Pharmaceutics

28 pages, 6539 KiB

Open AccessArticle

Hydrogel–Nanolipid Formulations for the Complex Anti-Inflammatory and Antimicrobial Therapy of Periodontitis

by Rabia Ashfaq, Nóra Tóth, Anita Kovács, Szilvia Berkó, Gábor Katona, Rita Ambrus, Tamás Ferenc Polgár, Mária Szécsényi, Katalin Burián and Mária Budai-Szűcs

Pharmaceutics 2025, 17(5), 620; https://doi.org/10.3390/pharmaceutics17050620 - 7 May 2025

Abstract

Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation [...] Read more.

Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation was integrated into three hydrogels, hypromellose (HPMC), zinc hyaluronate (ZnHA), and sodium hyaluronate (NaHA), to conduct a comparative analysis focusing on enhanced localized drug delivery, improved mucoadhesion, prolonged retention, and significant therapeutic outcomes. Methods: NLC–Melox was prepared by homogenization and characterized by dynamic light scattering (DLS). Subsequently, NLC–Melox-loaded gels were subjected to transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Raman spectroscopy, and rheological analysis. In vitro drug release, anti-inflammatory activity (BSA denaturation assay), and antibacterial efficacy (MIC, MBC) were investigated to assess therapeutic potential. Results: DLS revealed a particle size of 183 nm with a polydispersity index of 0.26, indicating homogeneity. TEM confirmed consistent morphology and uniform nanoparticle distribution. DSC and XRD demonstrated the amorphous nature of Melox, enhancing solubility and stability. Spectroscopy confirmed no chemical interactions between components. Rheological studies identified ZnHA as the most mucoadhesive and structurally stable gel. In vitro release studies showed sustained drug release over 24 h. Melox and CO-loaded formulations demonstrated significant anti-inflammatory activity and notable antibacterial efficacy due to the antibacterial oil. Conclusions: The study highlighted the potential of NLC-based mucoadhesive hydrogels as an effective strategy for periodontitis treatment. The formulation offered improved drug solubility, therapeutic efficacy, mucoadhesivity, and prolonged delivery, making it a promising candidate for localized therapy. Full article

(This article belongs to the Special Issue Recent Insights Concerning the Use of Supramolecular Systems for Biomedical Applications)

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24 pages, 564 KiB

Open AccessReview

Pharmacokinetics of Different Tacrolimus Formulations in the Early Post-Liver Transplant Period: A Scoping Review

by Paloma Barriga-Rodríguez, Marta Falcón-Cubillo, Marta Mejías-Trueba, Pablo Ciudad-Gutiérrez, Ana Belén Guisado-Gil, Miguel Ángel Gómez-Bravo, Manuel Porras-López, María Victoria Gil-Navarro and Laura Herrera-Hidalgo

Pharmaceutics 2025, 17(5), 619; https://doi.org/10.3390/pharmaceutics17050619 - 6 May 2025

Abstract

Background: Tacrolimus (TAC) is the cornerstone of immunosuppression after liver transplantation (LT). TAC has a narrow therapeutic index and high inter- and intra-individual pharmacokinetic (PK) variability, requiring dose individualization. This variability is more noticeable in the early post-LT period. Objectives: This study aimed [...] Read more.

Background: Tacrolimus (TAC) is the cornerstone of immunosuppression after liver transplantation (LT). TAC has a narrow therapeutic index and high inter- and intra-individual pharmacokinetic (PK) variability, requiring dose individualization. This variability is more noticeable in the early post-LT period. Objectives: This study aimed to compare the PK of different TAC formulations in the early post-LT period and describe the main PK characteristics and plasma levels obtained with each TAC formulation used. Methods: The search was conducted in MEDLINE (PubMed) and EMBASE in accordance with PRISMA-ScR guidelines. The main inclusion criteria were clinical trials and observational studies focusing on the PK parameters of TAC in LT recipients during the first month post-transplant. Results: A total of 2169 articles were identified, of which 23 met the inclusion criteria. Various PK parameters were analyzed after LT for the different TAC formulations: intravenous (iv) and oral forms, such as immediate-release (IRT), prolonged-release (PRT), and extended-release (LCPT) formulations. PK variability was higher in the initial days after LT, with different TAC exposure between formulations. IV TAC allows the rapid attainment of therapeutic levels, but it has fallen into disuse. Regarding oral formulations, IRT reaches target levels faster than PRT and LCPT. PRT and LCPT exposure seem more stable during the first month post-LT than when using IRT. Conclusions: TAC formulations exhibit relevant differences in their PK profile in the early post-LT period. PK differences might influence the dose regimen and the time to achieve PK targets. Given these variations, therapeutic drug monitoring (TDM) is essential for optimizing treatment. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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18 pages, 14056 KiB

Open AccessArticle

Collagen–Chitosan Composites Enhanced with Hydroxytyrosol for Prospective Wound Healing Uses

by Miguel P. Batista, Margarida Pimenta, Naiara Fernández, Ana Rita C. Duarte, Maria do Rosário Bronze, Joana Marto and Frédéric Bustos Gaspar

Pharmaceutics 2025, 17(5), 618; https://doi.org/10.3390/pharmaceutics17050618 - 6 May 2025

Abstract

Background/Objectives: Recent studies highlight the excellent wound-healing properties of collagen and chitosan materials. Combining these polymers with a bioactive compound could enhance their effectiveness as next-generation wound dressings. Hydroxytyrosol (HT), an antioxidant derived from olive oil, may aid wound healing due to its [...] Read more.

