performed showing a burst release profile. The biocompatibility of the resulting PMs was confirmed by assessing their cytotoxic effect on human keratinocytes in vitro by colorimetric assay and flow cytometry. Results: The systems demonstrated the capability to reduce the biomass of pre-formed Gram-positive and Gram-negative bacterial biofilms. Conclusions: The obtained data clearly determine a trend for a strong combined effect between the PMs and the root extract, distinguishing them with an excellent anti-biofilm potential and prospects for future applications in medical practice. Full article

(This article belongs to the Special Issue Application of Polymeric Micelles for Drug and Gene Delivery, 2nd Edition)

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16 pages, 1258 KiB

Open AccessArticle

NLC-Based Rifampicin Delivery System: Development and Characterization for Improved Drug Performance Against Staphylococcus aureus

by Javiera Carrasco-Rojas, Felipe I. Sandoval, Christina M. A. P. Schuh, Carlos F. Lagos, Javier O. Morales, Francisco Arriagada and Andrea C. Ortiz

Pharmaceutics 2025, 17(6), 799; https://doi.org/10.3390/pharmaceutics17060799 - 19 Jun 2025

Viewed by 512

Abstract

Background/Objectives: Rifampicin is a typical antibiotic used for the treatment of Staphylococcus aureus (S. aureus) infections; however, its clinical utility is limited by poor aqueous solubility, chemical instability, and increasing bacterial resistance. Nanostructured lipid carriers (NLCs) offer a promising strategy [...] Read more.

Background/Objectives: Rifampicin is a typical antibiotic used for the treatment of Staphylococcus aureus (S. aureus) infections; however, its clinical utility is limited by poor aqueous solubility, chemical instability, and increasing bacterial resistance. Nanostructured lipid carriers (NLCs) offer a promising strategy to improve drug solubility, stability, and antimicrobial performance. Methods: In this study, rifampicin-loaded NLC (NLC-RIF) was developed using a hot homogenization with a low energy method and characterized in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, colloidal stability, and drug loading. Results: In vitro release studies under sink conditions demonstrated a biphasic release pattern, best described by the Korsmeyer–Peppas model, suggesting a combination of diffusion and matrix erosion mechanisms. Antimicrobial activity against S. aureus revealed a substantial increase in potency for NLC-RIF, with an IC₅₀ of 0.46 ng/mL, approximately threefold lower than that of free rifampicin. Cytotoxicity assays in HepG2 cells confirmed over 90% cell viability across all tested concentrations. Conclusions: These findings highlight the potential of NLC-RIF as a biocompatible and effective nanocarrier system for enhancing rifampicin delivery and antibacterial activity. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)

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22 pages, 2633 KiB

Open AccessReview

Implications of Anaphylaxis Following mRNA-LNP Vaccines: It Is Urgent to Eliminate PEG and Find Alternatives

by Jinxing Song, Dihan Su, Hongbing Wu and Jeremy Guo

Pharmaceutics 2025, 17(6), 798; https://doi.org/10.3390/pharmaceutics17060798 - 19 Jun 2025

Viewed by 2252

Abstract

The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination [...] Read more.

The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination with mRNA-LNP vaccines. Meanwhile, the US Food and Drug Administration (FDA) has added four black-box warnings in the instructions for mRNA-LNP vaccines. Numerous studies have proven that the observance of side effects after vaccination is indeed positively correlated to the level of anti-PEG antibodies (IgM or IgG), which are enhanced by PEGylated preparations like LNP vaccine and environmental exposure. After literature research and review in the past two decades, it was found that the many clinical trial failures (BIND-014, RB006 fell in phase II) of PEG modified delivery system or PEGylated drug were related to the high expression of anti-PEG IgM and IgG. In the background of shooting multiple mRNA-LNP vaccines in billions of people around the world in the past three years, the level of anti-PEG antibodies in the population may have significantly increased, which brings potential risks for PEG-modified drug development and clinical safety. This review summarizes the experience of using mRNA-LNP vaccines from the mechanism of the anti-PEG antibodies generation, detection methods, clinical failure cases of PEG-containing products, harm analysis of abuse of PEGylation, and alternatives. In light of the increasing prevalence of anti-PEG antibodies in the population and the need to avoid secondary injuries, this review article holds greater significance by offering insights for drug developers. It suggests avoiding the use of PEG excipients when designing PEGylated drugs or PEG-modified nano-formulations and provides references for strategies such as utilizing PEG-free or alternative excipients. Full article

(This article belongs to the Special Issue Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines)

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30 pages, 3428 KiB

Open AccessReview

Lipid-Polymer Hybrid Nanoparticles as a Smart Drug Delivery System for Peptide/Protein Delivery

by Alharith A. A. Hassan, Eslam Ramadan, Katalin Kristó, Géza Regdon, Jr. and Tamás Sovány

Pharmaceutics 2025, 17(6), 797; https://doi.org/10.3390/pharmaceutics17060797 - 19 Jun 2025

Viewed by 1201

Abstract

The efficient oral delivery of therapeutic proteins and peptides poses a tremendous challenge due to their inherent instability, large molecular size, and susceptibility to enzymatic degradation. Several nanocarrier systems, such as liposomes, solid lipid nanoparticles, and polymeric nanoparticles, have been explored to overcome [...] Read more.

