Pharmaceutics

33 pages, 4015 KB

Open AccessArticle

PEGylated Zein Micelles for Prostate Cancer Therapy: Influence of PEG Chain Length and Transferrin Targeting on Docetaxel Delivery

by Khadeejah Maeyouf, Jitkasem Meewan, Hawraa Ali-Jerman, Musa Albatsh, Sukrut Somani, Partha Laskar, Margaret Mullin, Craig Irving, Graeme MacKenzie and Christine Dufès

Pharmaceutics 2026, 18(1), 68; https://doi.org/10.3390/pharmaceutics18010068 (registering DOI) - 4 Jan 2026

Abstract

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that [...] Read more.

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

9 pages, 207 KB

Open AccessEditorial

Pharmacokinetics and Drug Interactions

by Min-Koo Choi and Im-Sook Song

Pharmaceutics 2026, 18(1), 67; https://doi.org/10.3390/pharmaceutics18010067 (registering DOI) - 4 Jan 2026

Abstract

Adverse drug reactions—including those caused by drug–drug interactions (DDIs)—are a major cause of emergency department visits and subsequent hospitalizations in the United States, with studies estimating that 10–30% of these visits are drug-related [...] Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

22 pages, 1744 KB

Open AccessReview

From Circulation to Regeneration: Blood Cell Membrane-Coated Nanoparticles as Drug Delivery Platform for Immune-Regenerative Therapy

by Yun-A Kim, Min Hee Lee, Hee Su Sohn and Han Young Kim

Pharmaceutics 2026, 18(1), 66; https://doi.org/10.3390/pharmaceutics18010066 (registering DOI) - 4 Jan 2026

Abstract

Cell membrane-coated nanoparticles represent a biomimetic drug delivery approach that integrates biological membrane functions with synthetic nanomaterials. Among the various membrane sources, those derived from blood cells such as red blood cells, platelets, and leukocytes offer distinctive advantages, including immune evasion, prolonged systemic [...] Read more.

Cell membrane-coated nanoparticles represent a biomimetic drug delivery approach that integrates biological membrane functions with synthetic nanomaterials. Among the various membrane sources, those derived from blood cells such as red blood cells, platelets, and leukocytes offer distinctive advantages, including immune evasion, prolonged systemic circulation, and selective tissue targeting. These properties collectively enable efficient and biocompatible delivery of therapeutic agents to diseased tissues, minimizing off-target effects and systemic toxicity. This review focuses on blood cell membrane-derived nanocarriers as drug delivery and immune-regenerative platforms, in which membrane-mediated immunomodulation synergizes with therapeutic payloads to address inflammatory or degenerative pathology. We discuss recent advances in blood cell membrane coating technologies, including membrane isolation, nanoparticle core selection, fabrication techniques, and the development of hybrid and engineered membrane systems that enhance therapeutic efficacy through integrated immune regulation and localized drug action. To illustrate these advances, we also compile membrane type-specific nanocarrier systems, summarizing their core nanoparticle designs, coating strategies, therapeutic cargoes, and associated disease models. Challenges related to biological source variability, scalability, safety, and regulatory standardization remain important considerations for clinical translation. In this review we systematically address these issues and discuss emerging solutions and design strategies aimed at advancing blood cell membrane-based nanocarriers toward clinically viable immune-regenerative therapies. Full article

(This article belongs to the Special Issue Cell-Mediated Delivery Systems)

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14 pages, 1318 KB

Open AccessArticle

In Silico Studies and Biological Evaluation of Thiosemicarbazones as Cruzain-Targeting Trypanocidal Agents for Chagas Disease

by Lidiane Meier, Milena F. C. V. de Melo, Heitor R. Abreu, Isabella M. e Oliveira, Larissa Sens, Thiago H. Doring, Renata Krogh, Adilson Beatriz, Adriano D. Andricopulo, Sumbal Saba, Aldo S. de Oliveira and Jamal Rafique

Pharmaceutics 2026, 18(1), 65; https://doi.org/10.3390/pharmaceutics18010065 (registering DOI) - 4 Jan 2026

Abstract

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided [...] Read more.