Background/Objectives: Recent studies highlight the excellent wound-healing properties of collagen and chitosan materials. Combining these polymers with a bioactive compound could enhance their effectiveness as next-generation wound dressings. Hydroxytyrosol (HT), an antioxidant derived from olive oil, may aid wound healing due to its anti-inflammatory, antimicrobial, and angiogenesis-stimulating properties, making it a beneficial addition to collagen–chitosan dressings. It could be a beneficial addition to collagen–chitosan dressings, thus improving their therapeutic effects. This study screens the potential of collagen–chitosan composites with HT for wound-healing applications and assesses the influence of the compound’s incorporation on the materials’ properties. Methods: The material production involved incorporating chitosan and HT into a marine collagen extract. The resulting collagen–chitosan–HT material was obtained through freeze-drying. Prototype dressing characterization included morphology by scanning electron microscopy, solid and hydrated state by textural and rheological studies, and in vitro HT release studies. The materials’ cytocompatibility screening was assessed using a mouse fibroblast cell line, and the antibacterial activity was evaluated against microorganisms commonly implicated in wound infections. Results: Burst strength, viscosity, frequency sweep test, tackiness, and adhesion results indicate that chitosan contributes to the material’s mechanical robustness by maintaining a high viscosity and preserving the material’s gel structure. The in vitro release studies suggest an HT-controlled release profile with a maximum release (70%) achieved after 10 h. Biological experiments confirmed the materials’ cytocompatibility with skin cells and very promising antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Conclusions: In conclusion, HT was successfully incorporated into a collagen–chitosan matrix, enhancing the therapeutic prospect of the resultant material. The collagen–chitosan–HT composite presents a promising potential as an advanced wound-healing material. Full article

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

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3 pages, 149 KiB

Open AccessEditorial

ADME Properties in Drug Delivery

by Luciana Scotti and Marcus Tullius Scotti

Pharmaceutics 2025, 17(5), 617; https://doi.org/10.3390/pharmaceutics17050617 - 6 May 2025

Abstract

In recent decades, the identification of thousands of lead compounds, through development of analytical, synthetic, and computational techniques has occurred [...] Full article

(This article belongs to the Special Issue ADME Properties in the Drug Delivery)

4 pages, 152 KiB

Open AccessEditorial

Advances in the Oral Delivery of Protein and Peptide Drugs

by Guanyu Chen

Pharmaceutics 2025, 17(5), 616; https://doi.org/10.3390/pharmaceutics17050616 - 6 May 2025

Abstract

Protein and peptide drugs (PPDs) are highly effective therapies for a wide range of diseases, including cancer, diabetes, and autoimmune disorders [...] Full article

(This article belongs to the Special Issue Advances in Oral Administration)

23 pages, 7191 KiB

Open AccessArticle

Interleukin-15Rα-Sushi-Fc Fusion Protein Co-Hitchhikes Interleukin-15 and Pheophorbide A for Cancer Photoimmunotherapy

by Zhe Li, Jiaojiao Xu, Hongzheng Lin, Sheng Yu, Jingwen Sun, Chen Zhang, Sihang Zhang, Tingting Li, Afeng Yang and Wei Lu

Pharmaceutics 2025, 17(5), 615; https://doi.org/10.3390/pharmaceutics17050615 - 5 May 2025

Abstract

Background: Interleukin-15 (IL-15) stimulates the proliferation of natural killer cells or T cells, which, in combination with photodynamic therapy (PDT), has emerged as an effective strategy for cancer photoimmunotherapy. Instead of direct cytokine receptor activation, IL-15 necessitates first binding to the IL-15 [...] Read more.

Background: Interleukin-15 (IL-15) stimulates the proliferation of natural killer cells or T cells, which, in combination with photodynamic therapy (PDT), has emerged as an effective strategy for cancer photoimmunotherapy. Instead of direct cytokine receptor activation, IL-15 necessitates first binding to the IL-15 receptor α chain subunit (IL-15Rα), followed by trans-presentation to the IL-15 receptor β/γ chain subunit on the effector cells for pharmacologic activation. Therefore, the delivery of IL-15 remains a major challenge owing to its short half-life, its lack of targeting activity, and the limited availability of IL-15Rα. Methods: A co-hitchhiking delivery approach using recombinant IL-15 (rIL-15) and a photosensitizer, pheophorbide A (PhA), is developed for enhanced combinatorial cancer immunotherapy with PDT. A recombinant IL-15Rα-sushi-Fc fusion protein (rILR-Fc) is designed to load rIL-15 through the IL-15Rα sushi domain, which mimics its trans-presentation. Moreover, the Fc moiety of rILR-Fc can load PhA based on its high binding affinity. Results: Through self-assembly, rILR-Fc/PhA/rIL-15 nanoparticles (NPs) are formulated to co-hitchhike PhA and rIL-15, which improves the tumor accumulation of PhA and rIL-15 through receptor-mediated transcytosis. Moreover, the nanoparticles prolong the blood half-life of rIL-15 but do not alter the elimination rate of PhA from the blood. The rILR-Fc/PhA/rIL-15 NPs effectively elicit potent systemic antitumor immunity and long-lasting immune memory against tumor rechallenge in model mice bearing orthotopic colon tumors. Conclusions: The enhanced antitumor therapeutic effect demonstrates that the co-hitchhiking delivery strategy, optimizing the pharmacokinetics of both the photosensitizer and IL-15, provides a promising strategy for combinatorial photodynamic and IL-15 immunotherapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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26 pages, 14079 KiB

