Pharmaceutics

0 pages, 1390 KB

Open AccessArticle

Sitagliptin Potentiates the Anticancer Activity of Doxorubicin Through ROS-Driven Apoptosis and MMP/TIMP Regulation in HeLa Cells

by Aşkın Evren Güler, Mehmet Cudi Tuncer and İlhan Özdemir

Pharmaceutics 2026, 18(1), 38; https://doi.org/10.3390/pharmaceutics18010038 (registering DOI) - 26 Dec 2025

Abstract

Background/Objectives: Cervical cancer remains a major global health challenge, and treatment resistance limits the long-term success of chemotherapy. Drug repurposing strategies offer new opportunities for improving therapeutic outcomes by combining existing agents with established chemotherapeutics. Sitagliptin, a DPP-4 inhibitor commonly used in type [...] Read more.

Background/Objectives: Cervical cancer remains a major global health challenge, and treatment resistance limits the long-term success of chemotherapy. Drug repurposing strategies offer new opportunities for improving therapeutic outcomes by combining existing agents with established chemotherapeutics. Sitagliptin, a DPP-4 inhibitor commonly used in type 2 diabetes, has recently gained attention for its potential anticancer effects. This study aimed to investigate the cytotoxic, apoptotic, and anti-metastatic effects of sitagliptin and doxorubicin, individually and in combination, on human cervical cancer cells (HeLa), and to determine whether their combined use exerts a synergistic anticancer effect. Methods: HeLa cells were treated for 48 h with increasing concentrations of sitagliptin, doxorubicin, or their combination. Cell viability was assessed using the MTT assay. Apoptosis was evaluated by Annexin V-FITC/PI staining and caspase-8/9 activity assays. Synergy was quantified using the Chou–Talalay method, and Combination Index (CI) values were used to determine synergistic interactions. Intracellular ROS levels were measured using the DCFDA assay. Migration and invasion capacities were analyzed using wound healing and Transwell assays. MMP-1, MMP-2, TIMP-1, and TIMP-2 levels were quantified via ELISA with normalization to viable cell counts. Gene expression levels of PI3K/Akt and MAPK/ERK pathway components were measured by qRT-PCR. Bioinformatic analyses (STRING, GeneMANIA, GO, KEGG) were performed to identify common molecular targets and enriched pathways affected by both agents. Results: The combination of sitagliptin and doxorubicin significantly reduced cell viability and demonstrated a synergistic interaction (CI < 1). Combined treatment induced a marked increase in ROS production and significantly elevated apoptosis rates compared to monotherapies. Caspase-8 and caspase-9 activities were also higher in the combination group. Migration and invasion assays revealed substantial suppression of cell motility and invasive capacity. After normalization to viable cell numbers, MMP and TIMP reductions remained significant, confirming true biological inhibition rather than cell-death–related artifacts. qRT-PCR analyses showed downregulation of Akt and ERK expression, indicating suppression of key survival and proliferation pathways. Bioinformatic analyses supported these findings by highlighting enrichment in apoptotic, oxidative stress, and metastasis-related pathways. Conclusions: Sitagliptin enhances the anticancer efficacy of doxorubicin by amplifying ROS-mediated apoptosis, inhibiting migration and invasion, and modulating PI3K/Akt and MAPK/ERK signaling in cervical cancer cells. The combination exhibits a clear synergistic effect and demonstrates strong potential as a supportive therapeutic strategy. These findings warrant further in vivo and clinical-level investigations to evaluate the translational applicability of sitagliptin in cervical cancer therapy. Full article

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

► Show Figures

Graphical abstract

0 pages, 2703 KB

Open AccessReview

Surfactant–Particle Engineering Hybrids: Emerging Strategies for Enhancing Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs

by Kyeong-Soo Kim, Hyuk Jun Cho, Fakhar Ud Din, Jung Hyun Cho and Han-Gon Choi

Pharmaceutics 2026, 18(1), 37; https://doi.org/10.3390/pharmaceutics18010037 (registering DOI) - 26 Dec 2025

Abstract

Background/Objectives: The poor aqueous solubility of many therapeutic compounds remains a key barrier to achieving optimal oral bioavailability. While traditional formulation strategies—such as surfactant-based solubilization, nanocrystals, and amorphous solid dispersions—have yielded varying degrees of success, they are often limited by poor physical stability, [...] Read more.

Background/Objectives: The poor aqueous solubility of many therapeutic compounds remains a key barrier to achieving optimal oral bioavailability. While traditional formulation strategies—such as surfactant-based solubilization, nanocrystals, and amorphous solid dispersions—have yielded varying degrees of success, they are often limited by poor physical stability, high excipient loads, inconsistent absorption, and safety concerns associated with long-term surfactant exposure. To address these challenges, this review evaluates surfactant–particle hybrid drug delivery systems as a next-generation platform for enhancing the oral delivery of poorly water-soluble drugs. Methods: A comprehensive literature analysis was conducted to examine the mechanistic foundations, formulation techniques, and translational hurdles associated with these hybrid systems. Representative in vitro and in vivo case studies were critically reviewed to assess performance consistency, particularly with respect to dissolution enhancement, supersaturation stabilization, and permeability modulation. Consideration was also given to manufacturing feasibility, excipient safety, scalability, and regulatory constraints. Results: Findings indicate that surfactant–particle hybrids provide synergistic benefits by integrating solubilization and stabilization functions with tailored particle design. These systems have shown consistent improvements in pharmacokinetic profiles and drug absorption across diverse drug candidates. However, limitations remain, including challenges in long-term physical stability and excipient compatibility that must be addressed for broader application. Conclusions: Surfactant–particle hybrid systems offer a versatile and promising approach to overcoming the limitations of poorly soluble drugs. With careful attention to formulation optimization and regulatory compliance, they have the potential to serve as a transformative platform in future oral drug delivery strategies. Full article

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)