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol’s reliability. Results: The top compounds—H7, H10 and H11—showed potent cruzain inhibition (IC₅₀ = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC₅₀ > 64 µM) and favorable selectivity. Structure–activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1′ subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. Conclusions: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain. Full article

(This article belongs to the Special Issue The Development of Drug Delivery Systems and Pharmaceutical Formulations for the Treatment of Infectious Diseases)

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17 pages, 3633 KB

Open AccessArticle

New Copper (II) Complexes Based on 1,4-Disubstituted-1,2,3-Triazole Ligands with Promising Antileishmanial Activity

by João P. C. Nascimento, Natali L. Faganello, Karolina F. Freitas, Leandro M. C. Pinto, Amarith R. das Neves, Diego B. Carvalho, Carla C. P. Arruda, Sidnei M. Silva, Rita C. F. Almeida, Amilcar M. Júnior, Davi F. Back, Lucas Pizzuti, Sumbal Saba, Jamal Rafique, Adriano C. M. Baroni and Gleison A. Casagrande

Pharmaceutics 2026, 18(1), 64; https://doi.org/10.3390/pharmaceutics18010064 (registering DOI) - 4 Jan 2026

Abstract

Background/Objectives: Leishmaniasis constitutes one of the most fatal parasitic diseases globally, adversely impacting the health of individuals residing in both intertropical and temperate zones. In these geographical areas, the administration of treatment is often inconsistent and largely ineffective with the available pharmaceuticals, as [...] Read more.

Background/Objectives: Leishmaniasis constitutes one of the most fatal parasitic diseases globally, adversely impacting the health of individuals residing in both intertropical and temperate zones. In these geographical areas, the administration of treatment is often inconsistent and largely ineffective with the available pharmaceuticals, as these exhibit more pronounced side effects than the therapeutic advantages they purport to provide. Methods: Consequently, the current investigation seeks to engage in molecular modeling of novel pharmacological candidates incorporating 1,2,3 disubstituted triazole moieties, coordinated with Cu^II metal centers, in pursuit of promising bioactive properties. Results: Two complexes were prepared and X-ray analysis revealed a comparable structural configuration surrounding the copper (II) atom. The planar square coordination geometry was elucidated through the assessment of the

τ_{4} = 0

(tau four) parameters. The comprehensive characterization encompasses HRMS-ESI (+), NMR, elemental analyses, mid-infrared, and UV-vis spectroscopic techniques. Time-dependent density functional theory (TD-DFT) analyses will substantiate the findings obtained through UV-vis spectroscopy. Crucially, the biological assays against Leishmania (L.) amazonensis revealed that Complex 1 exhibited outstanding potency against the intracellular amastigote form, demonstrating a half-maximal inhibitory concentration (IC₅₀) of 0.4 µM. This activity was 6-fold higher than that of amphotericin B (IC₅₀ = 2.5 µM) and 33-fold higher than pentamidine (IC₅₀ = 13.3 µM). Furthermore, Complex 1 showed a promising selectivity index (SI = 9.7) against amastigotes, surpassing the reference drugs and meeting the criteria for a lead compound. While less active on promastigotes, both complexes demonstrated high stability in DMSO solution, a prerequisite for biological testing. Conclusions: These results unequivocally identify Complex 1 as a highly promising candidate for the development of new antileishmanial therapies, warranting further in vivo studies. Full article

(This article belongs to the Special Issue The Development of Drug Delivery Systems and Pharmaceutical Formulations for the Treatment of Infectious Diseases)

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18 pages, 315 KB

Open AccessReview

Advances in Nanotechnology-Based Topical Delivery Systems for Skincare Applications

by Ziwei Yan, Sunxin Zhang, Guyuan Wu, Yunxiang Kang, Cong Fu, Zihan Wang, Guoqi Wang, Lu Tang and Wei Wang

Pharmaceutics 2026, 18(1), 63; https://doi.org/10.3390/pharmaceutics18010063 (registering DOI) - 3 Jan 2026

Abstract

The growing demand for effective skincare products that can effectively target specific dermatological concerns has accelerated the development of advanced delivery technologies. Among them, nanocarrier-based topical delivery systems have gained significant attention for their ability to enhance the performance of skincare formulations. Acting [...] Read more.

The growing demand for effective skincare products that can effectively target specific dermatological concerns has accelerated the development of advanced delivery technologies. Among them, nanocarrier-based topical delivery systems have gained significant attention for their ability to enhance the performance of skincare formulations. Acting as versatile delivery tools, nanocarriers not only stabilize and protect sensitive cosmetic ingredients but also improve their penetration through the skin barrier and enable controlled, sustained, or targeted release. Therefore, this review focuses on the recent achievements of nanocarrier-based topical delivery technology for skincare applications, which systematically summarizes the design principles, mechanisms and functional characteristics of diverse nano-based delivery platforms, including vesicular nanocarriers, lipid-based nanocarriers, emulsion-based nanocarriers, polymeric nanocarriers, inorganic nanoparticles, and inclusion complexes. Meanwhile, these nanocarriers are discussed according to their relevance to the pathogenesis of prevalent skin disorders, highlighting how tailored nanocarriers can address specific therapeutic or cosmetic needs. Overall, this review emphasizes the emerging trends and future perspectives of nanotechnology-based topical delivery systems in modern cosmetology, offering more opportunities for precise, effective and science-driven cosmetic solutions. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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25 pages, 2505 KB

Open AccessReview

Quality by Design for the Nanoformulation of Cosmeceuticals

by Gerardo Leyva-Gómez, Elizabeth Piñón-Segundo, Zaida Urban-Morlan, Nancy E. Magaña-Vergara, David Quintanar-Guerrero, Betzabeth Jaime-Escalante and Néstor Mendoza-Muñoz

Pharmaceutics 2026, 18(1), 62; https://doi.org/10.3390/pharmaceutics18010062 - 1 Jan 2026

Abstract

Cosmeceuticals are cosmetic formulations that are intended to alleviate skin conditions that affect its appearance and functionality. They are not considered medications but contain molecules that exert biological action on the skin beyond traditional cosmetic actions. Sometimes, the bioactives used have limitations for [...] Read more.