The efficient oral delivery of therapeutic proteins and peptides poses a tremendous challenge due to their inherent instability, large molecular size, and susceptibility to enzymatic degradation. Several nanocarrier systems, such as liposomes, solid lipid nanoparticles, and polymeric nanoparticles, have been explored to overcome these problems. Liposomes and other lipid-based nanocarriers show excellent biocompatibility and the ability to encapsulate hydrophobic and hydrophilic drugs; however, they often suffer from poor structural stability, premature leakage of the loaded drugs, and poor encapsulation efficiency for macromolecular peptides and proteins. On the other hand, polymeric nanoparticles are more stable and allow better control over drug release; nevertheless, they usually lack the necessary biocompatibility and cellular uptake efficiency. Recently, lipid-polymer hybrid nanoparticles (LPHNs) have emerged as an advanced solution combining the structural stability of polymers and the biocompatibility and surface functionalities of lipids to enhance the controlled release, stability, and bioavailability of protein and peptide drugs. In this review, an attempt was made to set a clear definition of the LPHNs and extend the concept and area, so to our knowledge, this is the first review that highlights six categories of the LPHNs based on their anatomy. Moreover, this review offers a detailed analysis of LPHN preparation methods, including conventional and nonconventional one-step and two-step processes, nanoprecipitation, microfluidic mixing, and emulsification methods. Moreover, the material attributes and critical process parameters affecting the output of the preparation methods were illustrated with supporting examples to enable researchers to select the suitable preparation method, excipients, and parameters to be manipulated to get the LPHNs with the predetermined quality. The number of reviews focusing on the formulation of peptide/protein pharmaceutics usually focus on a specific drug like insulin. To our knowledge, this is the first review that generally discusses LPHN-based delivery of biopharmaceuticals. by discussing representative examples of previous reports comparing them to a variety of nanocarrier systems to show the potentiality of the LPHNs to deliver peptides and proteins. Moreover, some ideas and suggestions were proposed by the authors to tackle some of the shortcomings highlighted in these studies. By presenting this comprehensive overview of LPHN preparation strategies and critically analyzing literature studies on this topic and pointing out their strong and weak points, this review has shown the gaps and enlightened avenues for future research. Full article

(This article belongs to the Special Issue Biomedical Applications of Nanocarriers in Targeted Delivery of Bioactive Compounds)

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12 pages, 1213 KiB

Open AccessArticle

Synthesis and In Vitro Evaluation of a Scandium-44 Radiolabeled Nanobody as a PD-L1 PET Imaging Probe

by Viktoria E. Krol, Aditya Bansal, Manasa Kethamreddy, Jason R. Ellinghuysen, Daniel J. Vail, Fabrice Lucien-Matteoni, Haidong Dong, Sean S. Park and Mukesh K. Pandey

Pharmaceutics 2025, 17(6), 796; https://doi.org/10.3390/pharmaceutics17060796 - 19 Jun 2025

Viewed by 470

Abstract

Background/Objective: Noninvasive PET imaging-based assessment of PD-L1 expression is of high clinical value for better patient selection and treatment response rates to PD-L1 immunotherapies. Due to their shorter biological half-life and faster clearance from the blood pool, radiolabeled antibody fragments are an [...] Read more.

Background/Objective: Noninvasive PET imaging-based assessment of PD-L1 expression is of high clinical value for better patient selection and treatment response rates to PD-L1 immunotherapies. Due to their shorter biological half-life and faster clearance from the blood pool, radiolabeled antibody fragments are an attractive alternative for imaging than their full-length IgG counterpart. This work investigated the radiosynthesis and in vitro cell uptake of anti-PD-L1-B11-nanobody radiolabeled with ⁴⁴Sc (t_1/2 = 4.04 h) as an alternative to anti-PD-L1-B11-IgG, better suited for longer half-life radioisotopes such as ⁸⁹Zr (t_1/2 = 78.41 h). Methods: The proteins were conjugated with p-SCN-Bn-DTPA and radiolabeled at room temperature with ⁴⁴Sc, achieving a radiochemical yield of a RCY of 94.8 ± 3.1% (n = 3) for [⁴⁴Sc]Sc-B11-IgG and 73.6 ± 12.1% (n = 3) for [⁴⁴Sc]Sc-B11-nanobody, before purification. Results: Significantly higher uptake in the PD-L1₊ cells than PD-L1_KO cells was observed for both probes. However, high non-specific uptake, particularly of the radiolabeled B11-nanobody, was also observed which may negatively impact its potential as a molecular imaging probe. Conclusions: Due to the high non-specific uptake in vitro, the ⁴⁴Sc radiolabeled nanobody was not progressed to further in vivo evaluation. These results should, however, not discourage future evaluations of other nanobody based probes radiolabeled with ⁴⁴Sc, due to their well-matched biological and physical half-life. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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12 pages, 3830 KiB

Open AccessArticle

Nasal Emulgel’s Role in Preventing Coronavirus Infection

by Francesca Accioni, Giovanna Rassu, Antonio Brunetti, Erika Plicanti, Giulia Freer, Antonio Carta, Paolo Giunchedi and Elisabetta Gavini

Pharmaceutics 2025, 17(6), 795; https://doi.org/10.3390/pharmaceutics17060795 - 19 Jun 2025

Viewed by 452

Abstract

Background/Objectives: Coronaviruses (CoVs) are a large family of respiratory viruses that cause respiratory illnesses ranging from mild colds to severe diseases such as severe acute respiratory syndrome and pandemics. The nasal cavity is a primary site for CoV entry and transmission. The study [...] Read more.