► Show Figures

Figure 1

0 pages, 14864 KB

Open AccessArticle

Harnessing Dual Power: Genistein-Loaded Pumpkisomes in Pullulan Microneedles for Potent Antioxidant and Anticancer Therapy Against Ehrlich Ascites Carcinoma and Breast Cancer Cells

by Sammar Fathy Elhabal, Mai S. Shoela, Mohamed Fathi Mohamed Elrefai, Fatma E. Hassan, Suzan Awad AbdelGhany Morsy, Wedian Younis Abdelgawad, Sahar K. Ali, Passant M. Mohie, Amal M. Elsharkawy, Tassneim M. Ewedah, Ibrahim S. Mousa, Marwa A. Fouad, Shady Allam and Ahmed Mohsen Elsaid Hamdan

Pharmaceutics 2026, 18(1), 36; https://doi.org/10.3390/pharmaceutics18010036 (registering DOI) - 26 Dec 2025

Abstract

Background/Objectives: Breast cancer remains one of the leading causes of cancer-related mortality. Still, limited drug delivery systems for genistein, a powerful natural anticancer agent, draw significant attention. We aimed to develop a co-therapeutic/synergistic dual-compartment system; genistein-loaded pumpkisome nanovesicles (GNS-PKs) incorporated into pullulan microneedle [...] Read more.

Background/Objectives: Breast cancer remains one of the leading causes of cancer-related mortality. Still, limited drug delivery systems for genistein, a powerful natural anticancer agent, draw significant attention. We aimed to develop a co-therapeutic/synergistic dual-compartment system; genistein-loaded pumpkisome nanovesicles (GNS-PKs) incorporated into pullulan microneedle patches (MNs), and to explore its anticancer activity. Methods: GNS-PKs were prepared and characterized for particle size (P.S), polydispersity (PDI), zeta potential (ZP), encapsulation efficiency (EE%), and stability. Afterward, they were embedded in pullulan-dissolving microneedle arrays and characterized for release kinetics, mechanical strength, and in vitro cytotoxicity. The in vivo efficacy was evaluated in mice with solid Ehrlich Ascites Carcinoma (EAC), focusing on tumor volume, oxidative stress, inflammatory cytokines, Epidermal Growth Factor (EGFR) expression biomarkers, and histopathological analysis. Results: The optimized nanovesicles had a particle size of 170 nm, a zeta potential of −42 mV, and an entrapment efficiency of up to 92%. Pullulan microneedles demonstrated significantly high mechanical strength and effective deep penetration. In addition to, it markedly decreased MCF-7 cellular viability (IC₅₀ = 3.5 µg/mL). Besides, it had a 76% reduction in tumor volume, significantly increased the antioxidant activity (SOD, CAT, GSH), decreased the levels of inflammatory biomarkers (IL-6, COX-2, NF-κB), and markedly downregulated the EGFR expression (p < 0.0001). Histological study revealed decreased mitotic activity and large tumor cells, with minimal systemic damage. Conclusions: GNS-PKs-pullulan microneedle system offers a hope for an innovative, potent, effective, and non-invasive strategy for breast cancer treatment with high antitumor efficacy. Full article

(This article belongs to the Special Issue From Nature to Pharmacy: Advances in Bio-Based Pharmaceutical Formulations)

► Show Figures

Graphical abstract

0 pages, 2171 KB

Open AccessArticle

Bridging the Knowledge Gap in Harmaline’s Pharmacological Properties: A Focus on Thermodynamics and Kinetics

by Tatyana Volkova, Olga Simonova and German Perlovich

Pharmaceutics 2026, 18(1), 35; https://doi.org/10.3390/pharmaceutics18010035 (registering DOI) - 26 Dec 2025

Abstract

Background/Objectives: Advancing information on the key physicochemical properties of biologically active substances enables the development of formulations with reduced dosing, lower toxicity, and minimal adverse effects. This work addresses the knowledge gap concerning the pharmacologically relevant properties of harmaline (HML), with a [...] Read more.

Background/Objectives: Advancing information on the key physicochemical properties of biologically active substances enables the development of formulations with reduced dosing, lower toxicity, and minimal adverse effects. This work addresses the knowledge gap concerning the pharmacologically relevant properties of harmaline (HML), with a focus on thermodynamic and kinetic aspects. New data were obtained on the compound’s solubility and distribution coefficients across a wide temperature range. Specifically, solubility was measured in aqueous buffers (pH 2.0 and 7.4), 1-octanol (OctOH), n-hexane (Hex), and isopropyl myristate (IPM), while distribution coefficients were determined in OctOH/pH 7.4, Hex/pH 7.4, and IPM/pH 7.4 systems. Methods: Three membranes—regenerated cellulose (RC), PermeaPad (PP) and polydimethylsiloxane-polycarbonate (PDS)—were used as barriers in permeability studies using a Franz diffusion cell. Results: At 310.15 K, the molar solubility of HML in the solvents decreased in the following order: OctOH > pH 2.0 > pH 7.4 > IPM > Hex. The distribution coefficient of HML showed a strong dependence on the nature of the organic phase, correlating with its solubility in the respective solvents. The OctOH/pH 7.4 distribution coefficient ranged from 0.973 at 293.15 K to 1.345 at 313.15 K, falling within the optimal range for potential drug bioavailability. The transfer of HML into OctOH (from either pH 7.4 or hexane) is thermodynamically spontaneous, whereas its transfer into Hex is unfavorable. Conclusions: Based on its permeability across the PP barrier, HML was classified as highly permeable. The distribution and permeation profiles of HML showed similar trends over 5 h in both the OctOH/pH 7.4–PP and IPM/pH 7.4–PDS systems. These systems were therefore proposed as suitable models for studying HML transport in vitro. Full article

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

► Show Figures

Graphical abstract

0 pages, 1828 KB

Open AccessReview

Breaking Barriers: Immune Checkpoint Inhibitors in Breast Cancer

by Bartosz Dmuchowski, Witold Wit Hryniewicz, Igor Barczak, Kacper Fręśko, Zuzanna Szarzyńska, Hubert Węclewski, Jan Kazimierz Ślężak, Paula Dobosz and Hanna Gryczka

Pharmaceutics 2026, 18(1), 34; https://doi.org/10.3390/pharmaceutics18010034 (registering DOI) - 26 Dec 2025

Abstract

Breast cancer remains the most commonly diagnosed malignancy among women worldwide and continues to pose significant therapeutic challenges, particularly in advanced and refractory disease. Although traditionally considered less immunogenic compared with other solid tumours, growing evidence demonstrates that subsets of breast cancer, particularly [...] Read more.