Open AccessArticle

Neutrophil-Camouflaged Stealth Liposomes for Photothermal-Induced Tumor Immunotherapy Through Intratumoral Bacterial Activation

by Xinxin Chen, Jiang Sun, Tingxian Ye and Fanzhu Li

Pharmaceutics 2025, 17(5), 614; https://doi.org/10.3390/pharmaceutics17050614 - 5 May 2025

Abstract

Objective: F. nucleatum, a tumor-resident bacterium colonizing breast cancer (BC), results in an immunosuppressive microenvironment and facilitates tumor growth and metastasis. This study aimed to develop a neutrophil-based liposome delivery system designed for dual-targeted elimination of tumor cells and F. nucleatum [...] Read more.

Objective: F. nucleatum, a tumor-resident bacterium colonizing breast cancer (BC), results in an immunosuppressive microenvironment and facilitates tumor growth and metastasis. This study aimed to develop a neutrophil-based liposome delivery system designed for dual-targeted elimination of tumor cells and F. nucleatum, while simultaneously upregulating pathogen-associated molecular patterns and damage-associated molecular patterns to potentiate tumor immunotherapy. Methods: The liposomes (PD/GA-LPs) loaded with the perylene diimide complex (PD) and gambogic acid (GA) were fabricated via the extrusion method. Subsequently, comprehensive evaluations including physicochemical characteristics, antibacterial activity, antitumor effect, and immunomodulatory effect evaluation were systematically conducted to validate the feasibility of this delivery system. Results: The resulting PD/GA-LPs exhibited a dynamic size (121.3 nm, zeta potential −44.1 mV) and a high encapsulation efficiency of approximately 78.1% (PD) and 91.8% (GA). In addition, the optimized PD/GA-LPs exhibited excellent photothermal performance and antibacterial efficacy. In vitro cellular experiments revealed that PD/GA-LPs exhibited enhanced internalization by neutrophils, followed by extracellular trap-mediated release, ultimately significantly inhibiting tumor cell proliferation and inducing immunogenic cell death. During in vivo treatment, PD/GA-LPs exhibited targeted tumor accumulation, where F. nucleatum-driven PD reduction activated near-infrared-responsive photothermal ablation. When combined with GA, this delivery system effectively eliminated tumor cells and F. nucleatum, while facilitating the subsequent T-cell infiltration. Conclusions: This strategy amplified the antitumor immune response, thus leading to effective treatment of BC and prevention of metastasis. In summary, this approach, grounded in the distinct microecology of tumor and normal tissues, offers novel insights into the development of precise and potent immunotherapies for BC. Full article

(This article belongs to the Special Issue Cutting-Edge Liposome Innovations for Precision Delivery and Cancer Treatment)

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19 pages, 5644 KiB

Open AccessArticle

3D Printing of PVA Capsular Devices for Applications in Compounding Pharmacy: Stability Evaluation and In Vivo Performance

by Juan Francisco Peña, Daniel Andrés Real, Juan Pablo Real, Santiago Daniel Palma, María del Pilar Zarazaga, Nicolás Javier Litterio, Loreana Gallo and Ivana Maria Cotabarren

Pharmaceutics 2025, 17(5), 613; https://doi.org/10.3390/pharmaceutics17050613 - 5 May 2025

Abstract

Background: The personalization of medication through 3D printing enables the development of capsular devices (CDs) tailored to patient-specific needs. This study aimed to evaluate the stability and in vivo performance of 3D-printed polyvinyl alcohol (PVA) CDs with 0.4 and 0.9 mm width [...] Read more.

Background: The personalization of medication through 3D printing enables the development of capsular devices (CDs) tailored to patient-specific needs. This study aimed to evaluate the stability and in vivo performance of 3D-printed polyvinyl alcohol (PVA) CDs with 0.4 and 0.9 mm width wall thicknesses (WT) compared to traditional hard gelatin capsules (HGCs). Methods: Capsules were tested for swelling, erosion, adhesion, water sorption, and in vitro disintegration. Additionally, the release of the model drug (losartan potassium) from CDs was evaluated. In vivo capsule opening times were assessed in dogs using X-ray imaging. Stability studies were conducted under natural (25 ± 2 °C, 60 ± 5% RH) and accelerated (40 ± 2 °C, 75 ± 5% RH) storage conditions. Results: CDs with 0.4 mm WT (CD–0–0.4) exhibited higher swelling and erosion, lower adhesion, and faster disintegration, leading to a more immediate drug release, comparable to HGCs. A strong correlation was found between in vitro and in vivo disintegration behavior. Water sorption tests revealed lower moisture affinity for PVA CDs compared to HGC. Stability studies showed that CD–0–0.4 retained its physical and chemical properties. Instead, CDs with 0.9 mm WT (CD–0–0.9) were sensitive to storage, particularly under accelerated aging, which affected their integrity and release profile. Conclusions: These findings highlight the potential of PVA-CDs, especially the 0.4 mm design, as a promising and stable alternative for compounding pharmacy applications, offering an effective platform for personalized oral drug delivery. Full article

(This article belongs to the Special Issue 3D Printing—Current Pharmaceutical Applications and Future Directions)

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17 pages, 1522 KiB

Open AccessPerspective

From Patterns to Pills: How Informatics Is Shaping Medicinal Chemistry

by Alexander Trachtenberg and Barak Akabayov

Pharmaceutics 2025, 17(5), 612; https://doi.org/10.3390/pharmaceutics17050612 - 5 May 2025

Abstract

In today’s information-driven era, machine learning is revolutionizing medicinal chemistry, offering a paradigm shift from traditional, intuition-based, and often bias-prone methods to the prediction of chemical properties without prior knowledge of the basic principles governing drug function. This perspective highlights the growing importance [...] Read more.

In today’s information-driven era, machine learning is revolutionizing medicinal chemistry, offering a paradigm shift from traditional, intuition-based, and often bias-prone methods to the prediction of chemical properties without prior knowledge of the basic principles governing drug function. This perspective highlights the growing importance of informatics in shaping the field of medicinal chemistry, particularly through the concept of the “informacophore”. The informacophore refers to the minimal chemical structure, combined with computed molecular descriptors, fingerprints, and machine-learned representations of its structure, that are essential for a molecule to exhibit biological activity. Similar to a skeleton key unlocking multiple locks, the informacophore points to the molecular features that trigger biological responses. By identifying and optimizing informacophores through in-depth analysis of ultra-large datasets of potential lead compounds and automating standard parts in the development process, there will be a significant reduction in biased intuitive decisions, which may lead to systemic errors and a parallel acceleration of drug discovery processes. Full article

(This article belongs to the Special Issue Advancements in AI and Pharmacokinetics)

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38 pages, 10556 KiB

Open AccessArticle

Augmented Marshmallow Extract Lipid Nanoparticles with Clove Oil Embedded in Collagen Sponge for Ultimate Antimicrobial Healing of Diabetic Mouth Ulcer

by Sammar Fathy Elhabal, Ahmed Mohsen Faheem, Sandra Hababeh, Jakline Nelson, Nahla A. Elzohairy, Yasmine F. Ibrahim, Tassneim M. Ewedah, Ibrahim S. Mousa, Khaled M. Allam and Ahmed Mohsen Elsaid Hamdan

Pharmaceutics 2025, 17(5), 611; https://doi.org/10.3390/pharmaceutics17050611 - 5 May 2025

Abstract

Background/Objectives: Diabetic mouth ulcers are a pathological condition of the oral mucosa leading to increases in susceptibility to infection and prolonged wound healing time. Still, there is a lack of natural formulations for treating this condition. Our principal objective was to formulate [...] Read more.

Background/Objectives: Diabetic mouth ulcers are a pathological condition of the oral mucosa leading to increases in susceptibility to infection and prolonged wound healing time. Still, there is a lack of natural formulations for treating this condition. Our principal objective was to formulate solid lipid nanoparticles (SLNs) that contained Althaea officinalis (marshmallow) (M.) extract with clove oil (CO.), subsequently integrated into a collagen sponge for enhancing stability, solubility, sustained release, antimicrobial efficacy, and healing power when targeting diabetic oral ulcers. Methods: A factorial design of 34 trials was established to evaluate the influence of lipid concentration (A), SAA concentration (B), lipid type (C), and SAA type (D). The optimized M-CO-SLNs was selected using Design Expert^®, the based Poly dispersibility index (Y2), zeta potential (MV) (Y3), and encapsulation efficiency (%) (Y4). The optimized SLNs were integrated into a collagen sponge matrix and tested for their antibacterial and antifungal efficacy against Pseudomonas aeruginosa, Escherichia coli, and Candida albicans, respectively. Moreover, they were tested for their wound healing power in a diabetic mouth ulcer model. Results: The optimized formula (Run 16: 5% lipid concentration, 4% SAA concentration, capric acid) demonstrated P.S (110 ± 0.76 nm), ZP (−24 ± 0.32 mV), PDI (0.18 ± 0.05), and EE% (90 ± 0.65%.). The optimized M-CO-SLNs formula was incorporated into a cross-linked collagen sponge and showed superior antimicrobial efficacy, an increased swelling ratio, and was effective in an in vivo oral ulcer study, as evidenced by ELISA biomarkers, gene expression analysis, and histological analysis. Conclusions: M-CO-SLNs embedded in collagen sponges is a promising therapeutic formula for clinical application against diabetic mouth ulcers. Full article

(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)

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24 pages, 4850 KiB

Open AccessReview

Anti-Cancer Drugs: Trends and Insights from PubMed Records

by Ferdinando Spagnolo, Silvia Brugiapaglia, Martina Perin, Simona Intonti and Claudia Curcio

Pharmaceutics 2025, 17(5), 610; https://doi.org/10.3390/pharmaceutics17050610 - 4 May 2025

Abstract

Background: In recent years, there has been an exponential growth in global anti-cancer drug research, prompting the necessity for comprehensive analyses of publication output and thematic shifts. Methods: This study utilized a comprehensive set of PubMed records from 1962 to 2024 and [...] Read more.

Background: In recent years, there has been an exponential growth in global anti-cancer drug research, prompting the necessity for comprehensive analyses of publication output and thematic shifts. Methods: This study utilized a comprehensive set of PubMed records from 1962 to 2024 and examined growth patterns, content classification, and co-occurrence of key pharmacological and molecular terms. Results: Our results highlight an exponential rise in publications, with an annual compound growth rate of over 14%, influenced by advancements in digital knowledge sharing and novel therapeutic breakthroughs. A pronounced surge occurred during the COVID-19 pandemic, suggesting a sustained shift in research dynamics. The content analyses revealed a strong emphasis on classical chemotherapeutic agents—often studied in combination with targeted therapies or immunotherapies—and a growing focus on immune checkpoint inhibitors and vaccine platforms. Furthermore, co-occurrence networks indicated robust links between chemotherapy and supportive care, as well as emerging synergies between immuno-oncology, precision medicine approaches. Conclusions: Our study suggests that while novel modalities are reshaping treatment paradigms, chemotherapy remains central, underscoring the value of integrative regimens. This trend toward personalized, combination-based strategies indicates a transformative era in oncology research, where multidimensional data assessment is instrumental in guiding future therapeutic innovations. Full article

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22 pages, 2643 KiB

Open AccessReview

Immune Modulation with Oral DNA/RNA Nanoparticles

by Ulpan Kart, Aigul Raimbekova, Sergey Yegorov and Gonzalo Hortelano

Pharmaceutics 2025, 17(5), 609; https://doi.org/10.3390/pharmaceutics17050609 - 4 May 2025

Abstract

The oral delivery of DNA/RNA nanoparticles represents a transformative approach in immunotherapy and vaccine development. These nanoparticles enable targeted immune modulation by delivering genetic material to specific cells in the gut-associated immune system, triggering both mucosal and systemic immune responses. Unlike parenteral administration, [...] Read more.

The oral delivery of DNA/RNA nanoparticles represents a transformative approach in immunotherapy and vaccine development. These nanoparticles enable targeted immune modulation by delivering genetic material to specific cells in the gut-associated immune system, triggering both mucosal and systemic immune responses. Unlike parenteral administration, the oral route offers a unique immunological environment that supports both tolerance and activation, depending on the formulation design. This review explores the underlying mechanisms of immune modulation by DNA/RNA nanoparticles, their design and delivery strategies, and recent advances in their application. Emphasis is placed on strategies to overcome physiological barriers such as acidic pH, enzymatic degradation, mucus entrapment, and epithelial tight junctions. Special attention is given to the role of gut-associated lymphoid tissue in mediating immune responses and the therapeutic potential of these systems in oral vaccine platforms, food allergies, autoimmune diseases, and chronic inflammation. Despite challenges, recent advances in nanoparticle formulation support the translation of these technologies into clinical applications for both therapeutic immunomodulation and vaccination. Full article

(This article belongs to the Special Issue Nanoparticle-Based Gene Delivery)

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22 pages, 1650 KiB

Open AccessSystematic Review

Efficacy and Safety of Antibody-Drug Conjugates for Lung Cancer Therapy: A Systematic Review of Randomized and Non-Randomized Clinical Trials

by Matteo Gallina, Anna Carollo, Anna Gallina, Sofia Cutaia, Sergio Rizzo and Alessio Provenzani

Pharmaceutics 2025, 17(5), 608; https://doi.org/10.3390/pharmaceutics17050608 - 3 May 2025

Abstract

Background/Objectives: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small-Cell Lung Cancer (NSCLC) accounts for 80–90% of all lung cancers. Antibody-Drug Conjugates (ADCs) represent an expanding targeted therapy option for the treatment of NSCLC. The aim is to perform a [...] Read more.

Background/Objectives: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small-Cell Lung Cancer (NSCLC) accounts for 80–90% of all lung cancers. Antibody-Drug Conjugates (ADCs) represent an expanding targeted therapy option for the treatment of NSCLC. The aim is to perform a systematic literature review to evaluate the efficacy and safety profiles of ADCs currently undergoing clinical trials for the treatment of NSCLC. Methods: The study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Literature searches were conducted in PubMed, ClinicalTrial.gov and Web of Science databases, covering the period from 2014 to 2024. Only randomized and non-randomized phase II-IV clinical trials focusing on ADC-based therapies for adult patients affected by NSCLC were selected. The Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2.0) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) were used to evaluate the overall risk of bias in the included randomized and non-randomized studies, respectively. While GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology was used to assess the certainty of the evidence. Efficacy endpoints were categorized based on primary outcomes while safety was assessed through the frequency and severity of Treatment-Emergent Adverse Events (TEAEs), and a qualitative summary of the findings was conducted. Results: A total of seven studies, including three randomized, three non-randomized, and one without specific allocation, were included, comprising 1287 patients, with 693 (54%) men, and an average age of 63 years old. Two studies were deemed to have a low risk of bias, while six had a moderate risk or some concerns. Five ADCs were evaluated: trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), telisotuzumab vedotin, patritumab deruxtecan, and datopotamab deruxtecan (Dato-DXd). T-DXd demonstrated superior efficacy in HER2-overexpressing and HER2-mutant NSCLC, with an ORR of 52.9% and 49.0%, respectively. However, HER2-mutant patients exhibited a longer median DOR (16.8 vs. 6.2 months) but a higher incidence of grade ≥ 3 TEAEs (38.6% vs. 22%). T-DM1 showed modest efficacy, with an ORR of 20% in HER2-overexpressing NSCLC and 6.7% in HER2-mutant patients. Dato-DXd demonstrated improved ORR (26.4% vs. 12.8%) and PFS (4.4 vs. 3.7 months) compared to docetaxel. Patritumab deruxtecan achieved an ORR of 39% in EGFR-mutant NSCLC, while telisotuzumab vedotin exhibited limited activity in c-MET-positive NSCLC (ORR 9%, median DOR 7.5 months). Frequency and severity of TEAEs varied across ADCs, with ILD being a major concern, highlighting the need for strict patient monitoring and early intervention to mitigate severe adverse events. Conclusions: ADCs represent a promising advancement in NSCLC treatment, offering targeted therapeutic options beyond conventional chemotherapy and immunotherapy. T-DXd has emerged as the most effective ADC for HER2-mutant NSCLC with manageable safety profile, whereas Dato-DXd provides a viable alternative for TROP2-expressing tumors. While ADCs offer significant clinical benefits, careful patient selection and proactive management of adverse events remain crucial. Ongoing and future trials will further refine the role of ADCs in personalized NSCLC treatment, potentially expanding their tumor-agnostic use to broader patient populations. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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21 pages, 2228 KiB

Open AccessArticle

Assessment of the Anti-Inflammatory Effectiveness of Diclofenac Encapsulated in Chitosan-Coated Lipid Microvesicles in Rats

by Ana-Maria Raluca Pauna, Liliana Mititelu Tartau, Alin Mihai Vasilescu, Angy Abu Koush, Ruxandra Teodora Stan, Marius Constatin Moraru, Cosmin Gabriel Popa, Liviu Ciprian Gavril, Roxana Florentina Gavril, Dragos Valentin Crauciuc, Ana Marina Radulescu and Cristinel Ionel Stan

Pharmaceutics 2025, 17(5), 607; https://doi.org/10.3390/pharmaceutics17050607 - 3 May 2025

Abstract

Background: Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug (NSAID), but its conventional formulations may have limited efficacy and are associated with adverse effects. This study aimed to evaluate the anti-inflammatory and antioxidant effects of diclofenac encapsulated in chitosan-coated lipid microvesicles [...] Read more.

Background: Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug (NSAID), but its conventional formulations may have limited efficacy and are associated with adverse effects. This study aimed to evaluate the anti-inflammatory and antioxidant effects of diclofenac encapsulated in chitosan-coated lipid microvesicles (DCF-m) compared to free DCF in a rat model of subacute inflammation. Method: DCF-m was prepared using L-α-phosphatidylcholine and coated with chitosan (CHIT). Subacute inflammation was induced using the cotton pellet granuloma model, and animals were divided into four groups (n = 5): a negative control group without granuloma receiving vehicle (double-distilled water), a control group with granuloma receiving vehicle, a group with granuloma treated with 15 mg/kg of free DCF, and a group with granuloma treated with 15 mg/kg of DCF-m. Results: Both DCF and DCF-m significantly reduced granuloma mass, body weight gain, and serum inflammatory markers compared to the control group with granuloma. Moreover, DCF-m treatment led to a more pronounced reduction in granulomatous inflammation and a greater enhancement of antioxidant enzyme activity than free DCF. Conclusions: These findings suggest that DCF-m exhibits superior anti-inflammatory and antioxidant properties compared to conventional diclofenac in a model of subacute inflammation. Full article

(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)

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38 pages, 8552 KiB

Open AccessReview

Enzyme-Based Anti-Inflammatory Therapeutics for Inflammatory Diseases

by Kannan Badri Narayanan

Pharmaceutics 2025, 17(5), 606; https://doi.org/10.3390/pharmaceutics17050606 - 2 May 2025

Abstract

Inflammation is a multifaceted biological response of the immune system against various harmful stimuli, including pathogens (such as bacteria and viruses), cellular damage, toxins, and natural/synthetic irritants. This protective mechanism is essential for eliminating the cause of injury, removing damaged cells, and initiating [...] Read more.

