Pharmaceutics

18 pages, 8849 KB

Open AccessArticle

Innovative Titanium Implants Coated with miR-21-Loaded Nanoparticle for Peri-Implantitis Prevention

by Anna Valentino, Raffaele Conte, Pierfrancesco Cerruti, Roberta Condò, Gianfranco Peluso and Anna Calarco

Pharmaceutics 2026, 18(1), 142; https://doi.org/10.3390/pharmaceutics18010142 - 22 Jan 2026

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Abstract

Background/Objectives: Peri-implantitis is a chronic inflammatory condition affecting tissues surrounding dental implants and is characterized by progressive marginal bone loss that can ultimately lead to implant failure. Reduced vascularization and impaired immune clearance in peri-implant tissues contribute to persistent inflammation and limited therapeutic [...] Read more.

Background/Objectives: Peri-implantitis is a chronic inflammatory condition affecting tissues surrounding dental implants and is characterized by progressive marginal bone loss that can ultimately lead to implant failure. Reduced vascularization and impaired immune clearance in peri-implant tissues contribute to persistent inflammation and limited therapeutic efficacy. MicroRNAs (miRNAs), particularly miR-21, have emerged as key regulators of inflammatory responses and bone remodeling. The objective of this study was to develop a bioactive dental implant coating capable of locally delivering miR-21 to modulate inflammation and promote peri-implant tissue regeneration, thereby preventing peri-implantitis. Methods: Cationic nanoparticles were synthesized using lecithin and low-molecular-weight polyethylenimine (PEI) as a non-viral delivery system for miR-21. Lecithin was employed to enhance biocompatibility, while PEI functionalization provided a positive surface charge to improve miRNA complexation and cellular uptake. The resulting lecithin–PEI nanoparticles (LEC–PEI NPs) were incorporated into a chitosan-based coating and applied to titanium implant surfaces to obtain a sustained miR-21–releasing system (miR21-implant). Transfection efficiency and biological activity were evaluated in human periodontal ligament fibroblasts (hPDLFs) and compared with a commercial transfection reagent (Lipofectamine). Release kinetics and long-term activity of miR-21 from the coating were also assessed. Results: MiR-21-loaded LEC–PEI nanoparticles demonstrated significantly higher transfection efficiency than Lipofectamine and retained marked biological activity in hPDLFs relevant to peri-implantitis prevention. The chitosan-based nanoparticle coating enabled controlled and sustained miR-21 release over time, supporting prolonged modulation of inflammatory and osteogenic signaling pathways involved in peri-implant tissue homeostasis. Conclusions: The miR21-implant system, based on lecithin–PEI nanoparticles incorporated into a chitosan coating, represents a promising therapeutic strategy for peri-implantitis prevention. By enabling sustained local delivery of miR-21, this approach has the potential to preserve peri-implant bone architecture, modulate chronic inflammation, and enhance the osseointegration of titanium dental implants. Full article

(This article belongs to the Special Issue Biomaterials and Agents: Pharmaceutical and Biomedical Applications in Dental Research, 2nd Edition)

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13 pages, 1337 KB

Open AccessArticle

Peripheral Analgesic Effect of a Novel Curcuminoid Derivative: Possible Involvement of Peripheral Opioid Receptor and ATP-Sensitive Potassium Ion Channel

by Ming Tatt Lee, Yu-Cheng Ho, Chau Ling Tham, Ahmad Akira, Nordin Lajis, Daud Ahmad Israf and Mohd Roslan Sulaiman

Pharmaceutics 2026, 18(1), 141; https://doi.org/10.3390/pharmaceutics18010141 - 22 Jan 2026

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Abstract

Background/Objectives: The present study investigated the local analgesic effect of a novel synthetic cyclohexanone derivative, 2,6-bis-4-(hydroxyl-3-methoxybenzilidine)-cyclohexanone, or BHMC, in a mouse model of peripheral nociception. Methods: Local administration of BHMC (0.5–60 µg/paw) intra-plantarly in the hindpaws of mice exhibited significant inhibition in carrageenan-induced [...] Read more.

Background/Objectives: The present study investigated the local analgesic effect of a novel synthetic cyclohexanone derivative, 2,6-bis-4-(hydroxyl-3-methoxybenzilidine)-cyclohexanone, or BHMC, in a mouse model of peripheral nociception. Methods: Local administration of BHMC (0.5–60 µg/paw) intra-plantarly in the hindpaws of mice exhibited significant inhibition in carrageenan-induced paw hyperalgesia. Intra-plantar pretreatment of naloxone (non-selective opioid receptor blocker), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP, selective µ-opioid receptor blocker), and nor-binaltorphimine (nor-BNI, selective κ-opioid receptor blocker), but not naltrindole hydrochloride (selective δ-opioid receptor blocker), reversed the anti-nociceptive effect of BHMC. The peripheral analgesic effect of BHMC was also reversed by intra-plantar pretreatment of methylene blue (soluble guanosyl cyclase blocker), but not N^G-nitro-L-arginine (L-NAME, nitric oxide synthase blocker). Involvement of the potassium channel in the local analgesic effect of BHMC was shown through the reversed analgesic effect by intra-plantar pretreatment of glibenclamide (ATP-sensitive potassium channel blocker), but not by charybdotoxin (large-conductance calcium-sensitive potassium channel blocker), apamin (small-conductance calcium-sensitive potassium ion channel blocker), or tetraethylammonium (voltage-sensitive potassium channel blocker). Results: Taken together, the present study demonstrated that the local administration of BHMC attenuated nociception, with possible mechanisms that may involve the desensitization of inflammatory mediators’ receptors, opioid receptor activation, and nitric oxide-independent cyclic guanosine monophosphate activation of ATP-sensitive potassium ion channel opening. Conclusions: The current findings may further support the exploration of BHMC as a new therapeutic agent for pain and inflammation, for the betterment of human health. Full article

(This article belongs to the Special Issue Emerging Drugs and Formulations for Pain Treatment)

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33 pages, 1466 KB

Open AccessReview

Current Evidence from Animal Models on Molecular Changes Underlying Antidepressant Effects of Psychobiotics

by Nevena Todorović Vukotić, Neda Đorđević, Andrijana Stanisavljević Ilić, Svetlana Soković Bajić and Ivana Perić

Pharmaceutics 2026, 18(1), 140; https://doi.org/10.3390/pharmaceutics18010140 - 22 Jan 2026

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Abstract

The treatment of depression is an uphill battle due to the low efficiency and delayed clinical response of antidepressants and the fact that most of them cause numerous side effects. Psychobiotics, probiotics that affect brain function and confer mental health benefits, emerged as [...] Read more.

The treatment of depression is an uphill battle due to the low efficiency and delayed clinical response of antidepressants and the fact that most of them cause numerous side effects. Psychobiotics, probiotics that affect brain function and confer mental health benefits, emerged as a promising ally showing protective effects against depressive- and anxiety-like behaviors in various animal models of depression. There is rapidly accumulating evidence that psychobiotics show protective effects at the molecular level as well, affecting several pathophysiological processes implicated in depression. This narrative review summarizes preclinical insights into molecular changes related to the hypothalamic-pituitary-adrenal (HPA) axis, peripheral inflammation, neuroinflammation, neurotransmission and tryptophan metabolism underlying psychobiotic-driven mitigation of depressive and anxiety symptoms in stress-based, corticosterone-induced and inflammation-induced animal models of depression. Research evidence indicates that psychobiotics normalize the activity of the HPA axis, decrease levels of inflammatory mediators in the intestine, circulation, and brain, normalize the levels of neurotransmitters and their receptors, and regulate tryptophan metabolism in various animal models of depression. The main setbacks in this field are the extensive diversity of studied probiotic strains, which are often insufficiently characterized, and the lack of mechanistic studies in animal models. However, despite these challenges, further study of psychobiotics in the pursuit of supportive therapies for depressive disorders is firmly grounded. Full article

(This article belongs to the Special Issue Anti-Inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside, 3rd Edition)

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16 pages, 1961 KB

Open AccessArticle

Solid Microneedles from Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate): A Solvent-Free, Biodegradable Platform for Drug Delivery

by Diana Araújo, Francisco Santos, Rui Igreja and Filomena Freitas

Pharmaceutics 2026, 18(1), 139; https://doi.org/10.3390/pharmaceutics18010139 - 22 Jan 2026

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Abstract

Background: Solid microneedles (MNs) are effective transdermal delivery devices but are commonly fabricated from metallic or non-biodegradable materials, raising concerns related to sustainability, waste management, and processing constraints. This study aimed to evaluate the suitability of the biodegradable biopolyester poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBHVHHx) as [...] Read more.