Background/Objectives: Coronaviruses (CoVs) are a large family of respiratory viruses that cause respiratory illnesses ranging from mild colds to severe diseases such as severe acute respiratory syndrome and pandemics. The nasal cavity is a primary site for CoV entry and transmission. The study aimed to prepare a novel mucoadhesive emulgel specifically formulated with simple, safe, and cost-effective excipients to create a barrier on the nasal mucosa that impedes CoV infection. This formulation strategy was specifically designed to enable rapid and straightforward in vivo translation, addressing a critical gap in preventive measures against respiratory viruses. Methods: Three emulgels, containing macadamia oil, Carbopol and different percentages of hydroxypropyl methylcellulose (1, 1.2 and 1.5% (w/v), HPMC), were properly prepared and characterized for mucoadhesion, viscosity, and spreadability. The biological activity against SARS-CoV-2 was evaluated in vitro on infected epithelial cells. Results: The emulgel with 1.2% HPMC demonstrated optimal physicochemical properties (mucoadhesion: 342 ± 9 mN/cm²; viscosity: 1080 ± 83 cp; spreadability: 7.27 ± 0.06 cm) suitable for nasal application. Importantly, in vitro biological assays demonstrated that this emulgel significantly inhibits SARS-CoV-2 infection in epithelial cells, indicating an effective barrier to viral diffusion. Conclusions: By employing readily available, safe, and inexpensive excipients, this novel mucoadhesive emulgel offers a practical, scalable, and rapidly translatable nasal prophylactic approach to prevent early SARS-CoV-2 infection, addressing a critical unmet need in pandemic preparedness. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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17 pages, 2898 KiB

Open AccessArticle

Selective Laser Sintering of Atomoxetine Tablets: An Innovative Approach for Small-Scale, Personalized Production

by Gordana Stanojević, Ivana Adamov, Snežana Mugoša, Veselinka Vukićević and Svetlana Ibrić

Pharmaceutics 2025, 17(6), 794; https://doi.org/10.3390/pharmaceutics17060794 - 18 Jun 2025

Viewed by 486

Abstract

Background/Objectives: The growing interest in personalized medicine has accelerated the exploration of three-dimensional (3D) printing technologies in pharmaceutical applications. This study investigates the potential of selective laser sintering (SLS) as a flexible, small-scale manufacturing method for atomoxetine tablets tailored for individualized therapy, comparing [...] Read more.

Background/Objectives: The growing interest in personalized medicine has accelerated the exploration of three-dimensional (3D) printing technologies in pharmaceutical applications. This study investigates the potential of selective laser sintering (SLS) as a flexible, small-scale manufacturing method for atomoxetine tablets tailored for individualized therapy, comparing it with conventional direct compression. Methods: Atomoxetine tablets were produced using SLS 3D printing with varying laser scanning speeds and compared to tablets made via a compaction simulator. Formulations were based on hydroxypropyl methylcellulose (HPMC) as the primary matrix former. The physical properties, drug content, disintegration time, and dissolution profiles were evaluated. The structural and chemical integrity were assessed using SEM, FTIR, DSC, and XRPD. Results: The SLS tablets exhibited comparable mechanical properties and drug content to those made by compaction. Lower laser speeds produced harder tablets with slower disintegration, while higher speeds yielded more porous tablets with ultra-rapid drug release (>85% in 15 min). All tablets met the European Pharmacopoeia dissolution criteria. No significant drug–excipient interactions or changes in crystallinity were detected. Conclusions: SLS printing is a viable alternative to traditional tablet manufacturing, offering control over drug release profiles through parameter adjustment. The technique supports the development of high-quality, patient-specific dosage forms and shows promise for broader implementation in personalized pharmaceutical therapy. Full article

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

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23 pages, 1742 KiB

Open AccessReview

Terpenes and Essential Oils in Pharmaceutics: Applications as Therapeutic Agents and Penetration Enhancers with Advanced Delivery Systems for Improved Stability and Bioavailability

by Greta Kaspute, Tatjana Ivaskiene, Arunas Ramanavicius, Simonas Ramanavicius and Urte Prentice

Pharmaceutics 2025, 17(6), 793; https://doi.org/10.3390/pharmaceutics17060793 - 18 Jun 2025

Viewed by 719

Abstract

This review examines the pharmaceutical applications of essential oils (EOs) and terpenes, highlighting their dual role as therapeutic agents and natural penetration enhancers. These volatile, hydrophobic compounds have well-documented antimicrobial, antioxidant, and anti-inflammatory properties. However, their clinical potential is limited by poor water [...] Read more.