Breast cancer remains the most commonly diagnosed malignancy among women worldwide and continues to pose significant therapeutic challenges, particularly in advanced and refractory disease. Although traditionally considered less immunogenic compared with other solid tumours, growing evidence demonstrates that subsets of breast cancer, particularly triple-negative and HER2-positive subtypes, exhibit immune-responsive features. This recognition has spurred the development and clinical evaluation of immunotherapeutic strategies, with immune checkpoint inhibitors (ICIs) emerging as the most prominent approach. This new class of drugs targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has demonstrated meaningful clinical activity in select patient populations, leading to regulatory approvals in combination with chemotherapy for advanced triple-negative breast cancer. Despite these advances, response rates remain modest, and the benefits are largely restricted to patients with PD-L1-positive tumours. Ongoing studies are evaluating predictive biomarkers, optimal treatment combinations, and mechanisms of resistance to expand the efficacy of ICIs across broader breast cancer subtypes. Furthermore, novel checkpoint targets such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) are under investigation, with the potential to enhance or complement PD-1/PD-L1 blockade. This review summarises the current state of knowledge on breast cancer immunotherapy with an emphasis on ICIs, highlighting key clinical trial findings, as well as emerging biomarkers of response, and strategies to overcome therapeutic resistance, if cancer cells eventually develop resistance. By integrating preclinical insights with clinical progress, we aim to provide a comprehensive overview of the evolving role of checkpoint blockade in breast cancer and outline future directions to optimise patient outcomes. Full article

(This article belongs to the Special Issue Personalized Medicine in Clinical Pharmaceutics)

0 pages, 5396 KB

Open AccessArticle

Development and Evaluation of Scaffolds Based on Perch Collagen–Hydroxyapatite for Advanced Synthetic Bone Substitutes

by Alina Elena Coman, Ana Maria Rosca, Maria Minodora Marin, Madalina Georgiana Albu Kaya, Raluca Gabor, Catalina Usurelu, Mihaela Violeta Ghica, Laurentiu Dinca and Irina Titorencu

Pharmaceutics 2026, 18(1), 33; https://doi.org/10.3390/pharmaceutics18010033 (registering DOI) - 26 Dec 2025

Abstract

Background/Objectives: Bone defects remain widespread. Type I collagen–hydroxyapatite composites suit bone engineering by mimicking matrix structure, making them pertinent materials for bone tissue engineering across a range of defect types. Their application is well aligned with non-load-bearing conditions, while use in load-bearing sites [...] Read more.

Background/Objectives: Bone defects remain widespread. Type I collagen–hydroxyapatite composites suit bone engineering by mimicking matrix structure, making them pertinent materials for bone tissue engineering across a range of defect types. Their application is well aligned with non-load-bearing conditions, while use in load-bearing sites requires mechanical properties that meet the demands of those environments. Marine collagen offers a low-cost source from processing by-products. This work aimed to develop perch collagen–hydroxyapatite scaffolds for bone tissue engineering. Methods: Composites with COLL:HAp ratios of 100:0, 50:50, 40:60, and 30:70 were prepared. After crosslinking and freeze-drying, porosity and water absorption were examined. SEM and X-EDS assessed morphology and elemental distribution. FT-IR confirmed the chemical composition. Compression tests evaluated mechanical behavior. Cell viability and colonization assessed the biological performance. Biodegradability, thermal stability, and antimicrobial activity were also determined. Results: FT-IR confirmed the characteristic absorption bands of both components. SEM and swelling behavior showed porous, interconnected structures with uniform hydroxyapatite dispersion. X-EDS indicated Ca/P ratios consistent with hydroxyapatite. Thermal analysis demonstrated scaffold stability. Compression tests showed mechanical resistance for all the scaffolds, with stiffness increasing with the inorganic content. Perch collagen enhanced biological functionality, supporting osteoblast viability and colonization. Biodegradation gradually proceeded. Antibacterial activity against the tested pathogens was detectable, though moderate. Conclusions: The developed scaffolds combined structural stability, controlled degradation, and favorable cell response, constituting a viable and promising candidate for applications in bone tissue engineering. Full article

(This article belongs to the Special Issue Biomaterial-Based Nanoencapsulation Systems for Drug Protection and Controlled Release)

► Show Figures

Figure 1

22 pages, 6783 KB

Open AccessArticle

In Silico Predictions Driving the Development of 3D-Printed Drug Delivery Systems

by Pooja Todke, Robertas Lazauskas and Jurga Bernatoniene

Pharmaceutics 2026, 18(1), 32; https://doi.org/10.3390/pharmaceutics18010032 (registering DOI) - 26 Dec 2025

Abstract

Background: Three-dimensional printing (3DP) is a promising technology for advancing pharmaceutical research by enabling the production of personalized drug products. However, its progress has been hindered by the conventional trial-and-error approach to excipient selection and optimization. Methods: In this study, the blend module [...] Read more.