Background: Solid microneedles (MNs) are effective transdermal delivery devices but are commonly fabricated from metallic or non-biodegradable materials, raising concerns related to sustainability, waste management, and processing constraints. This study aimed to evaluate the suitability of the biodegradable biopolyester poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBHVHHx) as a structuring material for solvent-free fabrication of solid MN arrays and to assess their mechanical performance, insertion capability, and drug delivery potential. Methods: PHBHVHHx MN arrays were fabricated by solvent-free micromolding at 200 °C. The resulting MNs were morphologically characterized by scanning electron microscopy. Mechanical properties were assessed by axial compression testing, and insertion performance was evaluated using a multilayer Parafilm skin simulant model. Diclofenac sodium was used as a model drug and applied via surface coating using a FucoPol-based formulation. In vitro drug release was assessed in phosphate-buffered saline under sink conditions and quantified by UV–Vis spectroscopy. Results: PHBHVHHx MN arrays consisted of sharp, well-defined conical needles (681 ± 45 µm length; 330 µm base diameter) with micro-textured surfaces. The MNs withstood compressive forces up to 0.25 ± 0.03 N/needle and achieved insertion depths of approximately 396 µm in the Parafilm model. Drug-coated MNs retained adequate mechanical integrity and exhibited a rapid release profile, with approximately 73% of diclofenac sodium released within 10 min. Conclusions: The results demonstrate that PHBHVHHx is a suitable biodegradable thermoplastic for the fabrication of solid MN arrays via a solvent-free process. PHBHVHHx MNs combine adequate mechanical performance, reliable insertion capability, and compatibility with coated drug delivery, supporting their potential as sustainable alternatives to conventional solid MN systems. Full article

(This article belongs to the Special Issue Biomaterials for Skin Drug Delivery)

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20 pages, 7024 KB

Open AccessArticle

Paving the Way for CCK2R-Targeted Peptide Receptor Radionuclide Therapy with [¹⁷⁷Lu]Lu-DOTA-MGS5 in Patients with Small Cell Lung Cancer

by Taraneh Sadat Zavvar, Giulia Santo, Leonhard Gruber, Ariane Kronthaler, Judith Hagenbuchner, Ira Skvortsova, Inken Piro, Katja Steiger, Vladan Martinovic, Danijela Minasch, Judith Löffler-Ragg, Gianpaolo di Santo, Irene J. Virgolini and Elisabeth von Guggenberg

Pharmaceutics 2026, 18(1), 138; https://doi.org/10.3390/pharmaceutics18010138 - 22 Jan 2026

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Abstract

Background/Objectives: Peptide receptor radionuclide therapy (PRRT) is an established treatment for neuroendocrine tumors (NETs), enabling targeted radiation delivery via radiolabeled peptides. Small cell lung cancer (SCLC) remains a major therapeutic challenge due to its aggressive nature and poor prognosis. Despite advances, relapse [...] Read more.

Background/Objectives: Peptide receptor radionuclide therapy (PRRT) is an established treatment for neuroendocrine tumors (NETs), enabling targeted radiation delivery via radiolabeled peptides. Small cell lung cancer (SCLC) remains a major therapeutic challenge due to its aggressive nature and poor prognosis. Despite advances, relapse rates are high and effective therapies are limited. We previously demonstrated the diagnostic potential of the cholecystokinin-2 receptor (CCK2R)-targeting minigastrin analog [⁶⁸Ga]Ga-DOTA-MGS5 in PET/CT imaging of different NETs. Building on this, we developed and evaluated [¹⁷⁷Lu]Lu-DOTA-MGS5 as a therapeutic PRRT agent. Methods: Preclinical studies investigating the receptor-mediated cellular internalization and intracellular distribution over time in A431 cells with and without CCK2R expression were performed using the fluorescent tracer ATTO-488-MGS5. Short- and long-term cytotoxic effects of [¹⁷⁷Lu]Lu-DOTA-MGS5 were evaluated on the same cell line using trypan blue exclusion and clonogenic survival assays. CCK2R expression was assessed by immunohistochemistry in 42 SCLC tissue specimens. In addition, the first PRRT with [¹⁷⁷Lu]Lu-DOTA-MGS5 was conducted in a patient with extensive disease SCLC (ED-SCLC) after confirming CCK2R-positive uptake in [⁶⁸Ga]Ga-DOTA-MGS5 PET/CT. Results: Rapid binding and internalization into A431-CCK2R cells, with progressive accumulation in intracellular compartments, was observed for ATTO-488-MGS5. Short-term irradiation effects of [¹⁷⁷Lu]Lu-DOTA-MGS5 were comparable for 4 h and 24 h incubation and were between the effects obtained with 2 and 4 Gy of external beam radiotherapy (EBRT). Clonogenic survival of A431-CCK2R cells incubated with increasing activity of [¹⁷⁷Lu]Lu-DOTA-MGS5 decreased in a dose-dependent manner. Immunohistochemistry on SCLC specimens confirmed moderate to high CCK2R expression in 16 out of 42 SCLC samples. In the first patient with SCLC treated with four cycles of [¹⁷⁷Lu]Lu-DOTA-MGS5 with a total activity of 17.2 GBq, an improvement in clinical symptoms was observed. Conclusions: The preclinical and clinical results confirm the feasibility of [¹⁷⁷Lu]Lu-DOTA-MGS5 PRRT in patients with SCLC and support further clinical studies investigating the therapeutic value and clinical applicability of this new CCK2R-targeted theranostic approach in larger patient cohorts. Full article

(This article belongs to the Special Issue Advances in Radiopharmaceuticals: Enhancing Targeted Delivery, Disease Diagnosis, and Therapeutic Applications)

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11 pages, 5225 KB

Open AccessArticle

Tropism Profiling of Lentiviral Vector Pseudotypes in Diverse Brain Tumor Models

by Johannes K. Andersen, Lars A. R. Ystaas, Rolf Bjerkvig, Hrvoje Miletic and Jubayer A. Hossain

Pharmaceutics 2026, 18(1), 137; https://doi.org/10.3390/pharmaceutics18010137 - 22 Jan 2026

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Abstract

Background: Lentiviral vectors (LVs) show promise as gene therapy tools for brain tumors, but optimal envelope protein choices for different tumor types have not been determined. Methodology: This study evaluated three pseudotyped LV variants—VSV-GP, FuG-B2, and LCMV-GP—across diverse brain tumor cell [...] Read more.

Background: Lentiviral vectors (LVs) show promise as gene therapy tools for brain tumors, but optimal envelope protein choices for different tumor types have not been determined. Methodology: This study evaluated three pseudotyped LV variants—VSV-GP, FuG-B2, and LCMV-GP—across diverse brain tumor cell lines including glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, and metastatic brain cancers. Results: VSV-GP and FuG-B2 pseudotypes significantly outperformed LCMV-GP across most tumor types. Both VSV-GP and FuG-B2 demonstrated high transduction efficiency in GBM and DIPG cells, though some cell lines displayed selective preferences for one pseudotype over the other. Medulloblastoma cells were challenging to transduce, with only VSV-GP achieving substantial efficacy. Metastatic brain cancers showed distinct tropism patterns: melanoma metastases were preferentially transduced by the FuG-B2 pseudotype, while lung metastases showed preference for the VSV-GP pseudotype. Conclusions: These findings suggest envelope protein selection should be tailored to specific brain tumor types. VSV-GP appears most suitable for medulloblastoma and lung metastases, FuG-B2 for melanoma metastases, and both for GBM and DIPG gene therapy applications. The study provides crucial guidance for translating lentiviral gene therapy to clinical applications, supporting personalized treatment strategies based on tumor-specific vector tropism profiles. Full article

(This article belongs to the Special Issue New Strategies in Gene and Cell Therapy for Neurological Disorders)

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6 pages, 457 KB

Open AccessEditorial

New Properties of Supramolecular Complexes and Drug Nanoparticles

by Elena V. Uspenskaya and Anton V. Syroeshkin

Pharmaceutics 2026, 18(1), 136; https://doi.org/10.3390/pharmaceutics18010136 - 22 Jan 2026

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Abstract

Supramolecular chemistry—is “the chemistry beyond the molecule bearing on the organized entities of higher complexity that result from the association of two or more chemical species held together by intermolecular forces”—J [...] Full article

(This article belongs to the Special Issue New Properties of Supramolecular Complexes and Drug Nanoparticles)

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19 pages, 8291 KB

Open AccessArticle

Thermosensitive Hydrogel for Controlled Delivery of PAD4 Inhibitor YJ-2 in Diabetic Wound Healing

by Kai Wang, Ayijiang Taledaohan, Liujia Chan, Yu Lu, Yijiang Jia and Yuji Wang

Pharmaceutics 2026, 18(1), 135; https://doi.org/10.3390/pharmaceutics18010135 - 22 Jan 2026

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Abstract

Background: Diabetic wound healing is hampered by persistent inflammation and excessive neutrophil extracellular traps (NET) formation. Peptidylarginine deiminase 4 (PAD4) is a key enzyme driving this pathology. This study developed a thermosensitive chitosan/β-glycerophosphate hydrogel for the local delivery of a novel PAD4 [...] Read more.