This review examines the pharmaceutical applications of essential oils (EOs) and terpenes, highlighting their dual role as therapeutic agents and natural penetration enhancers. These volatile, hydrophobic compounds have well-documented antimicrobial, antioxidant, and anti-inflammatory properties. However, their clinical potential is limited by poor water solubility, high volatility, and sensitivity to environmental factors, including light, heat, and oxygen. To address these challenges, various advanced delivery systems have been developed to enhance stability, bioavailability, and controlled release. These systems not only protect chemical integrity but also exploit these compounds’ abilities to interact with lipid membranes, facilitating the transport of active compounds across biological barriers. Additionally, their inherent antimicrobial properties can contribute to the overall stability of formulations. The review critically examines the incorporation of terpenes and major essential oil (EO) components, such as limonene, linalool, eugenol, α-pinene, and menthol, into delivery systems, assessing their performance in enhancing drug permeability and targeting specific tissues. Current challenges and future directions in terpenes and EO-based delivery strategies are discussed, highlighting their promising role in developing multifunctional and efficient pharmaceutical formulations. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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13 pages, 4641 KiB

Open AccessArticle

Formulation and Characterization of Bone-Targeting Vancomycin-Loaded Liposomes

by Basel Karzoun, Wala’a Albenayan, Shilpa Raut and Eman Atef

Pharmaceutics 2025, 17(6), 792; https://doi.org/10.3390/pharmaceutics17060792 - 18 Jun 2025

Cited by 1 | Viewed by 494

Abstract

Background: We report the successful formulation of a bone-targeted vancomycin-loaded liposomal carrier. Method: The basic liposomal structure is composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and dicetyl phosphate (DCP) in a molar ratio of 3:1:0.25, respectively. The dehydration–rehydration method was used to maximize the liposomal-encapsulation [...] Read more.

Background: We report the successful formulation of a bone-targeted vancomycin-loaded liposomal carrier. Method: The basic liposomal structure is composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and dicetyl phosphate (DCP) in a molar ratio of 3:1:0.25, respectively. The dehydration–rehydration method was used to maximize the liposomal-encapsulation efficiency of vancomycin after the initial preparation using thin-film hydration. Results: Sodium alendronate was used as a targeting moiety and was successfully conjugated to DSPE–PEG–COOH via carbodiimide chemistry, as was confirmed using IR spectroscopy. The resulting conjugate, DSPE–PEG-alendronate, was subsequently used in the formulation of bone-targeting vancomycin-loaded liposomes. In vitro binding assays with hydroxyapatite demonstrated preferential binding of the surface-modified liposomes to hydroxyapatite crystals. Furthermore, ex vivo studies revealed that the surface-modified liposomes exhibited enhanced binding affinity to the tibial bone tissue of 4-week-old male CD1 mice, in comparison to unmodified liposomes. Conclusions: The successfully formulated surface-modified vancomycin loaded liposomes showed enhanced bone affinity with a great potential for targeting the antibiotic to infected bones. Full article

(This article belongs to the Special Issue Optimizing Pharmacokinetics Through Formulation Science and Technology)

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18 pages, 3370 KiB

Open AccessArticle

Exploring a Novel Anti-Inflammatory Therapy for Diabetic Retinopathy Based on Glyco-Zeolitic-Imidazolate Frameworks

by Elena Díaz-Paredes, Francisco Martín-Loro, Rocío Rodríguez-Marín, Laura Gómez-Jaramillo, Elena M. Sánchez-Fernández, Carolina Carrillo-Carrión and Ana I. Arroba

Pharmaceutics 2025, 17(6), 791; https://doi.org/10.3390/pharmaceutics17060791 - 17 Jun 2025

Viewed by 650

Abstract

Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal [...] Read more.

Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp²-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response. Full article

(This article belongs to the Special Issue Advances in Bioactive Compounds and Nanotechnology: Sustainable Approaches for Pharmaceutical Applications)

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27 pages, 2807 KiB

Open AccessArticle

Development and Optimization of Grape Skin Extract-Loaded Gelatin–Alginate Hydrogels: Assessment of Antioxidant and Antimicrobial Properties

by Jovana Bradic, Anica Petrovic, Aleksandar Kocovic, Vukasin Ugrinovic, Suzana Popovic, Andrija Ciric, Zoran Markovic and Edina Avdovic

Pharmaceutics 2025, 17(6), 790; https://doi.org/10.3390/pharmaceutics17060790 - 17 Jun 2025

Viewed by 543

Abstract

Background: In this study, we aimed to develop and optimize unique eco-friendly gelatin–alginate hydrogels enriched with sustainable grape skin extract for advanced wound healing applications. Methods: Following confirmation of the extract’s antioxidant activity, hydrogels were synthesized by varying gelatin content and CaCl₂ [...] Read more.