Background: Three-dimensional printing (3DP) is a promising technology for advancing pharmaceutical research by enabling the production of personalized drug products. However, its progress has been hindered by the conventional trial-and-error approach to excipient selection and optimization. Methods: In this study, the blend module was employed to determine the miscibility parameters—mixing energy (E_mix) and Flory–Huggins interaction parameter (χ) to find the right excipients and drug–excipient ratio and examine the incorporation of plasticizers and lipids to enhance printability. Furthermore, molecular dynamics (MD) simulations were employed to calculate the cohesive energy density (CED) for predicting the dissolution behavior of 3DP formulations. Results: Data from 51 formulations were analyzed, enabling correlation and experimental validation of the in silico predictions. The predicted miscibility values demonstrated a strong correlation with experimental printability results. Furthermore, using a miscibility parameter, it was possible to accurately forecast minor changes in the drug-to-excipient ratio, plasticizer/lipid concentration, and hot-melt extrusion (HME) temperature that affect printability. Hydrophilic carriers exhibited lower CED values corresponding to faster drug release. In contrast, more hydrophobic carriers revealed high CED values, indicating stronger drug entrapment and sustained release. Conclusions: The miscibility parameters and MD-simulated CED values provide a practical framework for early-stage, high-throughput excipient screening. Overall, in silico prediction offers a viable strategy for modeling the entire 3DP workflow, minimizing the need for trial-and-error experimentation, and thereby accelerating the clinical translation of 3DP drug delivery systems. Full article

(This article belongs to the Special Issue Advancements in Industrial Pharmaceutics: Innovations and Future Directions)

► Show Figures

Figure 1

25 pages, 10271 KB

Open AccessArticle

Botanical Nanofiber Wound Dressing Loaded with Psidium guajava Leaf Extract: Preparation, Characterization, and In Vivo Evaluation

by Menna M. Abdellatif, Hesham A. Eliwa, Mohamed Aly Abd El Aziz El Degwy, Samah Shabana, Rafik M. Nassif, Hamada Sadki Mohamed and Rehab Abdelmonem

Pharmaceutics 2026, 18(1), 31; https://doi.org/10.3390/pharmaceutics18010031 - 25 Dec 2025

Abstract

Background/Objectives: This study aimed to develop botanical nanofibers loaded with Psidium guajava leaf extract to heal wounds effectively. Methods: A 2³ factorial design was conducted to study the impact of freeze-drying parameters—freezing time, vacuum, and lyophilization time—on the total phenolic [...] Read more.

Background/Objectives: This study aimed to develop botanical nanofibers loaded with Psidium guajava leaf extract to heal wounds effectively. Methods: A 2³ factorial design was conducted to study the impact of freeze-drying parameters—freezing time, vacuum, and lyophilization time—on the total phenolic and flavonoid content in the lyophilized extract. Then, a polyurethane-based nanofiber dressing loaded with Psidium guajava leaf extract was fabricated using a one-step electrospinning technique. The nanofiber was evaluated considering total polyphenol and flavonoid content, surface roughness, and morphological assessment by scanning electron microscopy. Finally, the nanofiber was evaluated using in vivo wound-healing studies, histopathological analyses, and assessments of tissue levels of tumor necrosis factor-alpha, interleukin-6, matrix metalloproteinase, and growth factors. Results: The optimal conditions for freeze-drying the aqueous extract of Psidium guajava leaves were a freezing time of 24 h, a vacuum adjusted to 0.02 bar, and a lyophilization time of 48 h. The total polyphenol and flavonoid content within the nanofiber was 96 ± 1.2% and 91.83 ± 2.4%, respectively. Incorporating lyophilized extract in the nanofiber led to a decreased roughness average and root mean square roughness of the nanofiber. The nanofiber was continuous and had a smooth, uniform surface. The in vivo wound-healing assay showed superior wound-healing compared to the commercial Panthenol cream. These results were confirmed with histopathological studies. Conclusions: The extraction technique and lyophilization parameters significantly affect the bioactive content of Psidium guajava leaf extract. The botanical-loaded nanofiber showed greater wound-healing potential than a commercial cream, confirming its potential in regenerative medicine and wound repair applications. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

► Show Figures

Figure 1

27 pages, 1152 KB

Open AccessSystematic Review

Cell Therapy in Multiple Sclerosis: Clinical Advances, Limitations, and Future Perspectives from Clinical Studies—A Systematic Review

by Ola Mohamed Fathy Kamal, Doddy Denise Ojeda-Hernández, Belén Selma-Calvo, Marina García-Martín, María Teresa Larriba-González, Lucia Martin-Blanco, Jordi A. Matias-Guiu, Jorge Matias-Guiu and Ulises Gomez-Pinedo

Pharmaceutics 2026, 18(1), 30; https://doi.org/10.3390/pharmaceutics18010030 - 25 Dec 2025

Abstract

Background: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), characterised by inflammation, demyelination, and progressive neurodegeneration. Although current disease-modifying therapies (DMTs) can reduce relapse rates and inflammatory activity, they rarely stop long-term progression or repair neurological [...] Read more.

Background: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), characterised by inflammation, demyelination, and progressive neurodegeneration. Although current disease-modifying therapies (DMTs) can reduce relapse rates and inflammatory activity, they rarely stop long-term progression or repair neurological damage. In recent years, cell-based therapies have emerged as promising approaches to promote immune regulation and neuroregeneration in MS. Methods: This review summarises the current clinical evidence from studies in humans investigating cell-based treatments for MS, including autologous haematopoietic stem cell transplantation (AHSCT), mesenchymal stem cells (MSCs), and neural stem or progenitor cells (NSCs). A systematic literature search was performed using PubMed, Scopus, and ClinicalTrials.gov, focusing on human clinical trials that met specific inclusion criteria. Results: Prevailing findings show that AHSCT provides the most consistent benefit, achieving long-term immune reconstitution and remission in patients with highly active relapsing–remitting MS (RRMS), although it carries procedural risks. MSC therapies have demonstrated good safety and biological activity, especially when delivered intrathecally (IT) in progressive MS, though clinical results remain variable. Conclusions: NSC-based treatments are still at an early stage of clinical research but show potential for CNS repair. The main limitations across studies include differences in protocols, small sample sizes, and short follow-up periods. Further large-scale, randomised controlled trials are needed to confirm long-term efficacy, define optimal delivery methods, and establish standardised clinical protocols. Full article

(This article belongs to the Section Biologics and Biosimilars)