Background: Diabetic wound healing is hampered by persistent inflammation and excessive neutrophil extracellular traps (NET) formation. Peptidylarginine deiminase 4 (PAD4) is a key enzyme driving this pathology. This study developed a thermosensitive chitosan/β-glycerophosphate hydrogel for the local delivery of a novel PAD4 inhibitor, YJ-2, to promote diabetic wound repair. Methods: A YJ-2-loaded hydrogel (CGY) was synthesized and characterized. In vitro studies used HaCaT cells and macrophages to assess proliferation, migration, NETs (via H3cit), and polarization. Efficacy was evaluated in diabetic C57 mouse wound models. Results: CGY exhibited temperature-sensitive gelation and sustained YJ-2 release. In vitro, YJ-2 inhibited NETs formation, reduced pro-inflammatory markers, promoted HaCaT migration, and induced M2 macrophage polarization. In vivo, CGY treatment significantly accelerated wound closure. Conclusions: Local hydrogel delivery of the PAD4 inhibitor YJ-2 effectively mitigates inflammation and NETs, promoting healing in diabetic wounds. This strategy represents a promising targeted therapy for diabetic wounds. Full article

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

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22 pages, 7468 KB

Open AccessArticle

Pulmonary Delivery of Inhalable Sustained Release Nanocomposites Microparticles Encapsulating Osimertinib for Non-Small Cell Lung Cancer Therapy

by Iman M. Alfagih, Alanood Almurshedi, Basmah Aldosari, Bushra Alquadeib, Baraa Hajjar, Hafsa Elwali, Hadeel ALtukhaim, Eman Alzahrani, Sara Alhumaidan and Ghaida Alharbi

Pharmaceutics 2026, 18(1), 134; https://doi.org/10.3390/pharmaceutics18010134 - 21 Jan 2026

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Abstract

Background/Objective: Osimertinib (OSI) is a third-generation tyrosine kinase inhibitor approved for non-small cell lung cancer (NSCLC) therapy. OSI is administered orally; this route limits the amount of OSI reaching the tumor in the lungs and is associated with serious systemic toxicity. This study [...] Read more.

Background/Objective: Osimertinib (OSI) is a third-generation tyrosine kinase inhibitor approved for non-small cell lung cancer (NSCLC) therapy. OSI is administered orally; this route limits the amount of OSI reaching the tumor in the lungs and is associated with serious systemic toxicity. This study aimed to develop a dry powder inhalable formulation to provide tumor-targeted delivery and minimize systemic toxicity. To the best of our knowledge, this is the first study to prepare and evaluate a dry powder inhalation formulation of OSI. Methods: Chitosan-coated PLGA nanoparticles (PLGA-C NPs) encapsulating OSI were prepared using a single emulsion-solvent evaporation technique. PLGA-C NPs were assembled into respirable nanocomposite microparticles (NCMPs) via spray drying with L-leucine as a carrier. PLGA-C NPs were characterized for particle size, zeta-potential, encapsulation efficiency, and in vitro efficacy in A-549 cell line. NCMPs were evaluated for solid-state properties, aerosolization performance, stability and in vitro release. Results: PLGA-C NPs exhibited a particle size of 145.18 ± 3.0 nm, high encapsulation efficiency and a positive zeta potential. In vitro studies demonstrated a 3.6-fold reduction in IC50 compared to free OSI, superior antimigratory effects and enhanced cell cycle arrest. Solid-state characterization of NCMPs demonstrated drug encapsulation in the polymer without chemical interaction. NCMPs exhibited excellent aerosolization (mass median aerodynamic diameter of 1.09 ± 0.23 μm, fine particle fraction of 73.48 ± 8.6%) and sustained drug release (61.76 ± 3.9% at 24 h). Stability studies confirmed the physicochemical stability integrity. Conclusions: These findings suggest that this novel dry powder inhalable OSI formulation may improve therapeutic outcomes while reducing systemic toxicity. Full article

(This article belongs to the Special Issue Anticancer Nanotherapeutics for Lung Cancer Therapy)

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24 pages, 8216 KB

Open AccessArticle

Formulation and Evaluation of Alginate-Based Hydrogel Membranes Loaded with Colistin for Effective Management of Multidrug-Resistant Wound Infections

by Nizar Muhammad, Syed Sikandar Shah, Ashfaq Ahmad Shah Bukhari, Jamil Ahmed, Shahnaz Usman, Shujaat Ali Khan, Aftab Alam, Syed Arman Rabbani and Junaid Asghar

Pharmaceutics 2026, 18(1), 133; https://doi.org/10.3390/pharmaceutics18010133 - 21 Jan 2026

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Abstract

Background: Combating antimicrobial resistance and developing dressings that match all aspects of wound healing will always be challenging. Methods: In this study, hydrogel membranes composed of sodium alginate (SA), polyvinyl alcohol (PVA), and Pluronic-f-127 (F-127) loaded with colistin (C) were formulated. The [...] Read more.

Background: Combating antimicrobial resistance and developing dressings that match all aspects of wound healing will always be challenging. Methods: In this study, hydrogel membranes composed of sodium alginate (SA), polyvinyl alcohol (PVA), and Pluronic-f-127 (F-127) loaded with colistin (C) were formulated. The formulations were divided into two groups: group 1 (SA-PVA-C) and group 2 (SA-PVA-F127-C). Results: The membranes were characterized using multiple techniques, which confirmed component compatibility, physical cross-linking, an amorphous structure, and suitable surface morphology with acceptable porosity. Mechanical testing showed that both groups were suitable for wound-dressing applications. Differences in drug release across media (water, normal saline, and phosphate) were non-significant (p value > 0.05). Drug-loaded membranes (n = 3) from both groups showed antibacterial activity against multidrug-resistant Gram-negative Pseudomonas aeruginosa (ZOI = 20.33 ± 2.51 mm, 21.66 ± 2.08 mm). Conclusions: Overall, the developed hydrogel membranes (both group 1 and group 2) demonstrated promising in vitro potential as colistin delivery systems for wound infection management. Full article

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

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15 pages, 1778 KB

Open AccessArticle

Clinical Characteristics, Long-Term Pharmacokinetics, and Outcomes in Kidney Transplant Recipients from an African Tertiary Centre: A 10-Year Single-Centre Retrospective Review

by Sadiq Aliyu Hussaini, Caroline Dickens, Confidence Makgoro, Therese Dix-Peek, Badar Munir, Jeevan Perumala, Simran Patel, Qaiser Goolam, Graham Paget, Bala Waziri and Raquel Duarte

Pharmaceutics 2026, 18(1), 132; https://doi.org/10.3390/pharmaceutics18010132 - 21 Jan 2026

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Abstract

Background: Kidney transplantation outcomes in resource-limited settings remain underreported. This 10-year retrospective review examined the clinical characteristics, long-term pharmacokinetics, and outcomes of kidney transplant recipients at a South African public hospital. Methods: Data from kidney transplant recipients between January 2012 and December 2022 [...] Read more.

Background: Kidney transplantation outcomes in resource-limited settings remain underreported. This 10-year retrospective review examined the clinical characteristics, long-term pharmacokinetics, and outcomes of kidney transplant recipients at a South African public hospital. Methods: Data from kidney transplant recipients between January 2012 and December 2022 were analysed. Graft and patient survival were assessed using Kaplan–Meier analysis. Cox proportional hazards models were used to evaluate the associations between clinical and pharmacokinetic variables and outcomes. Results: The one- and five-year graft survival rates were 87.9% and 65.6%, respectively. Acute rejection, as confirmed by biopsy, was associated with graft failure (HR, 2.46; p = 0.010). Increasing recipient age at transplantation increased the graft failure risk by about 5.0% per year (HR: 1.05, p = 0.006). Tacrolimus trough and normalised trough levels were lower in the graft loss group 73% and 93% of the time, respectively, despite similar tacrolimus doses. Whereas achieving optimal tacrolimus concentration did not significantly affect graft survival, maintaining a haemoglobin level >10 g/dL improved the chances of 3-, 4-, and 5-year graft survival (p-value, 0.001, 0.001, and <0.001, respectively). Patient survival rates were more favourable than graft survival rates. The 1-year and 5-year patient survival rates were 90.0% and 77.4%, respectively. Conclusions: This study offers insights into transplant outcomes in low-resource public health settings. The findings emphasise the impact of rejection and age on the risk of graft failure and the significance of maintaining adequate haemoglobin levels after transplantation. The results also indicate the need for more nuanced and personalised approaches to tacrolimus monitoring in the long-term following transplantation. Full article

(This article belongs to the Special Issue Optimizing Drug Therapy in Kidney Diseases: Effectiveness and Safety)

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29 pages, 1806 KB

Open AccessReview

Impeding the NHEJ Pathway for Overcoming Radioresistance in the Context of Precision Radiotherapy of Cancer

by Dragoș Andrei Niculae, Radu Marian Șerban, Dana Niculae and Doina Drăgănescu

Pharmaceutics 2026, 18(1), 131; https://doi.org/10.3390/pharmaceutics18010131 - 20 Jan 2026

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Abstract

Non-homologous end joining (NHEJ) is a critical DNA double-strand break (DSB) repair pathway that operates throughout the cell cycle to maintain the genomic stability of the cell. Unlike homologous recombination (HR), NHEJ is capable of repairing DSBs without the need for a homologous [...] Read more.