Cosmeceuticals are cosmetic formulations that are intended to alleviate skin conditions that affect its appearance and functionality. They are not considered medications but contain molecules that exert biological action on the skin beyond traditional cosmetic actions. Sometimes, the bioactives used have limitations for transdermal passage, and it has been suggested that the use of nanocarriers can increase the effectiveness of cosmeceutical products. The degree of sophistication of nanocosmeceuticals requires that safety and efficacy aspects be verified before going on the market. In this regard, the application of the Quality by Design (QbD) approach during product development ensures that products meet the consumer needs in full. This review analyzes the implementation of QbD in the development of nanocosmeceuticals, considering the main characteristics of the most used bioactive groups and nanocarriers that have proven to be ideal vehicles for topical and transdermal applications. Full article

(This article belongs to the Special Issue Controlled Delivery of Cosmeceuticals Using Nanotechnology)

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24 pages, 4478 KB

Open AccessArticle

Citicoline Triggers Proteome Remodeling and Proteostatic Adaptation: Evidence from Shotgun Proteomics

by Dario Cavaterra, Sara Giammaria, Irene Pandino, Gabriele Antonio Zingale, Valerio Delli Paoli, Rebecca Fiore, Manuele Michelessi, Gloria Roberti, Carmela Carnevale, Lucia Tanga, Daniela Cazzato, Elisa Peroni, Giuseppe Grasso, Gianluca Manni, Alessio Bocedi, Francesco Oddone, Massimiliano Coletta, Diego Sbardella and Grazia Raffaella Tundo

Pharmaceutics 2026, 18(1), 61; https://doi.org/10.3390/pharmaceutics18010061 - 1 Jan 2026

Abstract

Background/Objectives: Citicoline, also known as CDP-choline, is a nootropic agent currently used in the treatment of glaucoma and is undergoing evaluation as a first-line therapy in a multi-center, international, phase III, randomized clinical trial involving citicoline eyedrops (ClinicalTrials.gov ID: NCT05710198). Numerous clinical [...] Read more.

Background/Objectives: Citicoline, also known as CDP-choline, is a nootropic agent currently used in the treatment of glaucoma and is undergoing evaluation as a first-line therapy in a multi-center, international, phase III, randomized clinical trial involving citicoline eyedrops (ClinicalTrials.gov ID: NCT05710198). Numerous clinical and preclinical studies have linked the neuroenhancement and neuroprotective effects of citicoline to its role as a metabolic precursor for structural and functional components of cell membranes (such as phosphatidylcholine and sphingomyelin) and for neurotransmitters (e.g., acetylcholine and dopamine). However, compelling evidence suggests that the molecular mechanisms underlying its cytoprotective activity involve additional as-yet uncharacterized pharmacological actions. Methods: To further elucidate its pharmacology, we investigated the effect of two cytoprotective doses of citicoline (0.1 mM and 1 mM) on the global proteome of neuroblastoma cells using an unbiased shotgun proteomics approach. Results: With over 4000 unique proteins identified and quantified per experimental condition, the proteomics analysis revealed that citicoline, after 6 h of stimulation, induces a profound and robust remodeling of the intracellular proteome compared to untreated cells. Importantly, this effect was observed to significantly diminish by 18 h of stimulation, highlighting its transient nature (data are available via ProteomeXchange with identifier PXD061053). The clustering and rationalization of proteins upregulated by citicoline treatment identified the enrichment of key pathways for mRNA splicing, protein translation, proteostasis balance through the ubiquitin proteasome system (UPS), and mitochondrial metabolism. Conclusions: These proteomics findings introduce previously uncharacterized biological effects of citicoline and foster the working hypothesis that this drug may exert its cytoprotective activity through molecular mechanisms linked to the hormesis principle. These data further support the rationale for its clinical application in neurodegenerative processes and human disorders characterized by proteotoxicity. Full article

(This article belongs to the Special Issue Advances in Drug Delivery Systems for Targeted Neurological Therapies)

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33 pages, 1610 KB

Open AccessReview

Advancing Tuberculosis Treatment with Next-Generation Drugs and Smart Delivery Systems

by Ayman Elbehiry, Eman Marzouk and Adil Abalkhail

Pharmaceutics 2026, 18(1), 60; https://doi.org/10.3390/pharmaceutics18010060 - 1 Jan 2026

Abstract

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies [...] Read more.