► Show Figures

Graphical abstract

19 pages, 2541 KB

Open AccessArticle

Mesalazine Regulates DUSP1, DUSP4, and DUSP5 Expression in Colorectal Cancer: In Vitro and Bioinformatic Evidence

by Marcel Madej, Ilona Nowak, Barbara Strzałka-Mrozik, Magdalena Kimsa-Dudek, Celina Kruszniewska-Rajs and Joanna Magdalena Gola

Pharmaceutics 2026, 18(1), 29; https://doi.org/10.3390/pharmaceutics18010029 (registering DOI) - 25 Dec 2025

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with its development closely linked to dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways. Background: Dual-specificity phosphatases (DUSPs), as key regulators of MAPKs, play a crucial role in maintaining [...] Read more.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with its development closely linked to dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways. Background: Dual-specificity phosphatases (DUSPs), as key regulators of MAPKs, play a crucial role in maintaining the balance between proliferation and apoptosis. Methods: In this study, we investigated the effect of mesalazine (MES) on the expression and activity of selected DUSP family members in normal colon epithelial cells (CCD-841CoN) and colorectal cancer cells (DLD-1). Results: Microarray analysis identified 24 transcripts with altered expression upon mesalazine treatment. The number of significantly regulated genes decreased with increasing fold-change (FC) thresholds, from 20 genes (FC > 1.1) to 13 (FC > 1.5) and 5 (FC > 2.0), all with p < 0.001. Among the DUSP genes, DUSP4 and DUSP5 showed the most pronounced and cell-type-dependent modulation. Mesalazine upregulated DUSP4 and DUSP5 expression in DLD-1 cells (p < 0.001), while reducing their expression in normal CCD-841CoN cells. ELISA confirmed a 1.56-fold increase in DUSP5 protein concentration in mesalazine-treated cancer cells compared with controls (p < 0.001). Conclusions: These findings suggest that mesalazine differentially modulates DUSP gene expression in normal and malignant colon epithelial cells, potentially contributing to its antiproliferative and pro-apoptotic effects through the regulation of MAPK signaling. These results provide new insights into the molecular mechanisms underlying the anticancer effects of mesalazine in colorectal cancer. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Disease: Insights into Drug Delivery and Cellular and Molecular Mechanisms for Therapy)

► Show Figures

Figure 1

39 pages, 2900 KB

Open AccessReview

Smart Cells Against Cancer: Advances in Cell-Based Drug Delivery and Diagnostics

by Lisa Gherardini, Giovanni Inzalaco, Sara Gargiulo, Lorenzo Franci and Monia Taranta

Pharmaceutics 2026, 18(1), 28; https://doi.org/10.3390/pharmaceutics18010028 - 25 Dec 2025

Abstract

Cell-based drug delivery has emerged as a powerful strategy to improve therapeutic targeting while reducing systemic toxicity. This approach is particularly valuable for anticancer agents, which are often limited by severe side effects arising from off-target activity and non-specific distribution. By using cells [...] Read more.

Cell-based drug delivery has emerged as a powerful strategy to improve therapeutic targeting while reducing systemic toxicity. This approach is particularly valuable for anticancer agents, which are often limited by severe side effects arising from off-target activity and non-specific distribution. By using cells as carriers, drugs can evade immune clearance, achieve prolonged circulation, and improve pharmacokinetic profiles, ultimately enhancing therapeutic efficacy. This review surveys the current landscape of cell-mediated drug delivery in oncology, emphasizing both fundamental principles and practical applications. We discuss the design and preparation of cellular carriers, examine the unique characteristics of commonly used cell types, and highlight recent technological innovations that are expanding their theranostic potential, focusing on strategies for delivery to challenging anatomical sites, with a dedicated focus on the brain. By consolidating recent advances and insights, this review aims to provide a comprehensive perspective on the promise and future directions of cell-based drug delivery for cancer therapy. Full article

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

30 pages, 2344 KB

Open AccessReview

Microglia-Targeted Nanotherapeutics in Major Depressive Disorder: An Integrative Perspective on Neuroinflammation and Drug Delivery

by Pablo R. da Silva, Nayana M. M. V. Barbosa, Joandra M. da Silva Leite, Larissa P. Alves, Jéssica C. de Andrade, Allessya L. D. Formiga, Ana Flávia C. Uchôa, Luiza C. D. Neri, Arthur Lins Dias, Adriana M. F. de Oliveira-Golzio, Francisco H. Xavier-Júnior, Ricardo D. de Castro, Cícero F. Bezerra Felipe, Marcus T. Scotti and Luciana Scotti

Pharmaceutics 2026, 18(1), 27; https://doi.org/10.3390/pharmaceutics18010027 (registering DOI) - 25 Dec 2025

Abstract

Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by complex neurobiological mechanisms, including oxidative stress and neuroinflammation, with microglial activation playing a key role in its pathophysiology. Conventional antidepressants, though widely used, often fail to achieve remission due to limited [...] Read more.

Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by complex neurobiological mechanisms, including oxidative stress and neuroinflammation, with microglial activation playing a key role in its pathophysiology. Conventional antidepressants, though widely used, often fail to achieve remission due to limited efficacy, adverse effects, and poor patient adherence. In this context, nanotechnology-based drug delivery systems have emerged as promising strategies to overcome pharmacological limitations, enhance blood–brain barrier (BBB) penetration, and target neuroinflammatory pathways. This narrative review explores the role of microglia as both mediators of neuroinflammation and potential therapeutic targets in MDD. We examine different nanocarriers and their ability to modulate microglial activation, promote a shift from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype, and enhance antidepressant efficacy. Preclinical studies have demonstrated that nanoparticle-based systems not only improve drug bioavailability and brain targeting but also potentiate neuroprotective effects by reducing oxidative stress, promoting neurogenesis, and restoring synaptic plasticity. These findings highlight the potential of nanotechnology as a novel approach to precision neuropsychopharmacology. This review aims to provide an integrative perspective on how nanocarrier-based strategies targeting microglia could redefine future therapeutic paradigms for MDD. Full article

(This article belongs to the Special Issue Targeted Drug Delivery: Innovations to Overcome Biological and Technical Barriers)