Non-homologous end joining (NHEJ) is a critical DNA double-strand break (DSB) repair pathway that operates throughout the cell cycle to maintain the genomic stability of the cell. Unlike homologous recombination (HR), NHEJ is capable of repairing DSBs without the need for a homologous template, making it a rapid response mechanism, but potentially prone to errors. Central to NHEJ function and essential for the ligation through the recruitment and activation of additional repair factors, such as Artemis, XRCC4, and DNA ligase IV, is the DNA-dependent protein kinase (DNA-PK) complex. Dysregulation in the NHEJ pathway contributes to genomic instability, oncogenesis, and resistance to genotoxic therapies. Consequently, inhibitors of DNA-PK have emerged as promising therapeutic agents to sensitize tumor cells to radiation and DNA-damaging chemotherapeutics. Inhibiting the DNA-PK ability to recruit the protein complex needed for successful DSB repair promotes cell death through apoptosis or mitotic catastrophe. While inhibitors of DNA-PK can be used to enhance the effects of genotoxic therapies, the field still struggles to address critical problems: how to best exploit the differential DNA repair capacities among tumor subtypes, how to maximize radiosensitization of cancerous cells while sparing normal tissues, and how to translate preclinical studies into clinical benefits. Given that NHEJ constitutes the primary line of defense against radiation-induced damage, rapidly repairing the majority of double-strand breaks throughout the cell cycle, this review concentrates on targeting the DNA-PK complex, as the master regulator of this rapid-response mechanism, highlighting why its inhibition represents a strategic action to overcome intrinsic radioresistance. The implementation of DNA-PK inhibitors into medical practice can enable the stratification of oncologic patients into two categories, based on the tumors’ vulnerability to NHEJ disruptions. Thus, the therapeutic pathways of patients with NHEJ tumors could branch, combining traditional genotoxic therapies (radiation and DNA-damaging chemotherapeutics) with DNA-PK inhibitors to achieve an enhanced effect and improved survival outcomes. Full article

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

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19 pages, 808 KB

Open AccessReview

Albumin Nanoparticles as Multifunctional Carriers for Advanced Therapeutics

by Bogusława Konopska, Janusz Sokołowski, Anna Woźniak, Mikołaj Kondracki, Jakub Federowicz, Wojciech Grodzki, Agnieszka Bronowicka-Szydełko and Katarzyna Madziarska

Pharmaceutics 2026, 18(1), 130; https://doi.org/10.3390/pharmaceutics18010130 - 20 Jan 2026

Viewed by 503

Abstract

Modern medicine requires effective, continuous, and safe therapies, which largely depend on the targeted delivery and activity of the drug. This goal can be achieved by designing drug delivery systems with improved pharmacokinetic properties and enhanced drug transport to the affected tissue. Human [...] Read more.

Modern medicine requires effective, continuous, and safe therapies, which largely depend on the targeted delivery and activity of the drug. This goal can be achieved by designing drug delivery systems with improved pharmacokinetic properties and enhanced drug transport to the affected tissue. Human serum albumin (HSA) is an attractive carrier for the synthesis of therapeutic nanoparticles, several of which have already been approved by the United States Food and Drug Administration (FDA). The success of Abraxane as an effective treatment for metastatic breast cancer and non-small cell lung carcinoma, the application of Optison in ultrasound imaging, and the use of Nanocoll as an agent for SPECT diagnostics in sentinel node localisation confirm the strong potential of albumin-based systems. Further benefits are expected in patients with soft tissue cancers, as LadRx is seeking FDA marketing approval for Aldoxorubicin. The future of oncology lies in theranostics, which combines a tumour-localising factor on one platform with a drug targeting cancer cells and a factor that activates the cytotoxicity of the drug after it reaches the target tissue. This article presents recent advancements in albumin-based nanoparticles for drug delivery, targeting, and imaging. It also briefly discusses methods of synthesis and surface modification of albumin nanocarriers to enable targeted delivery to pathological sites. Finally, it outlines the latest approaches in multimodal theranostic platforms, highlighting albumin’s potential to improve cancer therapy. Full article

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

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20 pages, 1579 KB

Open AccessArticle

Phthalimide Derivatives as Anti-Inflammatory Agents: In Silico COX-2 Targeting and In Vitro Inhibition of PGE₂ Production

by Héctor M. Heras Martínez, Blanca Sánchez-Ramírez, Linda-Lucila Landeros-Martínez, David Rodríguez-Guerrero, José C. Espinoza-Hicks, Gerardo Zaragoza-Galán, Alejandro Bugarin and David Chávez-Flores

Pharmaceutics 2026, 18(1), 129; https://doi.org/10.3390/pharmaceutics18010129 - 20 Jan 2026

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Abstract

Background/Objectives: The development of specific inhibitors for cyclooxygenase-2 (COX-2) is a challenge for public health. A series of 17 N-phthalimide hybrids was evaluated using a functional M06 meta-GGA hybrid in combination with a polarized 6-311G (d, p) basis set. The top [...] Read more.

Background/Objectives: The development of specific inhibitors for cyclooxygenase-2 (COX-2) is a challenge for public health. A series of 17 N-phthalimide hybrids was evaluated using a functional M06 meta-GGA hybrid in combination with a polarized 6-311G (d, p) basis set. The top three candidates (6, 10, and 17) were synthesized and evaluated as selective COX-2 inhibitors of PGE-2 using an integrated in silico–in vitro approach. Methods: Molecular docking against COX-2 (PDB 5KIR) and COX-1 (PDB 6Y3C), supported by homology modeling and DFT geometry optimization (B3LYP/6-31G*), revealed that the phthalimide carbonyl groups and the 3,4,5-trimethoxyphenyl or geranyl-derived moieties establish key hydrogen bonds and hydrophobic contacts with Arg120, Tyr355, Tyr385, and Ser530 in the COX-2 active site, conferring predicted selectivity ΔGCOX−2 vs. COX−1 = −1.4 to −2.8 kcal/mol. Results: The compounds complied with Lipinski’s and Veber’s rules and displayed favorable ADMET profiles. In vitro assessment in LPS-stimulated J774A.1 murine macrophages confirmed potent inhibition of PGE₂ production, 3.05 µg/mL, with compound 17 exhibiting the highest efficacy, 97.79 ± 5.02% inhibition at 50 µg/mL, and 10 showing 95.22 ± 6.03% inhibition at 50 µg/mL. Notably, all derivatives maintained >90% cell viability up to 250 µg/mL by resazurin assay and showed no evidence of cytotoxicity or mitosis potential in the tests at 24 h. Conclusions: These results demonstrate that strategic hybridization of phthalimide with natural and synthetic product-derived fragments yields highly potential PGE2 inhibitors. Therefore, compounds 6, 10, and 17 are promising lead candidates for the development of safer anti-inflammatory agents. Full article

(This article belongs to the Special Issue Natural Pharmaceuticals Focused on Anti-inflammatory Activities)

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27 pages, 370 KB

Open AccessReview

Pharmaceutical Cocrystals in Drug-Delivery Technologies: Advances from Rational Design to Therapeutic Applications

by Marina Monserrat Marcos Valdez, Norma Rebeca Sperandeo, Maria Soledad Bueno and Claudia Garnero

Pharmaceutics 2026, 18(1), 128; https://doi.org/10.3390/pharmaceutics18010128 - 20 Jan 2026

Viewed by 512

Abstract

Pharmaceutical cocrystals are a well-established class of solid-state forms that can modulate the solubility, dissolution, stability, and bioavailability of active pharmaceutical ingredients without altering their molecular identity. Although traditional oral formulations have demonstrated translational potential, recent research has emphasized the importance of integrating [...] Read more.

Pharmaceutical cocrystals are a well-established class of solid-state forms that can modulate the solubility, dissolution, stability, and bioavailability of active pharmaceutical ingredients without altering their molecular identity. Although traditional oral formulations have demonstrated translational potential, recent research has emphasized the importance of integrating cocrystals into emerging drug-delivery technologies. This review systematically analyzes recent advances in conventional and innovative cocrystal-based platforms, critically evaluating their therapeutic relevance. A comprehensive literature search was conducted, focusing on publications from the last decade, with emphasis on studies from 2020 to 2025, including peer-reviewed articles, patents, and regulatory documents. Evidence was organized into traditional oral, inhalable, intranasal, and transdermal formulations, followed by emerging platforms such as 3D printing, nano-cocrystals, and microneedles. Case studies and preclinical/clinical data were critically assessed to identify strengths, limitations, and future directions. Advancements in formulation science and novel delivery technologies are allowing pharmaceutical cocrystals to transition from laboratory innovations to clinical applications. Despite challenges in scalability, stability, and regulatory clarity, the application of cocrystals into emerging platforms highlights their potential as transformative tools in next-generation therapeutics. Full article

(This article belongs to the Special Issue Advances in Pharmaceutical Cocrystal Design and Technological Applications)

23 pages, 2250 KB

Open AccessArticle

MHY498 Nanosuspensions for Improved Topical Drug Delivery: Understanding of Its Solubility Behavior in DEGME + Water Mixtures and Preparation of Nanosuspension Using Box–Behnken Design

by Eun-Sol Ha, Ha Nim Lee, Seon-Kwang Lee, Ji-Su Jeong, Jeong-Soo Kim, Hyung Ryong Moon, In-hwan Baek, Heejun Park and Min-Soo Kim

Pharmaceutics 2026, 18(1), 127; https://doi.org/10.3390/pharmaceutics18010127 - 20 Jan 2026

Viewed by 387

Abstract

Background/Objectives: MHY498, a tyrosinase inhibitor, exhibits poor water solubility, which limits its topical delivery. Despite the importance of solubility data in rational formulation design, comprehensive information on its solubility behavior in various solvents and across a range of temperatures remains limited. Thus, [...] Read more.

Background/Objectives: MHY498, a tyrosinase inhibitor, exhibits poor water solubility, which limits its topical delivery. Despite the importance of solubility data in rational formulation design, comprehensive information on its solubility behavior in various solvents and across a range of temperatures remains limited. Thus, this study aimed to systematically evaluate the solubility characteristics of MHY498 and to develop a nanosuspension formulation using an antisolvent precipitation approach to facilitate the development of an optimized topical formulation. Methods: In this study, we measured the solubility of MHY498 in various monosolvents and diethylene glycol monoethyl ether (DEGME) + water solvent mixtures at 293.15–313.15 K using a solid–liquid equilibrium technique. Based on these solubility data, MHY498 nanosuspensions were prepared via antisolvent precipitation guided by a Box–Behnken design matrix. In vitro skin permeability was also assessed using a Franz diffusion cell system to assess the topical delivery potential of the MHY498 nanosuspensions. Results: Among the investigated monosolvents, MHY498 exhibited the highest solubility in dimethylformamide, dimethylacetamide, DEGME, while the lowest solubility was observed in water. The solubility increased with temperature and DEGME content in solvent mixtures, and the experimental data were well described by thermodynamic and semi-empirical models, indicating an endothermic and spontaneous dissolution process. Solvent–solute interaction analysis revealed that hydrogen-bonding and nonspecific polarity interactions played key roles in enhancing MHY498 solubility. All nanosuspensions prepared within the design space exhibited particle sizes below 150 nm, and the optimized formulation achieved an average particle size of 28.1 nm. The optimized nanosuspension demonstrated a 3.3-fold increase in the cumulative permeated amounts compared with the conventional microsuspension. Conclusions: These findings demonstrate that a rational solvent selection strategy based on thermodynamic solubility analysis and antisolvent precipitation enables effective nanosuspension formulation of MHY498. The DEGME–water system was identified as a formulation-relevant solvent environment that supports both adequate drug solubilization and reproducible formation of nanosized particles. The resulting nanosuspension exhibited favorable particle size characteristics and enhanced formulation feasibility for topical applications. Therefore, it was shown that the developed nanosuspension system, established through a solubility-driven systematic approach, represents a promising strategy for improving topical delivery of MHY498. Full article

(This article belongs to the Special Issue Methods of Potentially Improving Drug Permeation and Bioavailability)

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24 pages, 299 KB

Open AccessReview

Extemporaneous Formulations for Pediatric Patients: Global Necessities, Challenges and Opportunities

by Vinita Balakrishna Pai and Milap Chand Nahata

Pharmaceutics 2026, 18(1), 126; https://doi.org/10.3390/pharmaceutics18010126 - 19 Jan 2026

Cited by 1 | Viewed by 351

Abstract

Many commercially available medications are often unapproved or unavailable in suitable dosage forms for specific patient populations, particularly infants and children. This necessitates the use of extemporaneously compounded formulations to deliver individualized doses based on body weight or body surface area, and when [...] Read more.

Many commercially available medications are often unapproved or unavailable in suitable dosage forms for specific patient populations, particularly infants and children. This necessitates the use of extemporaneously compounded formulations to deliver individualized doses based on body weight or body surface area, and when a medication is unavailable at an appropriate concentration or contains excipients potentially unsafe for certain patients. Extemporaneous compounding is required for oral liquids when patients are unable to swallow tablets or capsules. It is also needed for topical preparations and sterile dosage forms when commercial products are unavailable. Across regions, practices follow national pharmacopeial standards for both sterile and non-sterile compounding. Stability factors influencing the safety and efficacy of compounded formulations must be carefully considered when assigning appropriate beyond-use dates. While stability information is available for some medications in monographs, peer-reviewed literature, prescribing information, and investigator’s brochures, such data is often lacking for many compounded preparations. Emerging extemporaneous formulations—such as orodispersible films, nanoparticle systems, and 3D-printed compounds—offer potential advantages over traditional compounded formulations but present unique challenges to widespread implementation. Despite the justified clinical need for extemporaneous compounding, significant barriers remain, including limited access to medications, insufficient compounding expertise or resources, gaps in pharmacokinetic and safety data, and regulatory constraints. This review critically appraises the current state of extemporaneous compounding—drawing primarily on the United States of America frameworks—and highlights its continued necessity, associated challenges, and pragmatic solutions for advancing personalized pharmacotherapy across pediatric age groups worldwide. Full article

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

15 pages, 2365 KB

Open AccessArticle

Menthol-Based Cream as a Novel Therapy for Diabetic Skin Wounds

by Ana Júlia Vieira, Fernando Pereira Beserra, Gabriel Bacil Prata, Emanuel Ricardo Monteiro Martinez, Rafael Henrique Nóbrega, Luis Fernando Barbisan, Claudia Helena Pellizzon and Ariane Leite Rozza

Pharmaceutics 2026, 18(1), 125; https://doi.org/10.3390/pharmaceutics18010125 - 19 Jan 2026

Viewed by 286

Abstract

Background/Objectives: Diabetes mellitus impairs skin wound healing by promoting a chronic inflammatory response and increased oxidative stress. This study aimed to investigate the healing potential of menthol in skin wounds of diabetic rats. Methods: A single dose of streptozotocin (50 mg/kg, [...] Read more.

Background/Objectives: Diabetes mellitus impairs skin wound healing by promoting a chronic inflammatory response and increased oxidative stress. This study aimed to investigate the healing potential of menthol in skin wounds of diabetic rats. Methods: A single dose of streptozotocin (50 mg/kg, i.p.) induced type 1 diabetes mellitus in male Wistar rats. After nine days, a skin wound was made on the rats’ back and treated with vehicle, insulin-based cream (0.5 U/g), or menthol-based cream (0.5%) for 14 days. After the euthanasia, the wound area was destined for assays of anti-inflammatory and antioxidant activity, protein expression levels by Western blotting, measurement of MPO activity, and quantitative mRNA expression. Nitrite levels were measured in blood plasma. Results: The group treated with menthol-based cream decreased the wound area by 94%. Also, menthol reduced the levels of TNF-α and IL-6 and increased IL-10 levels, besides stimulating the activity of antioxidant enzymes SOD, GPx, and GR, and enhancement in GSH and nitrite levels. Menthol downregulated the expression of Nfκb and upregulated the Il10 and Ki67 gene expression and the eNOS protein expression. Conclusions: Topically applied menthol accelerated the skin wound healing in diabetic rats through anti-inflammatory and antioxidant activities and increased cell proliferation, supporting its potential as a therapeutic strategy for diabetic wound management. Full article

(This article belongs to the Special Issue Anti-Inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside, 3rd Edition)

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60 pages, 7234 KB

Open AccessReview

Cellular Allies Against Glioblastoma: Therapeutic Potential of Macrophages and Mesenchymal Stromal Cells

by Bruno Agustín Cesca, Kali Pellicer San Martin and Luis Exequiel Ibarra

Pharmaceutics 2026, 18(1), 124; https://doi.org/10.3390/pharmaceutics18010124 - 19 Jan 2026

Viewed by 404

Abstract

Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, with limited therapeutic options and poor prognosis despite maximal surgery, radiotherapy, and chemotherapy. The complex and immunosuppressive tumor microenvironment, pronounced intratumoral heterogeneity, and the presence of the blood–brain barrier (BBB) [...] Read more.

Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, with limited therapeutic options and poor prognosis despite maximal surgery, radiotherapy, and chemotherapy. The complex and immunosuppressive tumor microenvironment, pronounced intratumoral heterogeneity, and the presence of the blood–brain barrier (BBB) severely restrict the efficacy of conventional and emerging therapies. In this context, cell-based strategies leveraging macrophages, mesenchymal stromal cells (MSCs), and their derivatives have gained attention as “cellular allies” capable of modulating the GBM microenvironment and acting as targeted delivery platforms. Methods: This review systematically analyzes preclinical and early clinical literature on macrophage- and MSC-based therapeutic strategies in GBM, including engineered cells, extracellular vesicles (EVs), membrane-coated nanoparticles, and hybrid biomimetic systems. Studies were selected based on relevance to GBM biology, delivery across or bypass of the BBB, microenvironmental modulation, and translational potential. Evidence from in vitro models, orthotopic and syngeneic in vivo models, and available clinical trials was critically evaluated, with emphasis on efficacy endpoints, biodistribution, safety, and manufacturing considerations. Results: The reviewed evidence demonstrates that macrophages and MSCs can function as active therapeutic agents or delivery vehicles, enabling localized oncolysis, immune reprogramming, stromal and vascular remodeling, and enhanced delivery of viral, genetic, and nanotherapeutic payloads. EVs and membrane-based biomimetic platforms further extend these capabilities while reducing cellular risks. However, therapeutic efficacy is highly context-dependent, influenced by tumor heterogeneity, BBB integrity, delivery route, and microenvironmental dynamics. Clinical translation remains limited, with most approaches at preclinical or early-phase clinical stages. Conclusions: Cell-based and cell-derived platforms represent a promising but still evolving therapeutic paradigm for GBM. Their successful translation will require rigorous biomarker-driven patient selection, improved models that capture invasive GBM biology, scalable GMP-compliant manufacturing, and rational combination strategies to overcome adaptive resistance mechanisms. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed? (2nd Edition))

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18 pages, 2428 KB

Open AccessArticle

Streamlined Radiosynthesis of [¹⁸F]Fluproxadine (AF78): An Unprotected Guanidine Precursor Enables Efficient One-Step, Automation-Ready Labeling for Clinical Use

by Xinyu Chen, Kaito Ohta, Hiroyuki Kimura, Yusuke Yagi, Takanori Sasaki, Naoko Nose, Masaru Akehi, Tomohiko Yamane, Rudolf A. Werner and Takahiro Higuchi

Pharmaceutics 2026, 18(1), 123; https://doi.org/10.3390/pharmaceutics18010123 - 19 Jan 2026

Viewed by 272

Abstract

Background/Objectives: [¹⁸F]Fluproxadine (formerly [¹⁸F]AF78) is a PET radiotracer targeting the norepinephrine transporter (NET) with potential applications in cardiac, neurological, and oncological imaging. Its guanidine moiety, while essential for NET binding, presents major radiosynthetic challenges due to high basicity and [...] Read more.

Background/Objectives: [¹⁸F]Fluproxadine (formerly [¹⁸F]AF78) is a PET radiotracer targeting the norepinephrine transporter (NET) with potential applications in cardiac, neurological, and oncological imaging. Its guanidine moiety, while essential for NET binding, presents major radiosynthetic challenges due to high basicity and the harsh deprotection conditions required for protected precursors. Previous methods relied on multistep procedures, strong acids, and complex purification, limiting clinical translation. This study aimed to develop a practical one-step radiosynthesis suitable for routine and automated production. Methods: A direct SN2-type nucleophilic [¹⁸F]fluorination was performed using an unprotected guanidine precursor to eliminate deprotection steps. Reaction parameters, including the base system, solvent composition, precursor concentration, and temperature, were optimized under conventional and microwave heating. Radiochemical conversion (RCC) and operational robustness were evaluated, and purification strategies were assessed for automation compatibility. Results: Direct [¹⁸F]fluorination using the unprotected precursor reduced the total synthesis time to 60–70 min. Optimal conditions employed a tert-butanol/acetonitrile (4:1) solvent system with K₂CO₃/Kryptofix222, affording RCC up to 33% under conventional heating. Microwave irradiation further improved efficiency, achieving RCC of up to 64% within 1.5 min at 140 °C. The method showed broad tolerance to variations in the base molar ratio and precursor concentration and enabled isocratic HPLC purification. Conclusions: This one-step radiosynthesis overcomes longstanding challenges in [¹⁸F]fluproxadine production by eliminating harsh deprotection and enabling high-yield, automation-ready synthesis, thereby improving clinical feasibility. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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27 pages, 30843 KB

Open AccessArticle

Targeted Inhibition of Oncogenic microRNAs miR-21, miR-17, and miR-155 Suppresses Tumor Growth and Modulates Immune Response in Colorectal Cancer

by Olga Patutina, Aleksandra Sen’kova, Svetlana Miroshnichenko, Mona Awad, Oleg Markov, Daniil Gladkikh, Innokenty Savin, Ekaterina Seroklinova, Sergey Zhukov, Maxim Kupryushkin, Mikhail Maslov, Valentin Vlassov and Marina Zenkova

Pharmaceutics 2026, 18(1), 122; https://doi.org/10.3390/pharmaceutics18010122 - 18 Jan 2026

Viewed by 351

Abstract

Background and Objectives: Aggressive cancer development is characterized by rapid tumor growth and progressive immune dysfunction. Tumor-derived microRNAs (miRNAs) emerge as master regulators of both malignant transformation and immune evasion, making them promising therapeutic targets. Using the highly aggressive CT-26 peritoneal adenomatosis model, [...] Read more.

Background and Objectives: Aggressive cancer development is characterized by rapid tumor growth and progressive immune dysfunction. Tumor-derived microRNAs (miRNAs) emerge as master regulators of both malignant transformation and immune evasion, making them promising therapeutic targets. Using the highly aggressive CT-26 peritoneal adenomatosis model, this study explored the potential of selective miRNA inhibition to simultaneously suppress tumor growth and overcome immunosuppression. Methods and Results: Our results revealed that inhibition of miR-155, miR-21, and miR-17 by methylsulfonyl phosphoramidate (mesyl) oligonucleotides exhibited markedly different therapeutic profiles. miR-155 inhibition demonstrated minimal efficacy. miR-21 suppression provided early tumor regression and prevented cancer-associated thymic atrophy, translating into extended survival. miR-17 inhibition displayed delayed but superior tumor growth inhibition, significantly reducing pathologically elevated polymorphonuclear myeloid-derived suppressor cell (MDSC) populations, and nearly doubled animal lifespan. Combination therapy targeting all three miRNAs integrated these complementary mechanisms, maintaining consistent anti-tumor efficacy across early and late stages while providing thymic protection and MDSC reduction. Importantly, therapeutic responses in vivo substantially exceeded predictions based on in vitro tumor cell proliferation and motility measurements, revealing critical contributions of systemic immunomodulation. Conclusions: These findings demonstrate that miRNA inhibition reshapes tumor–immune interactions, positioning anti-miRNA therapeutics as immunomodulatory agents for effective colorectal cancer treatment. Full article

(This article belongs to the Special Issue Recent Advances in Nucleic Acid-Based Therapeutics, Vaccines, and Drug Delivery Vehicles)

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22 pages, 3249 KB

Open AccessArticle

Freeze-Drying in Sucrose Followed by Cryomilling Enables the Formulation of sa-mRNA–LNP Powders for Inhalation

by E. M. Jansen, M. J. R. Ruigrok, M. S. Suh, P. M. Ruppel, Xiaole Cui, L. Opsomer, N. N. Sanders, H. W. Frijlink and W. L. J. Hinrichs

Pharmaceutics 2026, 18(1), 121; https://doi.org/10.3390/pharmaceutics18010121 - 18 Jan 2026

Viewed by 520

Abstract

Background: Self-amplifying mRNA (sa-mRNA) represents a promising platform for vaccines and gene therapies, offering sustained protein expression at low doses through self-replication. For vaccines targeting respiratory pathogens, pulmonary delivery of sa-mRNA lipid nanoparticles (LNPs) is particularly advantageous, enabling direct delivery to the infection [...] Read more.

Background: Self-amplifying mRNA (sa-mRNA) represents a promising platform for vaccines and gene therapies, offering sustained protein expression at low doses through self-replication. For vaccines targeting respiratory pathogens, pulmonary delivery of sa-mRNA lipid nanoparticles (LNPs) is particularly advantageous, enabling direct delivery to the infection site and induction of mucosal immunity. Objective: In this study, we evaluated the stability of sa-mRNA–LNPs under refrigerated and frozen conditions and developed a dry powder formulation suitable for inhalation, produced by freeze-drying followed by cryomilling with leucine. Methods: sa-mRNA–LNPs formulated in HEPES buffer with 20% (w/v) sucrose were stored for up to 8 weeks as liquid or freeze-dried samples at various temperatures (−80 °C, −20 °C, 4 °C, and 20 °C). Biological stability was assessed by transfection efficiency in HeLa cells, while physical stability was characterized by encapsulation efficiency, zeta potential, particle size, and polydispersity index. Results: Liquid formulations remained stable for at least 8 weeks at −80 °C and −20 °C but rapidly lost stability at 4 °C and 20 °C. Freeze-drying effectively preserved sa-mRNA–LNP functionality and structural integrity for up to 8 weeks at 4 °C, with only minor structural changes. Subsequent cryomilling in the presence of 4 wt-% leucine produced a respirable dry powder while retaining approximately 60% of the original sa-mRNA–LNP functionality. Although cryomilling induced some structural alterations, the remaining functional fraction remained stable during storage. The resulting powders displayed favorable aerosol performance for deep lung delivery, as demonstrated by cascade impaction (MMAD = 4.13 ± 0.26 µm). Conclusions: In conclusion, freeze-drying effectively preserved sa-mRNA–LNP integrity at 4 °C, whereas cryomilling with leucine produced a respirable dry powder suitable for pulmonary delivery, providing a foundation for globally accessible, needle-free sa-mRNA vaccines against respiratory diseases. Full article

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

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26 pages, 3289 KB

Open AccessArticle

Extracellular Vesicles from Probiotic and Beneficial Escherichia coli Strains Exert Multifaceted Protective Effects Against Rotavirus Infection in Intestinal Epithelial Cells

by Cecilia Cordero, Aitor Caballero-Román, Sergio Martínez-Ruiz, Yenifer Olivo-Martínez, Laura Baldoma and Josefa Badia

Pharmaceutics 2026, 18(1), 120; https://doi.org/10.3390/pharmaceutics18010120 - 18 Jan 2026

Viewed by 321

Abstract

Background/Objectives: Rotavirus remains a major cause of severe acute gastroenteritis in infants worldwide. The suboptimal efficacy of current vaccines underscores the need for alternative microbiome-based interventions, including postbiotics. Extracellular vesicles (EVs) from probiotic and commensal E. coli strains have been shown to mitigate [...] Read more.

Background/Objectives: Rotavirus remains a major cause of severe acute gastroenteritis in infants worldwide. The suboptimal efficacy of current vaccines underscores the need for alternative microbiome-based interventions, including postbiotics. Extracellular vesicles (EVs) from probiotic and commensal E. coli strains have been shown to mitigate diarrhea and enhance immune responses in a suckling-rat model of rotavirus infection. Here, we investigate the regulatory mechanisms activated by EVs in rotavirus-infected enterocytes. Methods: Polarized Caco-2 monolayers were used as a model of mature enterocytes. Cells were pre-incubated with EVs from the probiotic E. coli Nissle 1917 (EcN) or the commensal EcoR12 strain before rotavirus infection. Intracellular Ca²⁺ concentration, ROS levels, and the expression of immune- and barrier-related genes and proteins were assessed at multiple time points post-infection. Results: EVs from both strains exerted broad protective effects against rotavirus-induced cellular dysregulation, with several responses being strain-specific. EVs interfered with viral replication by counteracting host cellular processes essential for rotavirus propagation. Specifically, EV treatment significantly reduced rotavirus-induced intracellular Ca²⁺ mobilization, ROS production, and COX-2 expression. In addition, both EV types reduced virus-induced mucin secretion and preserved tight junction organization, thereby limiting viral access to basolateral coreceptors. Additionally, EVs enhanced innate antiviral defenses via distinct, strain-dependent pathways: EcN EVs amplified IL-8-mediated responses, whereas EcoR12 EVs preserved the expression of interferon-related signaling genes. Conclusions: EVs from EcN and EcoR12 act through multiple complementary mechanisms to restrict rotavirus replication, spread, and immune evasion. These findings support their potential as effective postbiotic candidates for preventing or treating rotavirus infection. Full article

(This article belongs to the Special Issue Probiotics in Pharmaceutics: Exploring the Therapeutic Potential and Formulation Strategies)

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18 pages, 3647 KB

Open AccessArticle

Colchicine Suppresses Adipogenic Differentiation of Mesenchymal Stem Cells: Implications for Bone Adiposity Control

by Miriam López-Fagúndez, María Piñeiro-Ramil, Andrés Pazos-Pérez, María Guillán-Fresco, Verónica López, Djedjiga Ait Eldjoudi, Susana Belén Bravo-López, Alberto Jorge-Mora, Ana Alonso-Pérez and Rodolfo Gómez

Pharmaceutics 2026, 18(1), 119; https://doi.org/10.3390/pharmaceutics18010119 - 16 Jan 2026

Viewed by 407

Abstract

Background: Gout is an inflammatory arthritis associated with increased bone anabolism and a higher risk of ectopic bone formation. Colchicine, used to prevent and treat acute gouty flares, inhibits microtubule polymerization and has been described to promote osteoblastogenesis. In bone disorders such [...] Read more.

Background: Gout is an inflammatory arthritis associated with increased bone anabolism and a higher risk of ectopic bone formation. Colchicine, used to prevent and treat acute gouty flares, inhibits microtubule polymerization and has been described to promote osteoblastogenesis. In bone disorders such as osteoporosis, disruption of the osteoblast–adipocyte balance contributes to pathology, yet no therapies directly target bone marrow adiposity. Thus, we decided to investigate the impact of colchicine on the osteoblast-adipocyte balance. Methods: C3H10T1/2 mesenchymal stem cells were differentiated to both cell fates in the presence or absence of colchicine. Differentiation was assessed by studying differentiation phenotypes as well as adipocytic and osteoblastic marker genes. Disrupting microtubule homeostasis through stathmin (STMN1) silencing was employed to mimic colchicine effects on differentiation. Proteomic analysis was performed to gain further insight into colchicine’s effects on adipogenesis. Results: Colchicine promoted transcriptional changes consistent with osteoblastogenic commitment and inhibited adipogenesis, as evidenced by reduced intracellular lipid accumulation and downregulation of adipogenic marker genes. These effects were observed following both continuous and transient exposure (median fold change across adipogenic markers 0.41 and 0.59, respectively). Consistent with colchicine-induced microtubule destabilisation, microtubule disruption by STMN1 silencing also suppressed adipogenic differentiation (median fold change = 0.66), suggesting that colchicine’s anti-adipogenic effect may be due to its impact on the cytoskeleton. Conclusions: These findings indicate that colchicine can suppress adipogenic differentiation while favouring osteoblast commitment in mesenchymal stem cells. Although further validation in relevant preclinical models is required, its efficacy following transient exposure supports the exploration of site-specific strategies that limit systemic toxicity. Full article

(This article belongs to the Special Issue Phytochemicals and Bioactive Compound-Based Pharmaceutical Formulations in Health and Disease: From Mechanisms to Therapeutic Applications)

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27 pages, 1270 KB

Open AccessReview

Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain

by Jurga Bernatoniene, Dalia M. Kopustinskiene, Roberto Casale, Alessandro Medoro, Sergio Davinelli, Luciano Saso and Kestutis Petrikonis

Pharmaceutics 2026, 18(1), 118; https://doi.org/10.3390/pharmaceutics18010118 - 16 Jan 2026

Viewed by 503

Abstract

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing [...] Read more.

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)

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17 pages, 1703 KB

Open AccessArticle

β-Cyclodextrin Inclusion Complexes of Cinnamomum camphora Essential Oil: A Comparative Study on Encapsulation Strategies, Physicochemical Stability, and Cytotoxic Profile

by José Adão Carvalho Nascimento Júnior, Anamaria Mendonça Santos, Ana Maria Santos Oliveira, Cláudio Carvalho Santana Júnior, Saravanan Shanmugam, Antonella Osses Toledo, Natalia Juica, Mikele Cândida Sousa de Sant’Anna, Adriano Antunes de Souza Araújo, Luis Constandil, Jeffri S. Retamal and Mairim Russo Serafini

Pharmaceutics 2026, 18(1), 117; https://doi.org/10.3390/pharmaceutics18010117 - 16 Jan 2026

Viewed by 415

Abstract

Background/Objectives: Essential oils (EOs) from plants of the genus Cinnamomum have been widely used based on their antimicrobial, antioxidant, and anti-inflammatory properties. However, their elevated volatility and limited aqueous solubility restrict their use in pharmaceutical and food formulations. Cyclodextrins (CDs) have emerged [...] Read more.

Background/Objectives: Essential oils (EOs) from plants of the genus Cinnamomum have been widely used based on their antimicrobial, antioxidant, and anti-inflammatory properties. However, their elevated volatility and limited aqueous solubility restrict their use in pharmaceutical and food formulations. Cyclodextrins (CDs) have emerged as a promising strategy to overcome these limitations through the formation of inclusion complexes. Methods: In this study, inclusion complexes of essential oil from C. camphora L. (EOCNM) with β-cyclodextrin (β-CD) were developed using physical mixing (PM), ultrasonic treatment (US), and freeze-drying (FD). The inclusion complexes were physicochemically characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TG/DTG), X-ray diffraction (XRD), and scanning electron microscopy (SEM) to evaluate their physicochemical interactions and complexation efficiency. Results: Our results demonstrated successful complex formation, with the FD and US methods showing greater amorphization and stronger inclusion characteristics compared to the PM method. Thermal analysis confirmed improved physicochemical stability of the essential oil when complexed with β-CD. Furthermore, the cytotoxicity assay of the complexes was assessed using the MTT assay and J774 macrophage cells. The complexes exhibited low cytotoxicity, indicating their potential biocompatibility for biomedical and food applications. Conclusions: Overall, β-CD encapsulation effectively enhanced the physicochemical stability and safety profile of C. camphora essential oil, providing a promising strategy for its controlled delivery and protection against degradation. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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30 pages, 2873 KB

Open AccessReview

Extracellular Vesicles: Orchestrators of Intrahepatic and Systemic Crosstalk in Metabolic Dysfunction-Associated Steatotic Liver Disease

by Yu Lei, Mei Liu and Xiang Tao

Pharmaceutics 2026, 18(1), 116; https://doi.org/10.3390/pharmaceutics18010116 - 16 Jan 2026

Viewed by 484

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a multifaceted systemic condition, with the mechanisms linking intrahepatic lesions to systemic complications remaining a significant enigma in the field. This review posits that extracellular vesicles (EVs) serve as pivotal mediators facilitating communication between the liver [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a multifaceted systemic condition, with the mechanisms linking intrahepatic lesions to systemic complications remaining a significant enigma in the field. This review posits that extracellular vesicles (EVs) serve as pivotal mediators facilitating communication between the liver and the entire organism. Within the hepatic environment, lipotoxic hepatocyte-derived EVs modulate macrophage populations and stellate cells, thereby promoting inflammatory and fibrotic processes. Systemically, the liver engages in bidirectional communication with adipose tissue, the intestinal tract, the cardiovascular system, and the pancreas via EVs, thus orchestrating metabolic homeostasis. Furthermore, we critically evaluate non-invasive diagnostic strategies and emerging therapies, including both natural and engineered EVs, based on EV-based interventions. We highlight the substantial potential and current challenges associated with achieving precision medicine in MASLD through targeted modulation of this specific communication network. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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26 pages, 2484 KB

Open AccessReview

Effective Non-Invasive Delivery of Epigenetic Drugs Using Functionalized Accessory Unit Conjugates

by Toshihiko Tashima

Pharmaceutics 2026, 18(1), 115; https://doi.org/10.3390/pharmaceutics18010115 - 15 Jan 2026

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Abstract

Epigenetics involves heritable changes in gene expression—such as DNA methylation (5-methylcytosine; 5mC), histone modifications, and regulation by non-coding RNAs at the mRNA translation level—without altering the underlying DNA sequence. As targeting these mechanisms enables intervention at the root cause of disease rather than [...] Read more.

Epigenetics involves heritable changes in gene expression—such as DNA methylation (5-methylcytosine; 5mC), histone modifications, and regulation by non-coding RNAs at the mRNA translation level—without altering the underlying DNA sequence. As targeting these mechanisms enables intervention at the root cause of disease rather than the symptoms alone, epigenetics has become a rapidly advancing field in pharmaceutical sciences. Various epigenetic modulators, including histone deacetylase (HDAC) inhibitors, histone acetyltransferase (HAT) inhibitors, DNA methyltransferase (DNMT) inhibitors, and microRNAs (miRNAs), have been developed, and some have already been approved for cancer therapy. However, these agents often face significant challenges such as poor membrane permeability, enzymatic instability, and suboptimal biodistribution. Incorporating functionalized accessory units—serving as vectors (e.g., transporter recognition units, cell-penetrating peptides, tumor-homing peptides, monoclonal antibodies) or as carriers (e.g., monoclonal antibodies, nanoparticles)—into epigenetic modulators may help overcome these delivery barriers. In this narrative review, I discuss the potential and advantages of effective non-invasive delivery of epigenetic drugs using such functionalized accessory unit conjugates. Full article

(This article belongs to the Special Issue Development and Drug Delivery in Epigenetic Therapy)

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19 pages, 4083 KB

Open AccessArticle

Metabolism of the Isoflavone Derivative Structural Isomers ACF-02 and ACF-03 in Human Liver Microsomes

by Zhuoning Liang, Eui-Hyeon Kim, Ga-Young Kim, Jin-Hyuk Choi, Hyung-Ju Seo, Kwang-Hyeon Liu and Moonjae Cho

Pharmaceutics 2026, 18(1), 114; https://doi.org/10.3390/pharmaceutics18010114 - 15 Jan 2026

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Abstract

Background/Objectives: Flavonoids are widely used as lead structures in drug discovery, and their pharmacological and metabolic properties are strongly influenced by structural features such as positional isomerism. This study aimed to compare the metabolic profiles and underlying mechanisms of two isoflavone-based positional isomers, [...] Read more.

Background/Objectives: Flavonoids are widely used as lead structures in drug discovery, and their pharmacological and metabolic properties are strongly influenced by structural features such as positional isomerism. This study aimed to compare the metabolic profiles and underlying mechanisms of two isoflavone-based positional isomers, ACF-02 (2-(4-hydroxy-3-methoxyphenyl)-6,7-dimethoxy-3-(4-methoxyphenyl)-4H-chromen-4-one) and ACF-03 (2-(3-hydroxy-4-methoxyphenyl)-6,7-dimethoxy-3-(4-methoxyphenyl)-4H-chromen-4-one). Methods: The metabolic pathways of synthetically prepared ACF-02 and ACF-03 were investigated using an in vitro incubation system with human liver microsomes (HLMs) supplemented with an NADPH-regenerating system, followed by liquid chromatography–high-resolution tandem mass spectrometry (LC–HRMS/MS) analysis. Metabolites were identified based on LC–HRMS/MS data and molecular networking-based node connectivity with the parent compounds. Major metabolites were further characterized by CYP phenotyping using recombinant CYP450 isoforms, and the potential for drug–drug interactions of ACF-03 was evaluated using a CYP probe substrate cocktail approach. Results: HLM incubation of ACF-02 and ACF-03 produced both hydroxylated and O-demethylated metabolites, with O-demethylation as the predominant pathway; notably, the most abundant O-demethylated metabolite differed in an isomer-dependent manner, occurring at the B₂ ring for ACF-02 and at the A ring for ACF-03, with distinct CYP isoform involvement. Molecular networking supported the relationships between the parent compounds and their metabolites, and both compounds exhibited relatively high metabolic stability with limited CYP inhibition. Conclusions: Despite differing only in the position of a single methyl substituent, ACF-02 and ACF-03 exhibited distinct isomer-dependent metabolic profiles. These findings demonstrate that even subtle positional isomerism can significantly influence metabolic behavior and should be carefully considered during lead optimization and drug design. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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33 pages, 5373 KB

Open AccessReview

Harnessing Phytochemicals and Nanotechnology Synergy for Molecular, Epigenetic, and Microbiota-Driven Regulation in Type 2 Diabetes Mellitus

by Gagan Prakash, Anis Ahmad Chaudhary, Ruchita Tanu, Mohamed A. M. Ali, Fehmi Boufahja, Pushpender K. Sharma, Sudarshan Singh Lakhawat, Tejpal Yadav, Navneet Kumar Upadhyay and Vikram Kumar

Pharmaceutics 2026, 18(1), 113; https://doi.org/10.3390/pharmaceutics18010113 - 15 Jan 2026

Viewed by 709

Abstract

Type 2 diabetes mellitus (T2DM) is a multifaceted metabolic disorder marked by impaired insulin action, pancreatic β-cell dysfunction, and the involvement of several interconnected mechanisms, including inflammation, oxidative stress, and epigenetic alterations. Despite progress in conventional therapies, achieving durable glycemic control and minimizing [...] Read more.

Type 2 diabetes mellitus (T2DM) is a multifaceted metabolic disorder marked by impaired insulin action, pancreatic β-cell dysfunction, and the involvement of several interconnected mechanisms, including inflammation, oxidative stress, and epigenetic alterations. Despite progress in conventional therapies, achieving durable glycemic control and minimizing complications remain major challenges. This review discusses the emerging role of bioactive phytochemicals—such as curcumin, berberine, resveratrol, flavonoids, and polysaccharides—in modulating essential molecular pathways including AMPK, PI3K/AKT, and cAMP/PKA, which contribute to enhanced insulin sensitivity, glucose regulation, and β-cell protection. These natural compounds also influence gut microbiota modulation and epigenetic mechanisms, offering additional metabolic and anti-inflammatory benefits. This review synthesizes evidence from peer-reviewed studies published between 2000 and 2024, incorporating bibliometric trends showing an increasing research focus on phytochemicals for T2DM management. However, limitations such as low solubility, instability, and poor absorption restrict their clinical application. Advances in nanotechnology-based delivery systems, including nanoparticles, liposomes, and nanoemulsions, have shown potential to overcome these barriers by improving stability, bioavailability, and targeted delivery of phytochemicals. The integration of gut microbiota modulation with nanocarrier-enabled phytochemical therapy supports a precision medicine approach for managing T2DM. Preliminary clinical evidence highlights significant improvements in glycemic control and inflammatory status, yet further large-scale, well-controlled trials are essential to ensure safety, optimize dosages, and standardize combination regimens. Overall, phytochemical therapies, reinforced by nanotechnology and microbiota modulation, present a promising, safe, and holistic strategy for T2DM management. Continued interdisciplinary research and clinical validation are crucial for translating these advances into effective therapeutic applications and reducing the global diabetes burden. Full article

(This article belongs to the Special Issue Advances in Delivery Systems for Antidiabetic Drugs and Beyond Glycaemic Control)

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Pharmaceutics, Volume 18, Issue 1 (January 2026) – 142 articles

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