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies can be translated “from molecule to patient” by coupling potent therapeutics with delivery platforms tailored to the lesion microenvironment. We survey emerging small-molecule classes, including decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) inhibitors, mycobacterial membrane protein large 3 (MmpL3) inhibitors, and respiratory chain blockers, alongside optimized uses of established agents and host-directed therapies (HDTs). These are mapped to inhalable and nanocarrier systems that improve intralesional exposure, macrophage uptake, and targeted release while reducing systemic toxicity. Particular emphasis is placed on pulmonary dry powder inhalers (DPIs) and aerosols for direct lung targeting, stimuli-responsive carriers that trigger release through pH, redox, or enzymatic cues, and long-acting depots or implants that shift daily dosing to monthly or quarterly schedules to enhance adherence, safety, and access. We also outline translational enablers, including model-informed pharmacokinetic/pharmacodynamic (PK/PD) integration, device formulation co-design, manufacturability, regulatory quality frameworks, and patient-centered implementation. Overall, aligning stronger drugs with smart delivery platforms offers a practical pathway to shorter, safer, and more easily completed TB therapy, improving both individual outcomes and public health impact. Full article

(This article belongs to the Special Issue Novel Therapeutic Agents and Innovative Delivery Systems Against Infectious Diseases)

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16 pages, 293 KB

Open AccessReview

The Role of Clinical Pharmacogenetics and Opioid Interactions in Pain Management: Current Evidence and Future Perspectives

by Clelia Di Salvo, Giulia Valdiserra, Stefano Balestrieri, Giuditta Beucci, Giulia Paciulli, Giovanna Irene Luculli, Alessandro De Vita, Matteo Fornai, Antonello Di Paolo and Luca Antonioli

Pharmaceutics 2026, 18(1), 59; https://doi.org/10.3390/pharmaceutics18010059 - 1 Jan 2026

Abstract

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the [...] Read more.

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches. Full article

(This article belongs to the Special Issue Personalized Medicine: Integrating Pharmacogenetics and Pharmacokinetics)

19 pages, 2802 KB

Open AccessArticle

In Vitro and In Silico Evaluation of Polymyxin B Aerosol Delivery in Adult Mechanical Ventilation

by Shengnan Zhang, Guanlin Wang, Jingjing Liu, Xuejuan Zhang and Qi Pei

Pharmaceutics 2026, 18(1), 58; https://doi.org/10.3390/pharmaceutics18010058 - 31 Dec 2025

Abstract

Background: Nebulized polymyxin B (PMB) therapy is widely used in intensive care units for treating hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria, yet its pulmonary delivery performance during invasive mechanical ventilation remains poorly characterized. Methods: An in vitro adult mechanical ventilation [...] Read more.

Background: Nebulized polymyxin B (PMB) therapy is widely used in intensive care units for treating hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria, yet its pulmonary delivery performance during invasive mechanical ventilation remains poorly characterized. Methods: An in vitro adult mechanical ventilation model was used. We evaluated two nebulizers (vibrating mesh nebulizer [VMN] and jet nebulizer [JN]) at three positions (standalone nebulizer, 15 cm from the Y-piece, and the humidifier’s dry end) with two artificial airway types (endotracheal and tracheostomy tubes). Lung deposition was predicted using the multiple-path particle dosimetry model, incorporating the Yeh/Schum five-lobe adult lung model. Results: In the standalone setup, the percentage of delivered dose of VMN and JN was approximately 40% and 34%, respectively. Mechanical ventilation significantly reduced the delivered dose (all p ≤ 0.0085), with VMN at the humidifier’s dry end delivering only 2.14–2.99% of the nominal dose. In all the tested ventilation scenarios, both the use of the JN and positioning the nebulizer 15 cm from the Y-piece significantly increased aerosol delivery (all p ≤ 0.021). While the ventilator circuit reduced the total drug amount, it filtered larger aerosols. This resulted in a smaller mass median aerodynamic diameter and a higher fine particle fraction (all p < 0.0001), which doubled the predicted alveolar deposition fraction (from 13–14% in standalone to 23–28% in ventilation scenarios) and eliminated extrathoracic deposition. Conclusions: This study provides the first in vitro and in silico assessment of PMB aerosol delivery during invasive mechanical ventilation. Nebulizer type, its placement within the circuit, and the artificial airway are critical factors that significantly alter the pulmonary delivery of PMB aerosol and subsequently impact its lung deposition. Full article

(This article belongs to the Special Issue Optimizing Aerosol Therapy: Strategies for Pulmonary Drug Delivery)

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26 pages, 3111 KB

Open AccessArticle

Preclinical Investigation of PLGA Nanocapsules and Nanostructured Lipid Carriers for Organoselenium Delivery: Comparative In Vitro Toxicological Profile and Anticancer Insights

by Bianca Costa Maia-do-Amaral, Taís Baldissera Pieta, Luisa Fantoni Zanon, Gabriele Cogo Carneosso, Laísa Pes Nascimento, Nayra Salazar Rocha, Bruna Fracari do Nascimento, Letícia Bueno Macedo, Tielle Moraes de Almeida, Oscar Endrigo Dorneles Rodrigues, Scheila Rezende Schaffazick, Clarice Madalena Bueno Rolim and Daniele Rubert Nogueira-Librelotto

Pharmaceutics 2026, 18(1), 57; https://doi.org/10.3390/pharmaceutics18010057 - 31 Dec 2025

Abstract

Background/Objectives: Cancer is a major health concern involving abnormal cell growth. Combining anticancer agents can enhance efficacy and overcome resistance by targeting multiple pathways and creating synergistic effects. Methods: This study used in silico approaches to evaluate the physicochemical and pharmacokinetic profiles of [...] Read more.

Background/Objectives: Cancer is a major health concern involving abnormal cell growth. Combining anticancer agents can enhance efficacy and overcome resistance by targeting multiple pathways and creating synergistic effects. Methods: This study used in silico approaches to evaluate the physicochemical and pharmacokinetic profiles of the innovative organoselenium nucleoside analog Di3a, followed by the design of two nanocarriers. Di3a-loaded PLGA nanocapsules and nanostructured lipid carriers based on compritol were prepared and evaluated alone and combined with doxorubicin (DOX) and docetaxel (DTX) for a synergistic effect. Results: Di3a subtly violated some of Lipinski’s rules, but still showed suitable pharmacokinetic properties. Both nanoparticles presented nanometric size, negative zeta potential and polydispersity index values < 0.20. Hemolysis assay suggested a pH-dependent pattern conferred by the surfactant 77KL, and evidenced the biocompatibility of the formulations, aligning with the results observed in the nontumor L929 cell line. The lack of drug release studies under varying pH conditions constitutes a limitation and warrants further investigation to validate the pH-responsive properties of the nanocarriers. MTT assay revealed that both formulations exhibited significant cytotoxic effects in the A549 cell line. However, neither formulation exhibited marked toxicity toward NCI/ADR-RES, a resistant tumor cell line. Conversely, when combined with DOX or DTX, the treatments were able to sensitize these resistant cells, achieving expressive synergistic antitumor activity. Conclusions: Despite the limitations in the in silico studies, the study highlights the potential of combining the proposed nanocarriers with conventional antitumor drugs to sensitize multidrug-resistant cancer cells and emphasizes the safety of the developed nanoformulations. Full article

(This article belongs to the Special Issue Application of PLGA Nanoparticles in Cancer Therapy)

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16 pages, 3831 KB

Open AccessArticle

Development of a Microwell System for Reproducible Formation of Homogeneous Cell Spheroids

by Miguel A. Reina Mahecha, Ginevra Mariani, Pauline E. M. van Schaik, Paulien Schaafsma, Theo G. van Kooten, Prashant K. Sharma and Inge S. Zuhorn

Pharmaceutics 2026, 18(1), 56; https://doi.org/10.3390/pharmaceutics18010056 - 31 Dec 2025

Abstract

Background/Objectives: Three-dimensional (3D) cell cultures are increasingly used because 3D cell aggregates better mimic tissue-level biological mechanisms and support studies of tissue physiology and drug screening. However, existing laboratory methods and commercial microwell platforms often yield inconsistent results and can be error-prone, time-consuming, [...] Read more.

Background/Objectives: Three-dimensional (3D) cell cultures are increasingly used because 3D cell aggregates better mimic tissue-level biological mechanisms and support studies of tissue physiology and drug screening. However, existing laboratory methods and commercial microwell platforms often yield inconsistent results and can be error-prone, time-consuming, or costly. The objective of this work was to develop a reproducible, high-yield, and cost-effective approach for generating homogeneous cell aggregates using custom 3D-printed microwell stamps. Methods: Custom conical and semi-spherical microwell stamps were fabricated using 3D printing. Stamp resolution was characterized by scanning electron microscopy (SEM). Negative imprints were cast in polydimethylsiloxane (PDMS), a biocompatible and hydrophobic polymer conducive to cell aggregation. These PDMS microwells were then used to generate pluripotent stem cell aggregates (embryoid bodies, EBs) and tumor spheroids from adherent cancer cell lines. Results: The 3D-printed stamps produced high-resolution conical and semi-spherical microwells in PDMS. Semi-spherical microwells enabled rapid, simple, and cost-effective formation of pluripotent stem cell aggregates that were homogeneous in size and shape. These aggregates outperformed those produced using commercial microwell plates and ultra-low attachment plates. The fabricated microwells also generated uniform tumor spheroids from adherent cancer cells, demonstrating their versatility. Conclusions: The in-house 3D-printed microwell stamps offer a reproducible, efficient, and economical platform for producing homogeneous cell aggregates. This system improves upon commercial alternatives and supports a broad range of applications, including pluripotent stem cell embryoid body formation and tumor spheroid generation. Full article