Inflammation is a multifaceted biological response of the immune system against various harmful stimuli, including pathogens (such as bacteria and viruses), cellular damage, toxins, and natural/synthetic irritants. This protective mechanism is essential for eliminating the cause of injury, removing damaged cells, and initiating the repair process. While inflammation is a fundamental component of the body’s defense and healing process, its dysregulation can lead to pathological consequences, contributing to various acute and chronic diseases, such as autoimmune disorders, cancer, metabolic syndromes, cardiovascular diseases, neurodegenerative conditions, and other systemic complications. Generally, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), antihistamines, biologics, and colchicine are used as pharmacological agents in the management of inflammatory diseases. However, these conventional treatments often have limitations, including adverse side effects, long-term toxicity, and drug resistance. In contrast, enzyme-based therapeutics have emerged as a promising alternative due to their high specificity, catalytic efficiency, and ability to modulate inflammatory pathways with reduced side effects. These enzymes function by scavenging reactive oxygen species (ROS), inhibiting cytokine transcription, degrading circulating cytokines, and blocking cytokine release by targeting exocytosis-related receptors. Additionally, their role in tissue repair and regeneration further enhances their therapeutic potential. Most natural anti-inflammatory enzymes belong to the oxidoreductase class, including catalase and superoxide dismutase, as well as hydrolases such as trypsin, chymotrypsin, nattokinase, bromelain, papain, serratiopeptidase, collagenase, hyaluronidase, and lysozyme. Engineered enzymes, such as Tobacco Etch Virus (TEV) protease and botulinum neurotoxin type A (BoNT/A), have also demonstrated significant potential in targeted anti-inflammatory therapies. Recent advancements in enzyme engineering, nanotechnology-based enzyme delivery, and biopharmaceutical formulations have further expanded their applicability in treating inflammatory diseases. This review provides a comprehensive overview of both natural and engineered enzymes, along with their formulations, used as anti-inflammatory therapeutics. It highlights improvements in stability, efficacy, and specificity, as well as minimized immunogenicity, while discussing their mechanisms of action and clinical applications and potential future developments in enzyme-based biomedical therapeutics. Full article

(This article belongs to the Special Issue Medical Applications of Biologic Drugs)

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9 pages, 400 KiB

Open AccessArticle

Diabetic Macular Edema in Maintenance Intravitreal Scheduling

by Enzo Maria Vingolo, Mattia Calabro, Simona Mascolo, Filippo Miccichè, Lorenzo Casillo, Stefano Lupo and Feliciana Menna

Pharmaceutics 2025, 17(5), 605; https://doi.org/10.3390/pharmaceutics17050605 - 2 May 2025

Abstract

Objectives: This study aimed to assess the impact of an oral formulation combining bromelain (250 mg) derived from Ananas comosus (L.) Merr. Jambs and diosmin mcgSMIN Plus (250 mg) on visual acuity and central retinal thickness (CRT) in patients undergoing anti-VEGF intravitreal maintenance [...] Read more.

Objectives: This study aimed to assess the impact of an oral formulation combining bromelain (250 mg) derived from Ananas comosus (L.) Merr. Jambs and diosmin mcgSMIN Plus (250 mg) on visual acuity and central retinal thickness (CRT) in patients undergoing anti-VEGF intravitreal maintenance therapy (IVT) for cystoid, center-involving diabetic macular edema (DME). Methods: A total of forty patients with type 2 diabetes and center-involving DME, all receiving anti-VEGF maintenance therapy, were prospectively enrolled in a case-control study. Group A (20 eyes) was administered one tablet containing 250 mg of bromelain and 250 mg of diosmin mcgSMIN Plus twice daily for a period of two months. Group B (20 eyes) was monitored without drug administration until the next IVT. After two months and IVT administration, the groups were switched. At the end of the study, the collected data were divided into two groups. The treatment group included data from patients who received the dietary supplement, and the control group consisted of data from patients who were only observed during anti-VEGF therapy. Best-corrected visual acuity (BCVA) and CRT measurements were assessed at baseline, after two months, and after four months. Results: A statistically significant improvement in CRT was observed in the treatment group compared to the control group during follow-up (p < 0.05). However, the improvement in BCVA was not statistically significant. Conclusions: Orally administered combination of bromelain 250 mg and 250 mg diosmin mcgSMIN Plus has positive impact on central retinal thickness in patients treated for cystoid center-involving diabetic macular edema (DME) with anti-VEGF intravitreal maintenance therapy. Full article

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

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28 pages, 7155 KiB

Open AccessReview

Accelerating Biologics PBPK Modelling with Automated Model Building: A Tutorial

by Abdallah Derbalah, Tariq Abdulla, Mailys De Sousa Mendes, Qier Wu, Felix Stader, Masoud Jamei, Iain Gardner and Armin Sepp

Pharmaceutics 2025, 17(5), 604; https://doi.org/10.3390/pharmaceutics17050604 - 2 May 2025

Abstract

Physiologically based pharmacokinetic (PBPK) modelling for biologics, such as monoclonal antibodies and therapeutic proteins, involves capturing complex processes, including target-mediated drug disposition (TMDD), FcRn-mediated recycling, and tissue-specific distribution. The Simcyp Designer Biologics PBPK Platform Model offers an intuitive and efficient platform for constructing [...] Read more.

Physiologically based pharmacokinetic (PBPK) modelling for biologics, such as monoclonal antibodies and therapeutic proteins, involves capturing complex processes, including target-mediated drug disposition (TMDD), FcRn-mediated recycling, and tissue-specific distribution. The Simcyp Designer Biologics PBPK Platform Model offers an intuitive and efficient platform for constructing mechanistic PBPK models with pre-defined templates and automated model assembly, reducing manual input and improving reproducibility. This tutorial provides a step-by-step guide to using the platform, highlighting features such as cross-species scaling, population variability simulations, and flexibility for model customization. Practical case studies demonstrate the platform’s capability to streamline workflows, enabling rapid, mechanistic model development to address key questions in biologics drug development. By automating critical processes, this tool enhances decision-making in translational research, optimizing the modelling and simulation of large molecules across discovery and clinical stages. Full article

(This article belongs to the Special Issue Advancing Biologic Drug Development Through Physiologically Based Pharmacokinetic Modelling and Simulations)

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38 pages, 3114 KiB

Open AccessReview

Nano-Drug Delivery Systems for Bone Metastases: Targeting the Tumor–Bone Microenvironment

by Mohamad Bakir, Ahmad Dawalibi, Mohammad Alaa Mufti, Ayman Behiery and Khalid S. Mohammad

Pharmaceutics 2025, 17(5), 603; https://doi.org/10.3390/pharmaceutics17050603 - 2 May 2025

Abstract

Bone metastases are a prevalent and debilitating consequence of various cancers, including breast and prostate carcinomas, which significantly compromise patient quality of life due to pain, fractures, and other skeletal-related events (SREs). This review examines the pathophysiology of bone metastases, emphasizing the role [...] Read more.

Bone metastases are a prevalent and debilitating consequence of various cancers, including breast and prostate carcinomas, which significantly compromise patient quality of life due to pain, fractures, and other skeletal-related events (SREs). This review examines the pathophysiology of bone metastases, emphasizing the role of the bone microenvironment in tumor progression through mechanisms such as osteotropism and the dysregulated bone remodeling cycle. The primary focus is on the emerging nano-drug delivery systems (DDS) designed to target the bone microenvironment and improve the therapeutic index of anticancer agents. Current treatments, mainly comprising bisphosphonates and radiotherapy, provide palliative benefits but often have limited efficacy and significant side effects. Innovative strategies, such as bisphosphonate-conjugated nanoparticles and targeted therapies that utilize the unique bone marrow niche, are explored for their potential to enhance drug accumulation at metastatic sites while minimizing systemic toxicity. These approaches include the use of liposomes, polymeric nanoparticles, and inorganic nanoparticles, which can be functionalized to exploit the biological barriers within the bone microenvironment. This review also discusses the challenges and future directions for nano-DDS in clinical settings, emphasizing the need for multidisciplinary research to effectively integrate these technologies into standard care protocols. Full article

(This article belongs to the Special Issue Challenges and Future Trends of Nano-Based Drug Delivery System in the Treatment of Bone Diseases)

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19 pages, 4874 KiB

Open AccessArticle

Achieving Permanent Male Infertility by Magnetic Nanoparticle Hyperthermia: A Breakthrough in Animal Fertility Management

by Juliana Lis Mendes Brito, Vanessa Nicolau Lima, José Luiz P. R. Jivago, Aline R. M. Marangon, Marcus Vinícius-Araújo, Andris Figueiroa Bakuzis, Juliana dos Anjos Ribeiro dos Santos, Paulo E. N. Souza, Ricardo Bentes Azevedo and Carolina Madeira Lucci

Pharmaceutics 2025, 17(5), 602; https://doi.org/10.3390/pharmaceutics17050602 - 2 May 2025

Abstract

Background/Objectives: Non-surgical neutering strategies have long been pursued for male animals. A previous study from our group showed that magnetic nanoparticle hyperthermia (MNH) applied directly to the testicles is a promising non-surgical sterilization method for male animals, causing testicular atrophy and complete [...] Read more.

Background/Objectives: Non-surgical neutering strategies have long been pursued for male animals. A previous study from our group showed that magnetic nanoparticle hyperthermia (MNH) applied directly to the testicles is a promising non-surgical sterilization method for male animals, causing testicular atrophy and complete disappearance of seminiferous tubules by the end of a 56 day observation. This long-term study was conducted to verify the long-term efficacy and safety of the method. Methods: Wistar rats treated with testicular MNH received an intratesticular injection of a magnetic fluid composed of manganese-ferrite nanoparticles functionalized with citrate (MnFe₂O₄-citrate) and were subsequently subjected to an alternating magnetic field. Reproductive parameters and animal health were evaluated by blood tests and abdominal ultrasound for 12 months. Results: All MNH-treated animals presented testicular degeneration and atrophy, together with severely reduced or undetectable serum testosterone levels. By the end of the experiment, all but two animals had no identifiable gonads. The only two animals still displaying gonadal-like structures were azoospermic, and histopathology revealed the remaining tissue was non-functional. The procedure was well-tolerated and MNH-treated animals presented no long-term side effects. Hemogram, ALT, AST, urea and creatinine levels were within the normal parameters for Wistar rats over the 12 month period. The liver, spleen, kidneys and lungs had normal structures as revealed by abdominal ultrasound and histopathological exams, with no nanoparticle accumulation in the organs over the long term. Conclusions: In conclusion, testicular MNH caused irreversible infertility in rats in a single application, with no adverse effects on general animal health. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems: Magnetic Gels)

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