Background: In this study, we aimed to develop and optimize unique eco-friendly gelatin–alginate hydrogels enriched with sustainable grape skin extract for advanced wound healing applications. Methods: Following confirmation of the extract’s antioxidant activity, hydrogels were synthesized by varying gelatin content and CaCl₂ concentration to achieve desirable crosslinking density, mechanical properties, and extract release behavior. Physicochemical characterization of hydrogels included equilibrium swelling analysis, mechanical testing, FTIR analysis, and in vitro release of extract from hydrogel. Moreover, the biocompatibility of hydrogels enriched with extract was assessed via MTT assay, while antimicrobial activity was tested against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 10145, and Candida albicans ATCC 10231. The antioxidant capacity of the hydrogels was evaluated using DPPH, ABTS, and FRAP assays. Results: Our results showed that higher gelatin and CaCl₂ concentrations produced denser crosslinked networks, leading to reduced swelling and increased stiffness. Additionally, the extract exhibited a biphasic release profile from hydrogels, featuring an initial rapid release followed by sustained release over 24 h. Conclusions: The hydrogels maintained high biocompatibility and demonstrated selective antimicrobial activity, particularly against Escherichia coli, and satisfactory antioxidant activity. Obtained multifunctional sustainable hydrogels enriched with grape skin extract represent promising agents for managing skin conditions associated with oxidative stress and bacterial infections. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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18 pages, 4066 KiB

Open AccessArticle

Intravenous Administration of sRNA Nanoparticles for Treatment of Osteoporosis in Mice

by Xuemeng Mu, Xinyi Du, Huitian Han, Fei Liu, Zhifa Zheng, Jing Hao, Lijin Liu, Su Liu, Ze Wei, Changfa Huang, Annan Liang, Wei Zou, Lina Zhao, Zhihong Wu and Jia Zhang

Pharmaceutics 2025, 17(6), 789; https://doi.org/10.3390/pharmaceutics17060789 - 17 Jun 2025

Viewed by 510

Abstract

Background: With the intensification of population aging, osteoporosis has become one of the significant public health issues affecting human health. Currently available medications for treating osteoporosis are associated with various adverse effects and resistance issues. Oligonucleotide drugs show great potential. Effective delivery [...] Read more.

Background: With the intensification of population aging, osteoporosis has become one of the significant public health issues affecting human health. Currently available medications for treating osteoporosis are associated with various adverse effects and resistance issues. Oligonucleotide drugs show great potential. Effective delivery systems are essential to enhance the stability, bioavailability, and targeting of sRNA drugs. Lipid nanoparticles (LNPs) show promise as alternative osteoporosis therapeutics. This study explores the potential of LNPs as an effective delivery system to treat osteoporosis. Methods: LNPs were prepared using microfluidic techniques with varying lipid compositions, and characterized in terms of size, zeta potential, and entrapment efficiency (EE%). Dynamic light scattering (DLS) was employed to determine the size of the LNPs. The zeta potential was measured using electrophoretic light scattering. The pharmacodynamic effects and safety were then evaluated in a mouse model through intravenous administration. Results: Several lipid nanoparticle (LNP) formulations with different nitrogen/phosphorus ratios and different DMG-PEG2000 ratios were examined, and a lead candidate that supports delivery of sRNA in animal models of osteoporosis was identified. In OVX mice, LNP-sRNA significantly improved bone mineral density (BMD), trabecular microstructure, and biomechanical strength. Safety assessments revealed no systemic toxicity. It is shown that the optimized LNPs can serve as a promising delivery system to mediate sRNA delivery to bone tissue. Conclusions: After comparison of in vitro and in vivo properties, the optimized LNPs demonstrated good comprehensive performance as a delivery system for osteoporosis treatment. These results highlight the potential of the optimized LNPs as an ideal delivery system for osteoporosis, offering improved therapeutic efficacy and reduced systemic side effects. Full article

(This article belongs to the Special Issue Biomaterials and Delivery Systems for Regenerative Medicine)

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17 pages, 3289 KiB

Open AccessArticle

Incorporation of Mometasone Furoate into a Cyclodextrin Metal-Organic Framework to Optimize Nasal Administration

by Jie Li, Yuhua Guo, Yan Liu, Qingfang Gao, Siwen Wang, Li Wu, Caifen Wang, Xiaohong Ren and Jiwen Zhang

Pharmaceutics 2025, 17(6), 788; https://doi.org/10.3390/pharmaceutics17060788 - 17 Jun 2025

Viewed by 455

Abstract

Background/Objectives: Mometasone furoate (MF) is a topical corticosteroid used to reduce allergic and inflammation symptoms. In this study, MF was incorporated into the hydrophobic cavities of γ-cyclodextrin metal-organic frameworks (CD-MOFs) to prepare MF@MOF powders for nasal delivery. Methods: MF@MOF particles were characterized [...] Read more.

Background/Objectives: Mometasone furoate (MF) is a topical corticosteroid used to reduce allergic and inflammation symptoms. In this study, MF was incorporated into the hydrophobic cavities of γ-cyclodextrin metal-organic frameworks (CD-MOFs) to prepare MF@MOF powders for nasal delivery. Methods: MF@MOF particles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and thermogravimetry. A transparent biomimetic model of the human nasal cavity was produced by 3D printing and used to evaluate intra-nasal depositions patterns. Results: Drug loading was optimized by incubating MF with a CD-MOF at a ratio of 4% for 1 h at 40 °C, and the cubic morphology and particle size of the nanoparticles were not altered using an incubation method. PXRD and FTIR analyses confirmed the successful loading of MF into the CD-MOF. Using a 3D biomimetic nasal cavity model, a 30° administration angle was found to result in reduced drug accumulation in the nasal vestibule and enhanced deposition in the respiratory and olfactory regions, compared with administration at 45°. Approximately 51% of the drug reached the respiratory zone in the model of the nasal cavity from male subjects, while almost 60% of the drug reached this zone in the model associated with female subjects. Compared with nasal sprays, nasal powder sprays had less deposition in the nasal vestibule and more deposits in the middle and inferior nasal concha. Conclusions: MF@MOF is suitable for intranasal administration. Delivery of MF as a nasal powder shows potential in the treatment of chronic rhinosinusitis. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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12 pages, 440 KiB

Open AccessArticle

Metronidazole Suspension for Paediatric Use in Developing Countries: Formulation, Quality, and Stability

by Francesca Baratta, Chiara Zingarelli, Federica Fanton, Editson Lamy, Gaetano Di Lascio and Paola Brusa

Pharmaceutics 2025, 17(6), 787; https://doi.org/10.3390/pharmaceutics17060787 - 17 Jun 2025

Viewed by 443

Abstract

Background/Objectives. The paediatric population is a heterogenous group that is known to be a therapeutic orphan despite the recent incentives to promote the development of children’s formulations. Especially in low and middle-income countries, there is still a worldwide shortfall for the treatment and [...] Read more.

Background/Objectives. The paediatric population is a heterogenous group that is known to be a therapeutic orphan despite the recent incentives to promote the development of children’s formulations. Especially in low and middle-income countries, there is still a worldwide shortfall for the treatment and prevention of a variety of paediatric conditions. In this context, we developed a formulation specifically intended to administer metronidazole to paediatric patients using basic and low-cost excipients and with a simple set-up method. Methods. Various mixtures of excipients were prepared to obtain a suitable metronidazole liquid formulation at a concentration of 250 mg/5 mL. The best formula was tested for its quality and stability, assessing the uniformity of content, the pH, and the dispersion quality. We evaluated the stability of the preparation for 180 days at room temperature (25 +/− 2 °C), in a thermostatic oven (40 +/− 2 °C), and in a fridge (4 +/− 2 °C). Results. The tests performed gave excellent results. No variation greater than 10% was detected in the metronidazole concentration or in pH values after 180 days regardless of the temperature conditions during storage. Moreover, the microscope analysis confirmed the absence of significant differences over time. Conclusions. The results were consistent in different environmental conditions, ensuring the possibility of using the formulation even in those tropical countries where is not always possible to guarantee the conservation of medicines in controlled conditions. Moreover, the simple composition and easy preparation procedure make it possible to produce the suspension in any context, ensuring the quality of the finished product. Full article

(This article belongs to the Special Issue Extemporaneous Formulations: Filling the Gap in the Pharmaceutical Industry with Personalized Medicines)

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15 pages, 2461 KiB

Open AccessArticle

Development of Ethosomes for the Topical Treatment of Androgenic Alopecia: Ethanol Effect on Dutasteride Targeting to the Hair Follicles

by Jayanaraian F. M. Andrade, Rafael V. Rocho, Breno N. Matos, Geisa N. Barbalho, Kariane M. Nunes, Marcilio Cunha-Filho, Guilherme M. Gelfuso and Tais Gratieri

Pharmaceutics 2025, 17(6), 786; https://doi.org/10.3390/pharmaceutics17060786 - 17 Jun 2025

Viewed by 608

Abstract

Background/Objectives: Treatment options for androgenic alopecia are still very limited and lack long-term efficacy. Dutasteride (DUT) has gained interest as a potent inhibitor of 5α-reductase, allowing for spaced applications, but DUT oral intake can cause serious adverse effects. Herein, we developed, characterized, and [...] Read more.

Background/Objectives: Treatment options for androgenic alopecia are still very limited and lack long-term efficacy. Dutasteride (DUT) has gained interest as a potent inhibitor of 5α-reductase, allowing for spaced applications, but DUT oral intake can cause serious adverse effects. Herein, we developed, characterized, and assessed the potential of DUT-loaded ethosomes with increasing ethanolic concentrations for hair follicle (HF) targeting to treat androgenic alopecia, hypothesizing that ethanol’s interaction with HFs’ sebum might increase DUT targeting to the HFs. Methods: Ethosomes were obtained using the water-dropping method. After a hydrodynamic size screening, a 30% ethanol concentration was fixed. Ethosomes with 30% ethanol were also prepared and had their ethanolic content removed by rotary evaporation for the evaluation of ethanol in targeting DUT to the HFs. The targeting factor (Tf) was calculated as the ratio between the DUT amount in HFs and the total DUT amount recovered from all skin layers after in vitro porcine skin penetration tests for 12 and 24 h. Results: The ethanolic concentration affected the vesicles’ size and the targeting potential. While the dried ethosomes could not increase DUT accumulation in the HFs at both time points (Tf: 0.27 in 12 h and Tf: 0.28 in 24 h), the presence of 30% ethanol in the vesicles increased the Tf from 0.28 (12 h) to 0.34 (24 h), significantly superior (p < 0.05) than the dried ethosome and control (Tf: 0.24) in 24 h. Conclusion: Ethosomes with a 30% ethanolic concentration were slightly more efficient in targeting HFs for dutasteride delivery. Full article

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

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18 pages, 2691 KiB

Open AccessArticle

DNA Tweezers with Replaceable Clamps for the Targeted Degradation of Cell Membrane Proteins

by Yang Sun, Yichen Huang, Daiquan Chen, Shangjiu Hu, Tao Pan, Yuanding Liu, Ruowen Wang and Weihong Tan

Pharmaceutics 2025, 17(6), 785; https://doi.org/10.3390/pharmaceutics17060785 - 17 Jun 2025

Viewed by 455

Abstract

Background: Cell membrane proteins play crucial roles in signal transduction and nutrient transport. Many membrane proteins are reportedly overexpressed in cancer cells, which is closely related to cancer progression. The targeted degradation of these membrane proteins has been demonstrated to be a [...] Read more.

Background: Cell membrane proteins play crucial roles in signal transduction and nutrient transport. Many membrane proteins are reportedly overexpressed in cancer cells, which is closely related to cancer progression. The targeted degradation of these membrane proteins has been demonstrated to be a promising strategy for tumor treatment. Several strategies using aptamers to mediate membrane protein lysis, such as lysosomal-mediated lysis and proteasome-mediated lysis, have been reported, but their efficiency is limited by the binding affinity of the aptamer to a single target. Methods: We constructed DNA tweezers with replaceable clamps, which can lyse different proteins upon clamp replacement. Moreover, the clamp improved the degradation efficiency of the target proteins by enhancing the specificity and improving the binding affinity. Results: Lysis was verified in different tumor cell lines and the antitumor activity was confirmed in zebrafish. Conclusions: Overall, these DNA tweezers improve the efficiency of the targeted delivery of functional nucleic acids, provide an efficient and versatile strategy for the degradation of disease-causing proteins, and expand the approach to antitumor therapy. Full article

(This article belongs to the Special Issue Naturally Derived Materials-Based Drug Delivery Systems and Their Biomedical Applications)

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30 pages, 933 KiB

Open AccessReview

Hydroxypropyl Methylcellulose—A Key Excipient in Pharmaceutical Drug Delivery Systems

by Robert-Alexandru Vlad, Andrada Pintea, Cezara Pintea, Emőke-Margit Rédai, Paula Antonoaea, Magdalena Bîrsan and Adriana Ciurba

Pharmaceutics 2025, 17(6), 784; https://doi.org/10.3390/pharmaceutics17060784 - 16 Jun 2025

Cited by 1 | Viewed by 1953

Abstract

Hydroxypropyl methylcellulose (Hypromellose, HPMC) is a well-known excipient used in the pharmaceutical and nutraceutical fields due to its versatile physicochemical properties. HPMC (derived from cellulose and obtained through etherification) varies in polymerization degree and viscosity, factors that both influence its functional applications. Usually, [...] Read more.

Hydroxypropyl methylcellulose (Hypromellose, HPMC) is a well-known excipient used in the pharmaceutical and nutraceutical fields due to its versatile physicochemical properties. HPMC (derived from cellulose and obtained through etherification) varies in polymerization degree and viscosity, factors that both influence its functional applications. Usually, an increased polymerization degree implies a higher viscosity, depending also on the amount of polymer used. Hypromellose plays a crucial role in solid dosage forms, serving as a binder in the case of controlled-release tablets, a film-forming agent in the case of orodispersible films and mucoadhesive films, and a release modifier due to its presence in different polymerization degrees in the case of extended or modified release tablets. However, its compatibility with other excipients and the active ingredient must be carefully evaluated to prevent formulation challenges via several analytical methods such as differential scanned calorimetry (DSC), Fourier Transformed Infrared spectroscopy (FT-IR), X-Ray Particle Diffraction (XRPD), and Scanning Electron Microscopy (SEM). This review explores the physicochemical characteristics, and diverse applications of HPMC, emphasizing its significance in modern drug delivery systems. Full article

(This article belongs to the Special Issue Solid Dispersions for Drug Delivery: Development, Preparation and In Vitro/In Vivo Characterization)

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42 pages, 2266 KiB

Open AccessReview

Innovative Approaches in Cancer Treatment: Emphasizing the Role of Nanomaterials in Tyrosine Kinase Inhibition

by Antónia Kurillová, Libor Kvítek and Aleš Panáček

Pharmaceutics 2025, 17(6), 783; https://doi.org/10.3390/pharmaceutics17060783 - 16 Jun 2025

Viewed by 767

Abstract

Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge [...] Read more.

Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge technologies, structure-based drug design, and personalized medicine, is critical for developing effective therapies, specifically anticancer treatments. Background/Objectives: One of the key drivers of cancer at the cellular level is the abnormal activity of protein enzymes, specifically serine, threonine, or tyrosine residues, through a process known as phosphorylation. While tyrosine kinase-mediated phosphorylation constitutes a minor fraction of total cellular phosphorylation, its dysregulation is critically linked to carcinogenesis and tumor progression. Methods: Small-molecule inhibitors, such as imatinib or erlotinib, are designed to halt this process, restoring cellular equilibrium and offering targeted therapeutic approaches. However, challenges persist, including frequent drug resistance and severe side effects associated with these therapies. Nanomedicine offers a transformative potential to overcome these limitations. Results: By leveraging the unique properties of nanomaterials, it is possible to achieve precise drug delivery, enhance accumulation at target sites, and improve therapeutic efficacy. Examples include nanoparticle-based delivery systems for TKIs and the combination of nanomaterials with photothermal or photodynamic therapies to enhance treatment effectiveness. Combining nanomedicine with traditional treatments holds promise and perspective for synergistic and more effective cancer management. Conclusions: This review delves into recent advances in understanding tyrosine kinase activity, the mechanisms of their inhibition, and the innovative integration of nanomedicine to revolutionize cancer treatment strategies. Full article

(This article belongs to the Special Issue Kinase Inhibitors: Innovative Delivery Strategies and Anticancer Potential)

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24 pages, 675 KiB

Open AccessArticle

Nano-Liposomal Carrier as Promising Dermal Delivery Platform for Fumaria officinalis L. Bioactives

by Rabiea Ashowen Ahmoda, Milena Milošević, Aleksandar Marinković and Aleksandra A. Jovanović

Pharmaceutics 2025, 17(6), 782; https://doi.org/10.3390/pharmaceutics17060782 - 14 Jun 2025

Viewed by 1295

Abstract

Background/Objectives: This study investigates the physical, rheological, and antioxidant properties of nano-liposomal formulations encapsulating Fumaria officinalis L. (fumitory) extract, focusing on their stability and performance under ultraviolet (UV) exposure, as well as polyphenol release within simulated skin conditions in a Franz diffusion cell. [...] Read more.

Background/Objectives: This study investigates the physical, rheological, and antioxidant properties of nano-liposomal formulations encapsulating Fumaria officinalis L. (fumitory) extract, focusing on their stability and performance under ultraviolet (UV) exposure, as well as polyphenol release within simulated skin conditions in a Franz diffusion cell. Methods: Liposomal formulations, composed of phospholipids with or without β-sitosterol or ergosterol, were evaluated for their encapsulation efficiency, liposome size, size distribution, zeta potential, viscosity, surface tension, density, oxidative stability, antioxidant capacity, and polyphenol recovery. Results: Encapsulation efficiency was the highest in phospholipid liposomes (72.2%) and decreased with the incorporation of sterols: 66.7% for β-sitosterol and 62.9% for ergosterol liposomes. Encapsulation significantly increased viscosity and reduced surface tension compared to the plain liposomes, suggesting modified interfacial behavior. The inclusion of fumitory extract significantly increased the viscosity of liposomes (from ~2.5 to 6.09–6.78 mPa × s), consistent with the observed reduction in particle size and zeta potential. Antioxidant assays (thiobarbituric acid reactive substances—TBARS, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid—ABTS, and 2,2-diphenyl-1-picrylhydrazyl—DPPH) confirmed enhanced lipid peroxidation inhibition and radical scavenging upon encapsulation, with ABTS activity reaching up to 95.05% in sterol-containing liposomes. Release studies showed that the free extract exhibited the fastest polyphenol diffusion (5.09 × 10⁻⁹ m²/s), while liposomes demonstrated slower/controlled release due to bilayer barriers. UV-irradiated liposomes released more polyphenols than untreated ones, particularly in the sterol-containing formulations, due to oxidative destabilization and pore formation. Conclusions: These findings highlight the potential of fumitory extract-loaded liposomes as stable, bioactive carriers with tunable polyphenol antioxidant release properties for dermal applications. Overall, liposomal formulations of fumitory extract exhibit significant potential for further development as a pharmaceutical, cosmetic, or dermo-cosmetic ingredient for use in the prevention and treatment of various skin disorders. Full article

(This article belongs to the Special Issue Emerging Trends in Skin Delivery Systems)

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37 pages, 17348 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 - 14 Jun 2025

Viewed by 738

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, [...] 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 - 14 Jun 2025

Viewed by 510

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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57 pages, 5820 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 - 13 Jun 2025

Cited by 1 | Viewed by 690

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 - 13 Jun 2025

Viewed by 552

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 - 13 Jun 2025

Viewed by 1041

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 - 13 Jun 2025

Viewed by 456

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 - 13 Jun 2025

Viewed by 1389

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

Viewed by 672

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

Viewed by 648

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

Cited by 1 | Viewed by 620

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

Viewed by 598

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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Pharmaceutics, Volume 17, Issue 6 (June 2025) – 122 articles

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