► Show Figures

Figure 1

17 pages, 2363 KB

Open AccessArticle

Comparative Phytochemical Profiling of Essential Oils from Selected Abies Species and Analysis of Their Antifungal and Antiradical Activity

by Rizvangul Ayupova, Emil Svajdlenka, Milan Zemlicka, Galiya Ibadullayeva, Karlygash Raganina, Urziya Alimova, Shamshabanu Nokerbek, Rauan Botabayeva, Lashyn Kiyekbayeva and Serzhan Mombekov

Pharmaceutics 2026, 18(1), 26; https://doi.org/10.3390/pharmaceutics18010026 - 25 Dec 2025

Abstract

Background/Objectives: The essential oils of Abies species possess a complex chemical composition and pronounced biological activity. However, comparative studies of interspecies differences and on the influence of extraction methods on their chemical profile and pharmacological properties are limited. Such data are necessary for [...] Read more.

Background/Objectives: The essential oils of Abies species possess a complex chemical composition and pronounced biological activity. However, comparative studies of interspecies differences and on the influence of extraction methods on their chemical profile and pharmacological properties are limited. Such data are necessary for identifying the most promising species and optimizing essential oil production technologies for pharmaceutical applications. The aim of this study was to comparatively evaluate the essential oils of seven Abies species obtained by steam distillation and to analyze the effects of three extraction methods on the chemical and biological characteristics of Abies sibirica L. oil. Methods: The essential oils of seven Abies species were isolated by steam distillation. For A. sibirica, supercritical CO₂ extraction and microwave-assisted steam distillation (MASD) were additionally used. Chemical composition was determined by GC-MS. Statistical analysis included ANOVA, PCA and hierarchical cluster modeling, and non-parametric tests. Antifungal activity was assessed against Candida albicans, and antiradical activity was assessed using densitometric analysis. Results: GC-MS analysis revealed significant differences in chemical composition between species and extraction methods. The main compounds were bornyl acetate, α-pinene, and camphene. ANOVA revealed significant differences in bornyl acetate and β-pinene content between species (p < 0.001) and methods (p < 0.01). PCA and clustering identified a bornyl acetate-rich chemotype (A. sibirica, A. grandis, A. lowiana). A. sibirica oil, obtained by MASD, exhibited high antifungal activity (82% inhibition), similar to that of 5-flucytosine (95%). Antiradical activity correlated with monoterpenes corresponding to peaks 2 and 7 of the densitogram. Conclusions: This study demonstrates that the species and extraction method significantly determine the chemical profile and biological properties of Abies oils. A. sibirica oil, obtained by MASD, demonstrated the highest activity, highlighting its potential as a source of biologically active compounds. Full article

(This article belongs to the Special Issue Essential Oils: From Biological Activity to Pharmaceutical Applications)

► Show Figures

Figure 1

28 pages, 6693 KB

Open AccessArticle

Optimization of Microfluidizer-Produced PLGA Nano-Micelles for Enhanced Stability and Antioxidant Efficacy: A Quality by Design Approach

by Esma Nur Develi Arslanhan, Fatemeh Bahadori, Zahra Eskandari, Muhammed Zahid Kasapoglu and Erkan Mankan

Pharmaceutics 2026, 18(1), 25; https://doi.org/10.3390/pharmaceutics18010025 - 25 Dec 2025

Abstract

Introduction: In this study, we aimed to optimize the microfluidizer-based preparation of poly(lactic-co-glycolic acid) nano-micelles (PLGANM), increasingly used for parenteral delivery of poorly water-soluble drugs but typically exhibiting poor physical stability when produced by conventional methods. Method: By systematically tuning microfluidization (MFZ) parameters, [...] Read more.

Introduction: In this study, we aimed to optimize the microfluidizer-based preparation of poly(lactic-co-glycolic acid) nano-micelles (PLGANM), increasingly used for parenteral delivery of poorly water-soluble drugs but typically exhibiting poor physical stability when produced by conventional methods. Method: By systematically tuning microfluidization (MFZ) parameters, we demonstrate an efficient strategy to enhance PLGANM stability and ensure robust, scalable manufacturing, relevant for long-term storage and clinical translation applications. The influence of several key factors designed by Central Composite Design (CCD), including the amount of PLGA and Tween 80, homogenization pressure, and number of passes of MFZ on the size, polydispersity (measured by DLS), and hence stability of the PLGANM, was analyzed for 60 days. 60 PLGANMs produced by the MFZ method (PMFZ) were compared with the PLGANM consisting of equivalent amounts of PLGA and T80 produced using the traditional oil-in-water method (POW). Desired limits were set to minimize standard deviations for Z-average, Zeta Potential, and PDI. Results: Coded variables for optimized PMFZ (OPMFZ) were found to be 82.96 mg PLGA, 6.78 mL 5% T80, 11,000 psi pressure, and 1 pass. Conclusions: This study demonstrates that microfluidization, when guided by a QbD framework, offers precise control over particle attributes and enables reproducible production of stable PLGANM. Full article

(This article belongs to the Special Issue PLGA Micro/Nanoparticles in Drug Delivery)

► Show Figures

Graphical abstract

17 pages, 2279 KB

Open AccessArticle

L19-Conjugated Gold Nanoparticles for the Specific Targeting of EDB-Containing Fibronectin in Neuroblastoma

by Chiara Barisione, Silvia Ortona, Veronica Bensa, Caterina Ivaldo, Eleonora Ciampi, Simonetta Astigiano, Michele Cilli, Luciano Zardi, Mirco Ponzoni, Domenico Palombo, Giovanni Pratesi, Pier Francesco Ferrari and Fabio Pastorino

Pharmaceutics 2026, 18(1), 24; https://doi.org/10.3390/pharmaceutics18010024 - 24 Dec 2025

Abstract

Background/Objectives: Neuroblastoma (NB) is the most common extracranial solid tumor in children and accounts for 12–15% of pediatric cancer-related deaths. Current multimodal therapies lack specific cellular targets, causing systemic toxicity and drug resistance. The development of innovative tumor-targeted nanoformulations might represent a [...] Read more.