(This article belongs to the Special Issue 3D Printing in Bioengineering and Pharmaceutical Manufacturing)

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25 pages, 876 KB

Open AccessReview

Selective Nanoparticulate Systems for Drug Delivery in Inflammatory Bowel Disease

by Alberta Ribeiro and Rute Nunes

Pharmaceutics 2026, 18(1), 55; https://doi.org/10.3390/pharmaceutics18010055 - 31 Dec 2025

Abstract

Inflammatory bowel disease is a result of inappropriate continuous non-specific inflammation in the intestinal tract, which in turn is aggravated by defects in the activation of the mucosal immune system and in the barrier function of the intestinal epithelium. The most prominent manifestations [...] Read more.

Inflammatory bowel disease is a result of inappropriate continuous non-specific inflammation in the intestinal tract, which in turn is aggravated by defects in the activation of the mucosal immune system and in the barrier function of the intestinal epithelium. The most prominent manifestations of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). UC is characterized by a continuous pattern that commonly starts with lesions in rectum mucosa and is contained in the colon. On the other hand, CD affects the ileum and colon in a discontinuous pattern, and the lesions are often transmural. Conventional therapies often face limitations such as systemic side effects, poor drug stability, and low site-specificity. In recent years, nanoparticle (NP) systems have emerged as a promising strategy to overcome these challenges, offering improved targeting, controlled release, and enhanced therapeutic efficacy. Several studies have shown that the preferential accumulation of NPs in the inflamed colon is influenced by the pathophysiological changes associated with IBD, including alterations in transit time, pH value, enzymatic activity, microbial composition, and mucus integrity. These disease-specific characteristics provide unique opportunities to design smart and responsive NPs that enhance drug delivery and therapeutic efficacy while minimizing systemic exposure. This work presents an overview of novel technologies based on nanosystems, with the ability to specifically target the affected areas of the GI tract in inflammatory bowel disease. Full article

(This article belongs to the Special Issue Inflammation-Targeted Nanomedicines for the Treatment of Chronic Inflammatory Diseases and Cancer)

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40 pages, 1786 KB

Open AccessReview

Folate-Functionalized Albumin-Containing Systems: Non-Covalent vs. Covalent Binding of Folic Acid

by Maria G. Gorobets, Anna V. Toroptseva, Madina I. Abdullina, Derenik S. Khachatryan and Anna V. Bychkova

Pharmaceutics 2026, 18(1), 54; https://doi.org/10.3390/pharmaceutics18010054 - 31 Dec 2025

Abstract

Nano- and submicron particles (NSPs) with folate for targeting are actively used for the treatment and diagnosis of cancer and inflammatory diseases. Albumin-containing systems have enhanced biocompatibility, circulation time, and colloidal stability, which are important for medical applications. The outstanding binding properties of [...] Read more.

Nano- and submicron particles (NSPs) with folate for targeting are actively used for the treatment and diagnosis of cancer and inflammatory diseases. Albumin-containing systems have enhanced biocompatibility, circulation time, and colloidal stability, which are important for medical applications. The outstanding binding properties of albumin allow the transport of numerous therapeutic and/or imaging agents. This review summarizes multiple aspects of binding a folate residue (or folic acid) to NSPs and the functioning of folate-albumin-NSPs. Special attention in the review is given to the types of bonds between folic acid and albumin, i.e., covalent and non-covalent, and to the confirmation and quantification of binding by different physicochemical methods. The process of binding, the qualitative and quantitative characteristics of binding and forming product, and its functioning are interconnected with the binding conditions; thus, an analysis of reaction conditions is provided. For the proper functioning of folate-albumin-NSPs, the state of albumin within them is important; thus, considerable focus in the review is placed on the features of structure modification of serum albumin in folate-albumin binding, i.e., the amino acid residues involved in this process and the conformational state of the protein. The stability and the functioning of the protein within folate-albumin-NSPs are discussed. Also, the effectiveness of targeting by folate is viewed as dependent on many characteristics of folate-albumin-NSPs, particularly on the peculiarities of binding between the folic acid residue and albumin. Furthermore, the authors discussed and suggested solutions concerning the shortcomings highlighted in the studies devoted to obtaining folate-modified albumin-containing NSPs. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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29 pages, 3472 KB

Open AccessArticle

Emulsome-Based Nanocarrier System for Controlled 4-Phenylbutyric Acid Delivery and Mechanistic Mitigation of Arsenical-Induced Skin Injury via Foam Application

by Nethra Viswaroopan, Meheli Ghosh, Sharvari M. Kshirsagar, Jasim Khan, Jennifer Toral-Orduno, Ritesh K. Srivastava, Mohammad Athar and Ajay K. Banga

Pharmaceutics 2026, 18(1), 53; https://doi.org/10.3390/pharmaceutics18010053 - 30 Dec 2025

Abstract

Background: Lewisite, a potent chemical warfare agent, induces rapid and progressive cutaneous damage, necessitating treatment strategies that offer both immediate decontamination and prolonged therapeutic action. This study aimed to develop and evaluate a composite topical formulation comprising 4-phenylbutyric acid (4-PBA)-loaded emulsomes embedded [...] Read more.

Background: Lewisite, a potent chemical warfare agent, induces rapid and progressive cutaneous damage, necessitating treatment strategies that offer both immediate decontamination and prolonged therapeutic action. This study aimed to develop and evaluate a composite topical formulation comprising 4-phenylbutyric acid (4-PBA)-loaded emulsomes embedded within a foam vehicle to address both aspects of vesicant-induced skin injury intervention. Methods: Emulsomes composed of a stearic acid–cholesterol solid lipid core stabilized by a lecithin shell were prepared via thin film hydration and optimized by varying lipid ratios and drug loading parameters. Formulations were characterized for drug loading, particle size, and zeta potential. Physicochemical compatibility was assessed using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses. Stability was evaluated under accelerated refrigerated (25 °C/60% RH) and room temperature (40 °C/75% RH) conditions. The optimized formulation was incorporated into a foam base and evaluated for decontamination efficiency, drug release kinetics, in vitro permeation, and in vivo efficacy. Results: The selected formulation (E2) exhibited high drug loading (17.01 ± 0.00%), monodisperse particle size (PDI = 0.3 ± 0.07), and stable zeta potential (−40 ± 1.24 mV). FTIR and DSC confirmed successful encapsulation with amorphous drug dispersion. The emulsome-foam demonstrated dual functionality: enhanced decontamination (66.84 ± 1.27%) and sustained release (~30% over 24 h), fitting a Korsmeyer–Peppas model. In vitro permeation showed significantly lower 4-PBA delivery from E2 versus free drug, confirming sustained release, while in vivo studies demonstrated therapeutic efficacy. Conclusions: This emulsome-foam system offers a promising platform for topical treatment of vesicant-induced skin injury by enabling both immediate detoxification and prolonged anti-inflammatory drug delivery. Full article

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

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25 pages, 11658 KB

Open AccessArticle

Effect of Treatment with a Combination of Dichloroacetate and Valproic Acid on Adult Glioblastoma Patient-Derived Primary Cells Xenografts on the Chick Embryo Chorioallantoic Membrane

by Rūta Skredėnienė, Donatas Stakišaitis, Aidanas Preikšaitis, Angelija Valančiūtė, Vaiva Lesauskaitė and Ingrida Balnytė

Pharmaceutics 2026, 18(1), 52; https://doi.org/10.3390/pharmaceutics18010052 - 30 Dec 2025

Abstract

Background/Objectives: The ineffectiveness of current treatments for glioblastoma underscores the urgent need for effective alternatives. This study aimed to investigate the effectiveness of sodium dichloroacetate (NaDCA) and a sodium valproate NaDCA combination (NaVPA–NaDCA) on formed patients’ primary cell tumors on the chick embryo [...] Read more.

Background/Objectives: The ineffectiveness of current treatments for glioblastoma underscores the urgent need for effective alternatives. This study aimed to investigate the effectiveness of sodium dichloroacetate (NaDCA) and a sodium valproate NaDCA combination (NaVPA–NaDCA) on formed patients’ primary cell tumors on the chick embryo chorioallantoic membrane (CAM). Methods: Glioblastoma tissue samples were obtained from three patients during tumor surgery. WHO grade IV, IDH wild-type, and a strong positive cytoplasmic GFAP reaction in tumor cells characterized the investigated glioblastoma cases. The tumor cells GBM2-2F, GBM2-3F, and GBM-4M from the patients were examined. Histological examination of tumor invasion into CAM, angiogenesis, and immunohistochemical expression of GFAP-, PCNA-, p53-, EZH2- and vimentin-positive cells were examined. Results: No difference in GFAP expression was observed between the patient’s GBM tumor tissue and the tumor formed on CAM from the same patient’s tumor cells. There were no significant differences in invasion or in the frequency of GFAP- and p53-positive cells among the study control groups. The expression of PCNA-, EZH2-, and vimentin-positive cells in control tumors varied significantly. Treatment significantly reduced the incidence of tumor invasion in GBM2-2F and GBM2-4M and did not affect GBM2-3F tumors; treatment also significantly reduced GFAP expression in GBM2-3F and GBM2-4M and did not affect GBM2-2F tumors. The treatment with NaVPA–NaDCA significantly reduced the expression of PCNA, p53, EZH2 and vimentin in the tested tumors. Conclusions: Data demonstrated an antitumor effect of NaVPA–NaDCA in an in vivo model of a patient’s primary glioblastoma cells. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies, 2nd Edition)

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19 pages, 4399 KB

Open AccessArticle

Novel Insights on the Synergistic Mechanism of Action Between the Polycationic Peptide Colistin and Cannabidiol Against Gram-Negative Bacteria

by Merlina Corleto, Matías Garavaglia, Melina M. B. Martínez, Melanie Weschenfeller, Santiago Urrea Montes, Martin Aran, Leonardo Pellizza, Diego Faccone and Paulo C. Maffía

Pharmaceutics 2026, 18(1), 51; https://doi.org/10.3390/pharmaceutics18010051 - 30 Dec 2025

Abstract

Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatment against MDR Gram-negative pathogens due to the development of extensively drug-resistant Gram-negative bacteria. Unfortunately, rapid global resistance towards colistin has emerged, which represents a major public health concern. In this context (CBD), [...] Read more.

Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatment against MDR Gram-negative pathogens due to the development of extensively drug-resistant Gram-negative bacteria. Unfortunately, rapid global resistance towards colistin has emerged, which represents a major public health concern. In this context (CBD), a lipophilic molecule derived from Cannabis sativa, exhibits antimicrobial activity mainly against Gram-positive bacteria but is generally ineffective against Gram-negative species. However, synergistic antibacterial activity between CBD and polymyxin B has been reported. The objective of this work is to analyze the colistin–CBD synergy against clinically relevant Gram-negative isolates displaying diverse mechanisms of colistin resistance and to explore the basis of the possible mechanism of action involved in the first steps of this synergy. Methods: Microbiological assays, minimal inhibitory concentration, cell culture, synergy tests by checker board and time kill, biofilm inhibition evaluation by crystal violet and MTT, SEM (scanning electron microscopy), molecules interaction analysis by nuclear magnetic resonance (NMR). Results: The colistin–CBD combination displayed synergy in colistin resistant Gram-negative bacteria and also disrupted preformed biofilms and killed bacteria within them. Time-kill assays revealed rapid bactericidal activity and SEM showed mild surface alterations on bacterial outer membranes after sublethal colistin monotherapy. Furthermore, a series of sequential treatment assays on colistin-resistant Escherichia coli showed that simultaneous exposure to both compounds was required for activity, as introducing a washing step between treatments abolished the antibacterial effect. In order to obtain deeper insight into this mechanism, NMR analyses were performed, revealing specific molecular interactions between CBD and colistin molecules. Conclusions: These results provide evidence for the first time that both molecules engage through a specific and structurally meaningful interaction and only display synergy when acting together on colistin-resistant bacteria. Full article

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

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26 pages, 4811 KB

Open AccessArticle

Boosting LNP Performance: Higher Concentrations of Lipid Mixtures Improve In Vivo Gene Expression and Storage Stability

by Blerina Shkodra, Ashish Muglikar, Janani Thangapandian, Matthias Schumacher, Burcu Binici and Yvonne Perrie

Pharmaceutics 2026, 18(1), 50; https://doi.org/10.3390/pharmaceutics18010050 - 30 Dec 2025

Abstract

Background: An efficient formulation of lipid nanoparticles (LNPs) is often considered crucial in the successful development of nucleic acid therapeutics. This study explores the impact of varying the lipid and payload concentrations as starting materials on key LNP properties. Results: The [...] Read more.

Background: An efficient formulation of lipid nanoparticles (LNPs) is often considered crucial in the successful development of nucleic acid therapeutics. This study explores the impact of varying the lipid and payload concentrations as starting materials on key LNP properties. Results: The outcomes of the study revealed that the desired particle properties could be retained even at a starting lipid mixture concentration of 70 mg/mL. Particle size remained largely unchanged despite changes in lipid mixture concentration, with polydispersity index values below 0.2. CryoTEM analysis revealed that LNPs prepared using higher lipid mixture concentrations were more uniform and more abundant in solid core morphologies. Buffer composition was shown to influence the LNP particle size, surface charge, and gene expression, as well as storage stability. In vivo studies in mice showed enhanced gene expression and biodistribution for LNPs formulated at higher lipid and RNA concentrations, with LNPs in Tris-sucrose eliciting superior gene expression compared to LNPs in PBS. Conclusions: This study demonstrated that intensified mixing processes based on confined jet-impingement allow the use of elevated starting material concentrations in LNP formulations, resulting in improved biological performance and stability of mRNA-LNPs, as well as enhanced scalability and throughput. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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