Background/Objectives: Neuroblastoma (NB) is the most common extracranial solid tumor in children and accounts for 12–15% of pediatric cancer-related deaths. Current multimodal therapies lack specific cellular targets, causing systemic toxicity and drug resistance. The development of innovative tumor-targeted nanoformulations might represent a promising approach to enhance NB diagnosis and antitumor efficacy, while decreasing off targets side effects. Fibronectin extra-domain B (FN-EDB) is upregulated in the tumor microenvironment. Methods: FN-EDB expression was evaluated by immunohistochemical staining in cell line-derived and tumor patient-derived animal models of NB. A gold nanoparticle, decorated with an antibody (Ab) recognizing FN-EDB (L19-AuNP) was developed by the company Nano Flow and its tumor binding was tested by ELISA in vitro and in patient-derived xenograft (PDX) models of NB by photoacoustic imaging in vivo. Results: All animal models of NB used have been shown to express FN-EDB. L19 Ab demonstrated excellent binding specificity to FN-EDB both when used in free form and after conjugation to AuNP. Compared to the non-functionalized (no Ab L19-coupled) AuNP, which showed an increase in PDI and zeta potential over time, making them unsuitable for use in in vivo studies, L19-AuNP demonstrated good stability. In vivo, L19-AuNP specifically homed into PDX models of NB, accumulating better in tumors expressing higher levels of FN-EDB. Negligible distribution to healthy organs occurred. Conclusions: In this preliminary study, L19-AuNP was shown to be a novel diagnostic tool specifically for binding NB expressing FN-EDB, paving the way for the development of theranostic nanoformulations co-encapsulating gold moiety and standard-of-care therapy for NB. Full article

(This article belongs to the Special Issue Nanomedicine and Nanotechnology: Recent Advances and Applications)

► Show Figures

Graphical abstract

23 pages, 3734 KB

Open AccessArticle

Evaluation of the Functional Suitability of Carboxylate Chlorin e₆ Derivatives for Use in Radionuclide Diagnostics

by Mariia Larkina, Anastasia Demina, Nikita Suvorov, Petr Ostroverkhov, Evgenii Plotnikov, Ruslan Varvashenya, Vitalina Bodenko, Gleb Yanovich, Anastasia Prach, Viktor Pogorilyy, Sergey Tikhonov, Alexander Popov, Maxim Usachev, Beatrice Volel, Yuriy Vasil’ev, Mikhail Belousov and Mikhail Grin

Pharmaceutics 2026, 18(1), 23; https://doi.org/10.3390/pharmaceutics18010023 - 23 Dec 2025

Abstract

Radionuclide-based molecular imaging modalities are active and developing areas of functional and molecular diagnosis. Among the radionuclides used for SPECT imaging in oncology, ^99mTc is a leading candidate for radiolabeling. At present, a sufficient number of complexons for ^99mTc have been [...] Read more.

Radionuclide-based molecular imaging modalities are active and developing areas of functional and molecular diagnosis. Among the radionuclides used for SPECT imaging in oncology, ^99mTc is a leading candidate for radiolabeling. At present, a sufficient number of complexons for ^99mTc have been described; however, the development of effective delivery systems for this isotope to the area of interest is a complex research task. The use of tumor-targeting molecules as carriers for radioactive tracers is an effective strategy that has enabled the development of many novel radiopharmaceuticals for cancer imaging. Background: To date, a number of studies have shown tumorotropicity of tetrapyrrole compounds to tumor tissues, in particular derivatives of natural chlorophyll A. Methods: Purification was performed using solid-phase extraction. Assessment of radiochemical yield and purity was performed via radio-ITLC. The in vitro tumor cell accumulation was assessed using SKOV-3 and A-431 cell lines. Dose-dependent biodistribution was evaluated in Nu/J mice bearing epidermoid carcinoma (A-431) xenografts. Results: In this work, we obtained complexes with ^99mTc based on water-soluble carboxylate chlorin e₆ derivatives in order to evaluate their potential for use as SPECT radiopharmaceuticals. We performed radiolabelling optimization of a series of the novel chlorins and primary preclinical studies, including an assessment of the effect of their lipophilicity and charge on tumor uptake. Conclusions: Modification of the periphery of the chlorin macrocycle with chelating groups allows for complexing a wide range of metals, including ^99mTc, which can be used for targeted delivery of the radionuclide to the area of interest. Full article

(This article belongs to the Special Issue Applications of Stable Nuclide and Radionuclides in the Area of Pharmacokinetic Process Control and Targeted Drug Therapy)

► Show Figures

Figure 1

7 pages, 763 KB

Open AccessArticle

Oral Bioavailability of Monoclonal Antibody

by Ashwni Verma, Shengjia Wu and Dhaval K. Shah

Pharmaceutics 2026, 18(1), 22; https://doi.org/10.3390/pharmaceutics18010022 - 23 Dec 2025

Abstract

Background/Objectives: Despite significant interest in the oral delivery of antibodies, the oral bioavailability of monoclonal antibodies (mAbs) is not known to date. To find out an answer to this question, we have performed a preclinical investigation in mice and rats, using a non-binding [...] Read more.

Background/Objectives: Despite significant interest in the oral delivery of antibodies, the oral bioavailability of monoclonal antibodies (mAbs) is not known to date. To find out an answer to this question, we have performed a preclinical investigation in mice and rats, using a non-binding humanized mAb trastuzumab as the prototype molecule. Methods: The antibody was administered at the dose of 100 mg/kg in mice and rats, and plasma pharmacokinetics (PK) was measured for 14 days. Published plasma PK of trastuzumab in mice and rats obtained after intravenous administration was also used for the analysis. Non-compartmental analysis (NCA), as well as compartmental modeling of PK data, was performed to estimate the oral bioavailability of the antibody in mice and rats. Results: It was found that the oral bioavailability of mAb in rats and mice determined using NCA was 0.027% and 0.014%, respectively. The model-estimated oral bioavailability of the mAb in rats and mice was 0.025% and 0.013%, respectively. The rate of absorption of the mAb from the gastrointestinal tract was found to be the same between rats and mice, as 0.78 h⁻¹. Conclusions: Overall, the oral bioavailability of the humanized mAb in rodents was found to be around 0.02%, suggesting only 1 out of 5000 mAb molecules administered orally makes it to the systemic circulation. To the best of our knowledge, this is the first study to report an absolute oral bioavailability value for a mAb. It remains to be seen if the observed value of 0.02% is generalizable across mAb molecules and other animal species, including humans. Full article

(This article belongs to the Special Issue Drug Product Performance: Bioavailability, Relative Bioavailability and Bioequivalence, 2nd Edition)

► Show Figures

Figure 1

19 pages, 4111 KB

Open AccessArticle

Non-Crosslinked Hyaluronic Acid Redensity 1^® Supports Cell Viability, Proliferation, and Collagen Deposition in Early Burn Management

by Zhifeng Liao, Xi Chen, Romain Brusini, Jimmy Faivre, Lee Ann Applegate, Killian Flegeau and Nathalie Hirt-Burri

Pharmaceutics 2026, 18(1), 21; https://doi.org/10.3390/pharmaceutics18010021 - 23 Dec 2025

Abstract

Background/Objectives: Burn injuries pose a significant challenge due to tissue damage and impaired healing. Cell-based therapies offer promise by delivering therapeutic cells to the wound site. However, effective cell delivery remains a critical hurdle. This study investigates the potential of non-crosslinked hyaluronic acid [...] Read more.

Background/Objectives: Burn injuries pose a significant challenge due to tissue damage and impaired healing. Cell-based therapies offer promise by delivering therapeutic cells to the wound site. However, effective cell delivery remains a critical hurdle. This study investigates the potential of non-crosslinked hyaluronic acid (HA) as a simple, versatile carrier for delivering autologous keratinocytes and fibroblasts to treat early burn wounds. Methods: Primary keratinocytes and fibroblasts were isolated from uninjured adult skin. In addition, fibroblasts and adipose stem cells (ASC) from polydactyly and progenitor fibroblasts were used. Non-cross-linked HA Redensity 1^® (RD1) solutions of varying concentrations were prepared and applied to various in vitro models. Cell viability, proliferation, migration, and collagen stimulation were assessed using standard assays. Additionally, cells were suspended in Redensity 1 and applied to an in vitro de-epidemalized dermis (DED) wound model to examine cell delivery and tissue reformation. Results: Preliminary data demonstrated the feasibility of using non-cross-linked HA RD1 gel as a cell carrier. RD1 gel enhanced cell viability, retention, migration, and collagen deposition. Histological analysis revealed improved cell adhesion and migration. Conclusions: This study provides valuable insight into the potential of non-cross-linked HA RD1 as a simple and effective delivery vehicle for cell therapies in early burn care. Successful translation of this approach could significantly improve clinical outcomes for burn patients. Full article

(This article belongs to the Topic Advanced Nanocarriers for Targeted Drug and Gene Delivery)

► Show Figures

Figure 1

23 pages, 89938 KB

Open AccessArticle

Bile Derivative T3K Ameliorates Colitis by Regulating the Intestinal Microbiota-Bile Acid Axis

by Yu Zhou, Yixiang Zhang, Ying Li, Yu Chen, Xiaoqian Chi, Zhongyu You, Haijing Zhang, Yong Li and Lianqiu Wu

Pharmaceutics 2026, 18(1), 20; https://doi.org/10.3390/pharmaceutics18010020 - 23 Dec 2025

Abstract

Background/Objectives: The pathogenesis of ulcerative colitis (UC) is complex, and there is an urgent need for effective therapeutic agents with low side effects. Recent studies highlight the critical roles of abnormal bile acid (BA) metabolism and gut microbiota dysbiosis in UC progression. [...] Read more.

Background/Objectives: The pathogenesis of ulcerative colitis (UC) is complex, and there is an urgent need for effective therapeutic agents with low side effects. Recent studies highlight the critical roles of abnormal bile acid (BA) metabolism and gut microbiota dysbiosis in UC progression. However, there is a significant knowledge gap about the relation between BA and gut microbiota. The BA derivative T3K exerts good anti-UC effect, and its mechanism is still unknown. In this study, we investigate how its anti-UC mechanism is involved in the modulation of the gut microbiota-BA axis and BA metabolism. Methods: Gene expression microarray GSE92415 of UC from the Gene Expression Omnibus was used to analyze BA metabolism. DSS-induced colitis mouse model, Caco-2 and IEC6 cells were used to confirm the anti-UC of T3K using intestinal permeability assay with FITC, Western-blot, immunohistochemical staining, immunofluorescenc and so on in vitro and in vivo. The changes in bile acid and microbiota were measured by 16S rRNA sequencing and bile acid analysis combined with pseudo-germ-free (PGF) models and fecal microbiota transplantation (FMT). Results: T3K demonstrated strong therapeutic effects, including reduced weight loss, lower disease activity index (DAI), and increased colon length. T3K also enhanced the expression of Occludin and Mucin2, and restored gut barrier integrity. Furthermore, T3K improved intestinal dysbiosis and abnormal BA metabolism in colitis mice. Through PGF models and FMT, we confirmed that T3K modulates BA metabolism via the gut microbiota. T3K specifically promotes the growth of beneficial bacteria, such as Akkermansia muciniphila, increases levels of hydrophilic BAs like muricholic acid (MCA), lithocholic acid (LCA) and its derivatives isoLCA and then repairs damaged intestinal mucosa. Conclusions: Bile acid derivative T3K, as a potential anti-UC candidate, effectively restores gut barrier integrity and then ameliorates colitis by improving gut microbiota composition and regulating BA metabolism, including increasing hydrophilic BAs. Full article

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

► Show Figures

Graphical abstract

Journal Description

Pharmaceutics

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI