Pharmaceutics

21 pages, 733 KB

Open AccessArticle

Engineering Regenerative Fibrin Scaffold from Balanced Protein-Concentrate Plasma: Structural and Biochemical Characterization

by Diego Delgado, Jon Mercader-Ruiz, Daniel Marijuán-Pinel, Pello Sánchez, Renato Andrade, João Espregueira-Mendes, Llanos Zuloaga, Jorge Knörr and Mikel Sánchez

Pharmaceutics 2025, 17(11), 1432; https://doi.org/10.3390/pharmaceutics17111432 - 5 Nov 2025

Abstract

Background: This study evaluates the impact of fibrinogen enrichment on the structural, mechanical, and bioactive properties of fibrin scaffold derived from balanced protein-concentrate plasma (BPCP), an autologous platelet-rich plasma (PRP) formulation with elevated extraplatelet content. Methods: A novel high-fibrinogen BPCP (HF-BPCP) scaffold was [...] Read more.

Background: This study evaluates the impact of fibrinogen enrichment on the structural, mechanical, and bioactive properties of fibrin scaffold derived from balanced protein-concentrate plasma (BPCP), an autologous platelet-rich plasma (PRP) formulation with elevated extraplatelet content. Methods: A novel high-fibrinogen BPCP (HF-BPCP) scaffold was produced by combining BPCP platelet lysate with a concentrated fibrinogen solution at a 1:1 ratio, yielding nearly four-fold physiological fibrinogen levels. Comparative analyses between HF-BPCP and standard BPCP included platelet and fibrinogen quantification, scanning electron microscopy (SEM), rheology, indentation, adhesion testing, coagulation kinetics, retraction assays, biodegradation profiling, and growth factor (GF) release kinetics. Results: HF-BPCP displayed significantly denser fibrin networks with thinner fibers, higher porosity, and markedly faster coagulation times compared to BPCP. Mechanically, HF-BPCP exhibited greater stiffness, higher energy dissipation, and more stable adhesion, while almost eliminating scaffold retraction at 24 h. Despite improved early handling and structural integrity, HF-BPCP degraded more rapidly in vitro under tissue plasminogen activator exposure. GF release analysis showed reduced early peaks of platelet-derived factors (TGF-β1, PDGF-AB, VEGF) but sustained release thereafter, while extraplatelet factors (IGF-1, HGF) exhibited similar profiles between scaffolds. Conclusions: These results indicate that fibrinogen enrichment synergizes with the elevated extraplatelet protein profile of BPCP to enhance scaffold mechanical stability, handling properties, and controlled GF delivery. HF-BPCP combines the adhesive, structural, and bioactive features of fibrin sealants with the regenerative potential of PRP, offering a fully autologous alternative for clinical applications requiring rapid coagulation, high mechanical support, and sustained GF availability. Further preclinical and clinical studies are needed to evaluate therapeutic efficacy in the regenerative medicine field. Full article

(This article belongs to the Special Issue Biomaterials: Pharmaceutical Applications)

12 pages, 467 KB

Open AccessArticle

Clinical Efficacy and Pharmacokinetics of Antivenom Viperfav^® in Vipera ammodytes ammodytes Envenomation

by Tihana Kurtović, Mojca Dobaja Borak, Damjan Grenc, Adrijana Leonardi, Igor Križaj, Boris Lukšić, Beata Halassy and Miran Brvar

Pharmaceutics 2025, 17(11), 1431; https://doi.org/10.3390/pharmaceutics17111431 - 5 Nov 2025

Abstract

Background: In Europe, Vipera ammodytes ammodytes (Vaa, nose-horned viper) is considered the most venomous of the European vipers. The antivenom Viperfav^®, composed of polyvalent equine F(ab′)₂ fragments, is effective against Vipera aspis, Vipera berus and Vaa. [...] Read more.

Background: In Europe, Vipera ammodytes ammodytes (Vaa, nose-horned viper) is considered the most venomous of the European vipers. The antivenom Viperfav^®, composed of polyvalent equine F(ab′)₂ fragments, is effective against Vipera aspis, Vipera berus and Vaa. Objectives: This study aimed to evaluate the clinical efficacy and pharmacokinetics of Viperfav in Vaa envenomations. Methods: Patients presenting with Vaa snakebite and treated with intravenous Viperfav were included. Clinical manifestations and laboratory findings were assessed on admission to the Emergency Department, prior to antivenom therapy, and monitored throughout hospitalization. Blood samples were collected on arrival and at defined intervals after Viperfav administration. Venom and antivenom concentrations in serum were determined by ELISA and subjected to pharmacokinetic analysis. Results: Twenty-one patients bitten by Vaa and classified with a severity score of 2b on the modified Audebert clinical severity scale received a single intravenous dose of Viperfav within 4 h of the bite. Viperfav attenuated the progression of local symptoms and prevented the development of new systemic manifestations. The serum concentrations of F(ab′)₂ fragments reached 196 µg/mL, far exceeding the venom concentration at admission (35 ng/mL). The prolonged elimination half-life of Viperfav (49 h) corresponded with the absence of recurrent symptoms after a single dose. Bradycardia or hypotension occurred in 10% of patients; no cases of anaphylaxis or serum sickness were observed. Conclusions: A single intravenous dose of Viperfav demonstrated clinical efficacy and a favourable pharmacokinetic profile in Vaa envenomed patients when administered within hours of the bite. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

4 pages, 148 KB

Open AccessEditorial

Ultrasound-Induced Acoustic Cavitation Takes Centre Stage to Enhance Drug Delivery and the Activation of the Immune System

by Petros Mouratidis, Ian Rivens and Gail ter Haar

Pharmaceutics 2025, 17(11), 1430; https://doi.org/10.3390/pharmaceutics17111430 - 5 Nov 2025

Abstract

Ultrasound therapy has emerged as a powerful tool for the non-invasive treatment of indications ranging from Parkinson’s disease and essential tremor to malignant solid tumours [...] Full article

(This article belongs to the Special Issue Recent Advances in the Use of Ultrasound to Enhance Drug Delivery and Efficacy for the Treatment of Cancer)

11 pages, 235 KB

Open AccessArticle

Clinical Outcomes of Piperacillin/Tazobactam Treatment in Outpatient Parenteral Antimicrobial Therapy (OPAT) Programs: Comparison of Two Models of Opat Care

by Santiago J. Lora-Escobar, Laura Herrera-Hidalgo, Nerea Castillo-Fernández, Zaira R. Palacios-Baena, Rafael Luque-Márquez, Arístides De Alarcón, Ana Belén Guisado-Gil, Belén Gutierrez-Gutierrez, María Dolores Navarro-Amuedo, Julia Praena-Segovia, Marta Mejías Trueba, Juan Manuel Carmona-Caballero, José Manuel Sánchez Oliva, María Victoria Gil-Navarro and Luis E. López-Cortés

Pharmaceutics 2025, 17(11), 1429; https://doi.org/10.3390/pharmaceutics17111429 - 4 Nov 2025

Abstract

Objectives: Piperacillin/tazobactam (P/T) is a broad-spectrum β-lactam antibiotic frequently used in outpatient parenteral antimicrobial therapy programs (OPAT). We aim to compare the clinical outcomes of P/T treatment in two models of OPAT care in order to maximize the utilization of health resources. [...] Read more.

Objectives: Piperacillin/tazobactam (P/T) is a broad-spectrum β-lactam antibiotic frequently used in outpatient parenteral antimicrobial therapy programs (OPAT). We aim to compare the clinical outcomes of P/T treatment in two models of OPAT care in order to maximize the utilization of health resources. Material and methods: We conducted a prospective observational study with retrospective analysis of a cohort of patients treated with P/T delivered every 24 or 48 h in an OPAT program. The primary outcomes were treatment failure during the OPAT episode and 30 day treatment failure. A bivariate and multivariate logistic regression model was built. A two-sided p < 0.05 was considered statistically significant. Results: Between 2012 and 2022, 247 patients were treated with P/T. Treatment was delivered daily in 176 patients (Group 24) and every two days in 71 patients (Group 48). The rate of treatment failure during OPAT in Group 24 and Group 48 was 12.4% (n = 22) and 5.6% (n = 4), respectively (p = 0.112); and the rate of treatment failure 30 days after OPAT treatment end was 18.2% (n = 32) and 21.1% (n = 15) in Group 24 and Group 48, respectively (p = 0.594). Treatment every 24 or 48 h was not associated with higher treatment failure during OPAT or 30 days after finishing OPAT in either bivariate or multivariate analysis. Conclusions: P/T administration in OPAT programs being replaced every two days is feasible without an increase in treatment failure, relapse, or mortality compared to daily drug replacement. These findings should motivate further research to facilitate the implementation of this novel delivery strategy in OPAT programs. Full article

(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy, 2nd Edition)

27 pages, 2493 KB

Open AccessReview

Targeting Drug-Tolerant Persister Cancer Cells: Can Nanomaterial-Based Strategies Be Helpful for Anti-DTP Therapies?

by Prachi Ghoderao, Eliza Kwiatkowska-Borowczyk, Sanjay Sahare and Hanna Dams-Kozlowska

Pharmaceutics 2025, 17(11), 1428; https://doi.org/10.3390/pharmaceutics17111428 - 4 Nov 2025

Abstract

Therapeutic resistance remains a critical barrier in oncology, frequently leading to cancer relapse after initial treatment response. Growing evidence suggests the presence of drug-tolerant persisters (DTPs), a rare subpopulation of cancer cells that survives chemotherapy by entering a reversible specific adaptation. Unlike classical [...] Read more.

Therapeutic resistance remains a critical barrier in oncology, frequently leading to cancer relapse after initial treatment response. Growing evidence suggests the presence of drug-tolerant persisters (DTPs), a rare subpopulation of cancer cells that survives chemotherapy by entering a reversible specific adaptation. Unlike classical cell resistance, the DTP phenotype is independent of genetic changes and maintained through dynamic regulatory mechanisms. DTPs are phenotypically heterogeneous and can exhibit stem-like and quiescent cell phenotypes, non- or slow proliferation, and remarkable plasticity due to a di-pause-like state and executing epithelial–mesenchymal transition (EMT) or transdifferentiation processes. Despite advances in research, the molecular mechanisms underlying DTPs’ biology and their role in cancer relapse remain only partially understood. The review summarizes the current progress in processes that lead to the acquisition of cellular persistence status, which, in turn, constitute areas of vulnerability that can be exploited in cancer therapy. We highlight anti-DTP therapeutic strategies, including epigenetic modification, cell signaling and transcriptional regulation, metabolic reprogramming, and modification of cell interactions within the tumor microenvironment. Furthermore, we focus on the potential role of nanomaterials in the combat against DTPs. Nanoparticles not only act as part of the drug delivery process, enabling precise DTP targeting and enhancing intracellular drug accumulation, but their intrinsic properties can also be used to eradicate DTPs directly or by enhancing the effectiveness of other therapeutic strategies. The integrated approach offers strong potential to eliminate tumor persistence, prevent recurrence, and improve long-term patient outcomes beyond conventional therapies. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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21 pages, 4185 KB

Open AccessArticle

Therapeutic Effect of Alpha Linolenic Acid on Cutaneous Wound Healing in Hyperglycemic Mice: Involvement of Neurotrophins

by Thais Paulino do Prado, Flávia Cristina Zanchetta, Aline Cristina Rosa Maria, Thaiane da Silva Rios, Guilherme Rossi de Assis-Mendonça, Maria Helena Melo Lima, Dennys Esper Correa Cintra, Joseane Morari, Lício A. Velloso and Eliana P. Araújo

Pharmaceutics 2025, 17(11), 1427; https://doi.org/10.3390/pharmaceutics17111427 - 4 Nov 2025

Abstract

Background: Alpha-linolenic acid (ALA) is an essential fatty acid from the omega-3 family that plays an important role in skin homeostasis. It is known for its anti-inflammatory properties, which can contribute to wound healing. Neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF), may also [...] Read more.

Background: Alpha-linolenic acid (ALA) is an essential fatty acid from the omega-3 family that plays an important role in skin homeostasis. It is known for its anti-inflammatory properties, which can contribute to wound healing. Neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF), may also play an important role in the skin, influencing nerve regeneration and pain modulation. Objectives: This article aims to explore the therapeutic effect of ALA on wound healing in streptozotocin-induced hyperglycemic mice, with an emphasis on the involvement of neurotrophins. Methods: We used keratinocyte cultures exposed or not to ALA and male C57BL6-J mice, which were randomly divided into four groups: non-hyperglycemic treated with vehicle; non-hyperglycemic treated with ALA; hyperglycemic treated with vehicle; and hyperglycemic treated with ALA. The treatment was administered continuously via a subcutaneous osmotic pump. Results: We found that controlled ALA administration potentiates the wound healing process in hyperglycemic mice by accelerating the inflammatory phase and promoting early granulation tissue formation (73.2% ± 0.7 vs. 92.2% ± 2.8 on day 7, n = 5; p < 0.05). This is supported by the balance between the expression of vimentin, CD31, and MMP-9. Furthermore, ALA modulates proteins linked to peripheral neurogenesis and gliogenesis, such as BDNF, NTRK2, SOX-10, CNTF, CTNFR, and STAT-3. It may also promote wound healing and nerve regeneration at the wound site in hyperglycemic animals. In non-hyperglycemic mice, ALA improves the quality of scars but does not accelerate the wound healing process, even with the positive modulation of certain genes relevant to skin healing. Conclusions: Alpha-linolenic acid improves skin wound healing and increases gene expression related to nerve regeneration in wounds of hyperglycemic mice. Full article

(This article belongs to the Section Gene and Cell Therapy)

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44 pages, 1960 KB

Open AccessReview

Targeted Drug Delivery Strategies in Overcoming Antimicrobial Resistance: Advances and Future Directions

by Ohoud M. Alidriss, Hamood AlSudais, Ohoud S. Alhumaidan, Haifa D. Altwaijry, Afnan Bakhsh, Yasir Almuhanna, Zeina S. Alkudmani, Ibrahim A. Alqarni, Daheeya Alenazi, Alanoud T. Aljasham and Yahya F. Jamous

Pharmaceutics 2025, 17(11), 1426; https://doi.org/10.3390/pharmaceutics17111426 - 4 Nov 2025

Abstract

Antimicrobial resistance (AMR) is a present, pressing global public health crisis associated with rising morbidity and mortality rates due to previously curable infectious disease. Targeted drug delivery is an important approach to address AMR due to its ability to improve the therapeutic performance [...] Read more.

Antimicrobial resistance (AMR) is a present, pressing global public health crisis associated with rising morbidity and mortality rates due to previously curable infectious disease. Targeted drug delivery is an important approach to address AMR due to its ability to improve the therapeutic performance of antibiotics without leading to any adverse effects or organ toxicities. In this review we explore molecular mechanisms of AMR and drawbacks of conventional antibiotic therapies and discuss unique drug delivery approaches to compensate these. Nanoparticulate carrier systems, stimuli-responsive systems, antibody–drug conjugates, and CRISPR-Cas systems are some of the carrier method designs that are promising for tackling hard to treat infections related to pathogenic strains and biofilms due to their features. Many of these are among the most significant advances in the field. However, there are many challenges to be overcome, with biological limitations, scaling and regulatory challenges, etc., before they can be employed in commercial applications. Materials are being developed, and an approach standardized and applicable to future work is in development to improve the efficiency of targeted delivery systems. Controlled drug delivery, which could be the answer to an increasing AMR problem, will not only help in alerting awareness among individuals but will also help in prolonging the activity of antibiotics by providing synergistic interdisciplinary solutions. This review emphasizes the complementary role of targeted drug delivery in transitioning from laboratory investigations to clinical therapy. It addresses underrepresented aspects, including new materials, scalability, regulatory considerations, and ethical implications, while offering a roadmap for translating innovations into next-generation antimicrobials. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery, 2nd Edition)

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30 pages, 777 KB

Open AccessReview

Matrix Metalloproteinase-9 (MMP-9) as a Therapeutic Target: Insights into Molecular Pathways and Clinical Applications

by Marta Wolosowicz, Slawomir Prokopiuk and Tomasz W. Kaminski

Pharmaceutics 2025, 17(11), 1425; https://doi.org/10.3390/pharmaceutics17111425 - 4 Nov 2025

Abstract

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase that plays a central role in extracellular matrix (ECM) remodeling, angiogenesis, immune cell trafficking, and cytokine activation. Dysregulated MMP-9 activity has been implicated in the pathogenesis of diverse conditions, including atherosclerosis, aneurysm formation, chronic obstructive pulmonary [...] Read more.

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase that plays a central role in extracellular matrix (ECM) remodeling, angiogenesis, immune cell trafficking, and cytokine activation. Dysregulated MMP-9 activity has been implicated in the pathogenesis of diverse conditions, including atherosclerosis, aneurysm formation, chronic obstructive pulmonary disease (COPD), asthma, neurodegeneration, and malignancy. Although broad-spectrum synthetic MMP inhibitors were initially developed as therapeutic agents, clinical trials failed due to lack of selectivity, poor tolerability, and impairment with physiological tissue repair. This outcome has shifted attention toward indirect pharmacological modulation of MMP-9 using drugs that are already approved for other indications. In this paper, we review the evidence supporting MMP-9 modulation by established therapeutics and adjunctive strategies. Cardiometabolic agents such as statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), metformin, and pioglitazone reduce MMP-9 expression and enzymatic activity, contributing to vascular protection, improved insulin sensitivity, and attenuation of aneurysm progression. Anti-inflammatory and respiratory drugs, including glucocorticoids, phosphodiesterase-4 (PDE4) inhibitors, macrolide antibiotics, montelukast, and nonsteroidal anti-inflammatory drugs (NSAIDs), suppress MMP-9-driven airway inflammation and pathological tissue remodeling in asthma, COPD, and acute lung injury. Tetracycline derivatives, particularly sub-antimicrobial dose doxycycline, directly inhibit MMP-9 activity and are clinically validated in the treatment of periodontal disease and vascular remodeling. Hormone-related therapies such as rapamycin, estradiol, and tamoxifen exert tissue- and disease-specific effects on MMP-9 within endocrine and oncologic pathways. In parallel, nutritional interventions—most notably omega-3 polyunsaturated fatty acids and antioxidant vitamins—provide adjunctive strategies for mitigating MMP-9 activity in chronic inflammatory states. Taken together, these findings position MMP-9 as a modifiable and clinically relevant therapeutic target. The systematic integration of approved pharmacologic agents with lifestyle and nutritional interventions into disease-specific treatment paradigms may facilitate safer, context-specific modulation of MMP-9 activity and unveil novel opportunities for therapeutic repurposing. Full article

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

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25 pages, 3645 KB

Open AccessArticle

DOPC Liposomal Formulation of Antimicrobial Peptide LL17-32 with Reduced Cytotoxicity: A Promising Carrier Against Porphyromonas gingivalis

by Jinyang Han, Josephine L. Meade and Francisco M. Goycoolea

Pharmaceutics 2025, 17(11), 1424; https://doi.org/10.3390/pharmaceutics17111424 - 4 Nov 2025

Abstract

Background/Objectives: The rapid emergence of antibiotic-resistant oral pathogens has rendered many conventional therapies increasingly ineffective. Antimicrobial peptides (AMPs) have emerged as a promising therapeutic alternative due to their unique mechanisms of action and low propensity for inducing resistance. The delivery of novel therapeutic [...] Read more.

Background/Objectives: The rapid emergence of antibiotic-resistant oral pathogens has rendered many conventional therapies increasingly ineffective. Antimicrobial peptides (AMPs) have emerged as a promising therapeutic alternative due to their unique mechanisms of action and low propensity for inducing resistance. The delivery of novel therapeutic AMPs against oral cavity bacterial infections requires effective pharmaceutical dosage formulations. This study investigated the potential of two liposomal formulations for the association and delivery of the antimicrobial peptide (AMP) LL17-32 against the dental bacterial pathogen Porphyromonas gingivalis. Methods: Liposomes composed of either negatively charged soya lecithin (SL) or neutrally charged dioleoyl-phosphatidylcholine (DOPC) phospholipids were formulated and characterized based on their hydrodynamic size distribution, ζ-potential, morphology, membrane fluidity, peptide association efficiency, stability and release of peptide in vitro under physiological conditions. The characterization of their biological activity included efficiency of bacterial killing, bacterial adherence, and mammalian cell cytotoxicity using human gingival keratinocyte (TIGK) cells. Results: Both liposomal formulations exhibited spherical morphology with hydrodynamic diameters smaller than ~170 nm and demonstrated good colloidal stability. LL17-32 showed high association efficiency with both liposomal membranes, with no detectable LL17-32 in vitro release. In biological assays, peptide-loaded DOPC liposomes exhibited dose-dependent bactericidal activity against P. gingivalis, whereas SL liposomes significantly attenuated the bactericidal effect of LL17-32. Both formulations displayed reduced cytotoxicity toward human gingival keratinocyte (TIGK) cells versus free peptide. Conclusions: These findings suggest that DOPC liposomes represent a promising delivery system for LL17-32 by adhering to P. gingivalis and exhibiting minimal cytotoxicity to mammalian cells. This study emphasises the critical role of lipid charge in designing AMP delivery systems for antibacterial applications, while it additionally demonstrates the utility of flow cytometry as a quantitative tool to assess liposome–bacteria association. Full article

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

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13 pages, 1946 KB

Open AccessArticle

Comparative Analysis of Classic and Novel Antitussives on Cough Suppression in Guinea Pigs

by Paula Montero, Inés Roger, Erika Esposito, Javier Milara and Julio Cortijo

Pharmaceutics 2025, 17(11), 1423; https://doi.org/10.3390/pharmaceutics17111423 - 3 Nov 2025

Abstract

Introduction: Cough is a common reflex that serves a protective role, but when persistent, it can severely affect patients’ quality of life. Despite its high prevalence, current treatment options remain limited. Traditional antitussives such as codeine and dextromethorphan present notable side effects, underscoring [...] Read more.

Introduction: Cough is a common reflex that serves a protective role, but when persistent, it can severely affect patients’ quality of life. Despite its high prevalence, current treatment options remain limited. Traditional antitussives such as codeine and dextromethorphan present notable side effects, underscoring the need for safer and more effective alternatives. Methods: This study evaluated and compared the antitussive efficacy of classic (codeine, cloperastine, dextromethorphan, levodropropizine) and novel (gefapixant) agents using a citric acid-induced cough model in guinea pigs. Animals were pretreated with the selected compounds, and cough frequency, latency to first cough, and cough intensity were assessed using acoustic recordings and quantitative analysis. Results: Codeine, cloperastine, and gefapixant produced a significant reduction in cough frequency and markedly increased latency to the first cough, with comparable efficacy at the highest doses tested. In contrast, dextromethorphan and levodropropizine did not significantly affect these parameters. Additionally, cloperastine, codeine, and gefapixant reduced cough intensity, while none of the treatments significantly altered cough duration. Conclusions: In this preclinical model, cloperastine and gefapixant demonstrated antitussive effects comparable to codeine but without the known narcotic-associated risks. These findings highlight the potential clinical relevance of both centrally and peripherally acting non-opioid alternatives. Continued investigation of these agents may help address the unmet need for safer and more effective cough treatments. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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15 pages, 3483 KB

Open AccessArticle

In Vivo Iterative Adjuvant Screening Identifies an Intranasal Vaccine Formulation for Elicitation of Protective Mucosal Immune Responses Against SARS-CoV-2

by Yang Jiao, Sara H. Mahmoud, Chengjin Ye, Yuan Luo, Wei-Chiao Huang, Qinzhe Li, Shiqi Zhou, Yiting Song, Moriya Tsuji, Luis Martinez-Sobrido and Jonathan F. Lovell

Pharmaceutics 2025, 17(11), 1422; https://doi.org/10.3390/pharmaceutics17111422 - 3 Nov 2025

Abstract

Background: Intranasal (I.N.) vaccination holds promise to elicit mucosal immunity that counters respiratory pathogens at the site of infection. For subunit protein vaccines, immunostimulatory adjuvants are typically required. Methods: We screened a panel of 22 lipid-phase adjuvants to identify which ones elicited antigen-specific [...] Read more.

Background: Intranasal (I.N.) vaccination holds promise to elicit mucosal immunity that counters respiratory pathogens at the site of infection. For subunit protein vaccines, immunostimulatory adjuvants are typically required. Methods: We screened a panel of 22 lipid-phase adjuvants to identify which ones elicited antigen-specific IgA with I.N. immunization of liposome-displayed SARS-CoV-2 receptor-binding domain (RBD). Results: Initial screening showed the TLR-4 agonist Kdo2-Lipid A (KLA) effectively elicited RBD-specific IgA. A second round of screening identified further inclusion of the invariant NKT cell ligands α-Galactosylceramide (α-GalCer) and its synthetic analog 7DW8-5 as complementary adjuvants for I.N. immunization, resulting in orders-of-magnitude-greater mucosal IgA response relative to intramuscular (I.M.) immunization. The inclusion of cationic lipids conferred capacity for mucosal adhesion and maintained immune responses. In K18 hACE2 transgenic mice, vaccination significantly reduced viral replication and prevented mortality from SARS-CoV-2 challenge. Conclusions: These results point towards the potential for the use of KLA and α-GalCer for I.N. subunit vaccines. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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23 pages, 5297 KB

Open AccessArticle

Pharmacogenomic Drug–Target Network Analysis Reveals Similarity Profiles Among FDA–Approved Cancer Drugs

by Alberto Berral-González, Monica M. Arroyo, Diego Alonso-López, María Jesús Rivas-López, José Manuel Sánchez-Santos and Javier De Las Rivas

Pharmaceutics 2025, 17(11), 1421; https://doi.org/10.3390/pharmaceutics17111421 - 3 Nov 2025

Abstract

Background: Defining specific molecular targets for cancer therapeutics remains a significant challenge in oncology. Many Food and Drug Administration (FDA)-approved anticancer drugs have incomplete target profiles, which limits our understanding of their mechanisms of action and opportunities for drug application. In this [...] Read more.

Background: Defining specific molecular targets for cancer therapeutics remains a significant challenge in oncology. Many Food and Drug Administration (FDA)-approved anticancer drugs have incomplete target profiles, which limits our understanding of their mechanisms of action and opportunities for drug application. In this context, this study aimed to establish novel, biologically meaningful relationships between anticancer drugs and protein-coding genes. Methods: We developed a pharmacogenomic method that integrates transcriptomic data with drug activity data from the NCI-60 cancer cell line panel to study the interactions between 124 FDA-approved anticancer drugs and 399 cancer-related genes. Through this analysis, we identified gene–drug relationships and created a bipartite interaction network. To evaluate drug similarity, we developed a new index called the B-index. This novel similarity coefficient measures the association between two drugs based on their shared gene targets in the network. The index calculates the intersection of two sets of drug targets while considering the relative proportion of targets exhibited by each drug. For an independent assessment, we compared this network-based similarity with the chemical structural similarity of the drugs, computed based on two structural coefficients: Maximum Common Substructure and Tanimoto. Results: The study identified 1304 statistically significant drug–gene relationships, providing a large-scale network of pharmacogenomic interactions. Clustering analysis of the network, based on the B-index, grouped drugs with common targets together. This grouping was consistent with well-established drug classes and structural characteristics. Well-established drug pairs, such as cytarabine–gemcitabine or afatinib–neratinib, exhibited high B-index and structural similarity values, validating the methodology. Several novel gene associations were discovered, yielding testable hypotheses for mechanism-based repurposing. Conclusions: This work presents a comprehensive, network-based strategy for elucidating cancer drug targets by combining gene expression and drug activity profiles. Additionally, the B-index provides an alternative to conventional chemical similarity metrics, which can facilitate the identification of new therapeutic relationships and inform new drug applications and repositioning. These findings pave the way for the proposal of novel oncology drug targets. Full article

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

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10 pages, 635 KB

Open AccessReview

Innovative Strategies for the Targeted Degradation of Viral Proteins: Paving the Way for Next-Generation Therapeutics

by Alexander S. Sobolev and Georgii P. Georgiev

Pharmaceutics 2025, 17(11), 1420; https://doi.org/10.3390/pharmaceutics17111420 - 3 Nov 2025

Abstract

Background/Objectives: This review discusses the development and application of targeted protein degradation strategies, particularly focusing on the ubiquitin–proteasome pathway and PROteolysis-TArgeting Chimeras (PROTAC) technology, for antiviral therapies. Methods/Results: The synthesis of specific PROTACs exemplifies the potential of this approach to inhibit [...] Read more.

Background/Objectives: This review discusses the development and application of targeted protein degradation strategies, particularly focusing on the ubiquitin–proteasome pathway and PROteolysis-TArgeting Chimeras (PROTAC) technology, for antiviral therapies. Methods/Results: The synthesis of specific PROTACs exemplifies the potential of this approach to inhibit viral replication. The discussion also covers ongoing efforts to develop broad-spectrum antivirals and explores the limitations of small-molecule ligands, proposing antibody mimetics as a versatile alternative. The review details innovative strategies involving engineered antibody mimetics, termed ‘diving antibodies’ (DAbs), capable of intracellular delivery and targeting viral proteins within cells. These molecules are engineered using modular nanotransporters to facilitate intracellular delivery. The integration of E3 ligase-binding sites into DAbs enhances their capacity to induce targeted protein degradation, with experimental evidence supporting their efficacy. Conclusions: Overall, the review underscores the potential of combining targeted degradation technologies with innovative delivery systems to create effective antiviral therapies, especially for viruses with limited treatment options. Full article

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

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20 pages, 669 KB

Open AccessArticle

A Systematic Intelligent Optimization Framework for a Sustained-Release Formulation Design

by Yuchao Qiao, Yijia Wu, Mengchen Han, Hao Ren, Yu Cui, Xuchun Wang, Yiming Lou, Chongqi Hao, Quan Feng and Lixia Qiu

Pharmaceutics 2025, 17(11), 1419; https://doi.org/10.3390/pharmaceutics17111419 - 1 Nov 2025

Abstract

Objectives: This study proposes a systematic strategy for optimizing sustained-release formulations using mixture experiments. Methods: Model variables were identified and screened via LASSO regression, Smoothly Clipped Absolute Deviation (SCAD), and Minimax Concave Penalty (MCP), leading to the construction of a quadratic inference function-based [...] Read more.

Objectives: This study proposes a systematic strategy for optimizing sustained-release formulations using mixture experiments. Methods: Model variables were identified and screened via LASSO regression, Smoothly Clipped Absolute Deviation (SCAD), and Minimax Concave Penalty (MCP), leading to the construction of a quadratic inference function-based objective model. Using this model, three multi-objective optimization algorithms—NSGA-III, MOGWO, and NSWOA—were employed to generate a Pareto-optimal solution set. Solutions were further evaluated through the entropy weight method combined with TOPSIS to reduce subjective bias. Results: The MCP-screened model demonstrated strong fit (AIC = 19.8028, BIC = 45.2951) and suitability for optimization. Among the Pareto-optimal formulations, formulation 45, comprising HPMC K4M (38.42%), HPMC K100LV (13.51%), MgO (6.28%), lactose (17.07%), and anhydrous CaHPO₄ (7.52%), exhibited superior performance, achieving cumulative release rates of 22.75%, 64.98%, and 100.23% at 2, 8, and 24 h, respectively. Compared with the original formulation, drug release was significantly improved across all time points. Conclusions: This integrated workflow effectively accounted for component interactions and repeated measurements, providing a robust and scientifically grounded approach for optimizing multi-component sustained-release formulations. Full article

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

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27 pages, 16394 KB

Open AccessArticle

Sustained Intraocular Pressure Reduction Using Bisoprolol-Loaded PLGA Nanoparticles: A Promising Strategy for Enhanced Ocular Delivery with Reduced GFAP Expression Indicative of Lower Glial Activation

by Sammar Fathy Elhabal, Omnia Mohamed Mahfouz, Mohamed Fathi Mohamed Elrefai, Mahmoud H. Teaima, Ahmed Abdalla and Mohamed El-Nabarawi

Pharmaceutics 2025, 17(11), 1418; https://doi.org/10.3390/pharmaceutics17111418 - 31 Oct 2025

Abstract

Background/Objectives: Glaucoma is a neurodegenerative optic disorder which occurs due to persistent elevation of the intraocular pressure. It leads to permanent blindness and currently affects over 75 million individuals worldwide. Nowadays, topical ocular medications are the leading therapy despite their poor ocular [...] Read more.

Background/Objectives: Glaucoma is a neurodegenerative optic disorder which occurs due to persistent elevation of the intraocular pressure. It leads to permanent blindness and currently affects over 75 million individuals worldwide. Nowadays, topical ocular medications are the leading therapy despite their poor ocular penetration and short residence time. Methods: The purpose of this research is to formulate bisoprolol hemifumarate-loaded polylactic-co-glycolic acid (PLGA) nanoparticles and improve their ocular penetration and bioavailability for the treatment of glaucoma by enhancing the delivery of the drug to the posterior part of eye. By using the solvent displacement method, formulations were prepared and optimum formula was elected using Design-Expert^® software. Results: In vitro characterization demonstrated that the optimum formula contained 25 mg BSP, 22.5 mg PLGA, and 60 mg Tween80, yielding high values of drug encapsulation (75%) and zeta potential (−18.7 ± 0.41 mV), with a low particle size (105 ± 0.35 nm) and polydispersity index (0.411 ± 0.71). Transmission electron microscopy and atomic force microscopy showed smooth and spherical nanosized particles. X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy revealed successful encapsulation of the drug inside the polymeric matrix. Ex vivo confocal laser scanning microscopy proved that there was better uptake of the drug upon using PLGA-NPs. In vitro release profiles indicated biphasic drug release from the PLGA-NPs, confirming a sustained drug release over 12 h. In vivo studies showed that BSP-PLGA-NPs significantly reduced the IOP compared to bisoprolol solution. Quantitative immunohistochemistry showed lower retinal GFAP expression with BSP-PLGA-NPs compared with induced controls and drug solution, which is indicative of attenuated glial activation. Conclusions: These data support improved ocular delivery and an improved pharmacodynamic effect; however, they demonstrate association rather than a direct mechanistic suppression of glial pathways. Full article

(This article belongs to the Special Issue Ocular Drug Delivery Systems and Formulations)

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26 pages, 4993 KB

Open AccessArticle

Amodiaquine Modulates Aggregation and Disassembly of Amyloid-β and Tau and Attenuates Neuroinflammatory Responses and Aβ Production

by Sinae Jang, Sujin Kim, Na-Hyun Kim, Soo Jung Shin, Vijay Kumar, Jeong Gyu Son, Minseok Lee, Choon-gil Kim, Eun-Kyung Lim, Hyunju Chung, Young Ho Koh, Yunkwon Nam and Minho Moon

Pharmaceutics 2025, 17(11), 1417; https://doi.org/10.3390/pharmaceutics17111417 - 31 Oct 2025

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of [...] Read more.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of Aβ and tau aggregation represents a promising therapeutic strategy. Amodiaquine (AQ), a quinoline-based antimalarial, has recently attracted attention for its ability to suppress protein aggregation. However, direct effects of AQ on both Aβ and tau aggregation remain unclear. Methods: The effects of AQ on the aggregation and dissociation of Aβ and tau were examined using a thioflavin T (ThT) assays. Molecular docking and molecular dynamics (MD) simulations were performed to examine binding characteristics and structural interactions. The effects of AQ on the expression of pro-inflammatory cytokines induced by Aβ and tau aggregation in BV2 microglial cells were analyzed by qRT-PCR. Results: ThT assay demonstrated a dose-dependent dual effect of AQ on Aβ, where 25 μM inhibited aggregation after 36 h, while 250 μM markedly accelerated it, reaching a plateau within 12 h. All concentrations of AQ promoted the disassembly of mature Aβ fibrils within 12 h. Molecular docking revealed stronger binding of AQ to aggregated Aβ (−45.17 and −23.32 kcal/mol for pentameric 2BEG and hexameric 2NAO) than to monomeric Aβ (−4.81 and −7.29 kcal/mol for 1Z0Q and 2BEG). MD simulation suggested that AQ disrupted the cross-β-sheet interactions of Aβ aggregates. In the case of tau, ThT assay showed that all concentrations of AQ inhibited tau aggregation from 6 h, and 350 μM AQ promoted the disassembly of mature fibrils from 6 h. Molecular docking indicated stronger binding of AQ to aggregated tau (−27.95 and −12.13 kcal/mol for the pentameric and decameric 5O3L) than to monomeric tau (−3.05 kcal/mol for 8Q96). MD simulations revealed no major structural changes in the aggregates. In BV2 cells, 1 and 10 μM AQ significantly reduced Aβ and tau-induced TNF-α and IL-6 mRNA expressions. In APP-H4 cells, 10 μM AQ decreased the level of Aβ compared to the control. Conclusions: AQ modulates both Aβ and tau aggregation and attenuates neuroinflammation and reduces Aβ pathology, supporting its potential as a dual-target therapeutic candidate for AD. Full article

(This article belongs to the Special Issue Application of Nanomedicine in Metabolic and Chronic Diseases)

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22 pages, 1129 KB

Open AccessReview

Pioglitazone-Based Combination Approaches for Non-Small-Cell Lung Cancer

by Sravya Aluru, Anita Thyagarajan and Ravi P. Sahu

Pharmaceutics 2025, 17(11), 1416; https://doi.org/10.3390/pharmaceutics17111416 - 31 Oct 2025

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) being the most prevalent subtype. NSCLC is marked by a complex genetic makeup, involving numerous driver mutations and epigenetic changes that drive tumor growth and resistance to treatment. [...] Read more.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) being the most prevalent subtype. NSCLC is marked by a complex genetic makeup, involving numerous driver mutations and epigenetic changes that drive tumor growth and resistance to treatment. While several approaches, including chemotherapy and targeted therapy, have been used for lung cancer treatment, their overall responses remain dismal, indicating the need to explore alternative targets implicated in cancer growth. Among various candidates, peroxisome proliferator-activated receptor-gamma (PPARγ), which plays critical roles in regulating cellular functions related to tumorigenesis, has been explored as a promising target for NSCLC intervention. To that end, thiazolidinediones, including pioglitazone, that target PPARγ have shown promise in multiple cellular and preclinical models of NSCLC. Mechanistically, pioglitazone inhibits cancer growth and induces apoptosis via downregulating key signaling pathways, including mitogen-activated protein kinase (MAPK), which play critical roles in regulating cellular activities such as epithelial-to-mesenchymal transition (EMT), cellular bioenergetics, and glucose metabolism. This review highlights the recent updates on the mechanistic insights and the efficacy of PPARγ agonist-based approaches, with an emphasis on pioglitazone, for the treatment of NSCLC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring pioglitazone’s effect on metabolic pathways, chemical-carcinogen-induced tumorigenesis, the targeting of cell signaling pathways, and then its combination with other therapeutic agents. We also present clinical studies that support pioglitazone’s potential in chemoprevention and underscore its further exploration in large cohorts of NSCLC patients. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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19 pages, 2962 KB

Open AccessArticle

8-Hydroxy-2-Anilino-1,4-Naphthoquinone Prevents Against Ferroptotic Neuronal Death and Kainate-Induced Epileptic Seizures

by Daseul Lee, Eun Jung Na, Yumi Heo, Jinha Yu and Hwa-Jung Kim

Pharmaceutics 2025, 17(11), 1415; https://doi.org/10.3390/pharmaceutics17111415 - 31 Oct 2025

Abstract

Background/Objectives: Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various acute and chronic brain disorders, including epilepsy. Although 1,4-naphthoquinone derivatives have been reported to regulate ferroptosis, their mechanistic roles in the nervous system remain [...] Read more.

Background/Objectives: Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various acute and chronic brain disorders, including epilepsy. Although 1,4-naphthoquinone derivatives have been reported to regulate ferroptosis, their mechanistic roles in the nervous system remain underexplored. Here, we investigated the protective effects of 8-hydroxy-2-anilino-1,4-naphthoquinone (8-HANQ) on ferroptotic neuronal death in vitro and seizure behaviors in vivo. Methods: HT22 hippocampal cells were exposed to ferroptosis inducers including glutamate, glutamate plus iron, or RSL3. Lipid reactive oxygen species (ROS), ferroptosis markers, and its related molecules were assessed by flow cytometry and Western blotting. In a kainate (KA)-induced seizure model, 8-HANQ was delivered intracerebroventricularly, followed by behavioral seizure scoring and analysis of hippocampal levels of PSD95, cathepsin-B, and FGFR1 at 72 h post-seizure. Results: 8-HANQ attenuated ferroptotic death in HT22 cells, reducing lipid ROS accumulation and abnormal acyl-coA synthetase long chain family member 4 (ACSL4), suggesting 8-HANQ’s anti-ferroptotic action. Moreover, 8-HANQ also prevented aberrant STAT3-dependent cathepsin-B overexpression while modulating soluble N-cadherin-mediated FGFR1 activation. In vivo, 8-HANQ decreased KA-induced seizure behavior, restored hippocampal cathepsin-B and PSD95 expression, and partially alleviated dysregulation of FGFR1 activation. Conclusions: 8-HANQ prevents ferroptotic neuronal death and synaptic deficits involving FGFR1/STAT3/cathepsin-B-driven ferroptosis while lowering seizure severity, suggesting that 8-HANQ may serve as a potential anti-ferroptotic and anti-seizure agent. Full article

(This article belongs to the Section Biopharmaceutics)

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35 pages, 4438 KB

Open AccessReview

Camptothecin in Cancer Therapy: Current Challenges and Emerging Strategies with Nanoemulsions

by Heber Uriel Pérez-Ortega, Rubén Ricardo Córdova-Espíritu, Sebastian Cano-Serrano, Eduardo García-González, Micael Gerardo Bravo-Sánchez, Ma. del Carmen Orozco-Mosqueda, Hugo Jiménez-Islas, Gabriel Luna-Bárcenas and Francisco Villaseñor-Ortega

Pharmaceutics 2025, 17(11), 1414; https://doi.org/10.3390/pharmaceutics17111414 - 31 Oct 2025

Abstract

Camptothecin (CPT) is a natural alkaloid with potent antiproliferative activity, mediated by the inhibition of Topoisomerase I (Topo I), an essential enzyme for deoxyribonucleic acid (DNA) replication. However, its clinical application has been limited by low solubility and the instability of the lactone [...] Read more.

Camptothecin (CPT) is a natural alkaloid with potent antiproliferative activity, mediated by the inhibition of Topoisomerase I (Topo I), an essential enzyme for deoxyribonucleic acid (DNA) replication. However, its clinical application has been limited by low solubility and the instability of the lactone ring under physiological conditions, both of which decrease its efficacy. Semi-synthetic analogs such as irinotecan (CPT-11) and topotecan (TPT) have been developed and approved for the treatment of various types of cancer; however, challenges related to drug resistance and side effects continue to arise. Therefore, nanomedicine and nanoparticle-based delivery systems, including nanoemulsions, liposomes, and antibody–drug conjugates (ADCs), emerge as promising strategies to improve the stability, bioavailability, and effectiveness of CPT, despite significant challenges such as scalability, pharmacokinetic variability, and regulatory requirements. This review discusses recent advances in CPT, its analogs, and these delivery platforms, highlighting its potential to optimize cancer therapy and reduce toxicity while outlining translational challenges such as scalability, pharmacokinetic variability, and regulatory requirements. Full article

(This article belongs to the Topic Application of Nanomaterials and Nanobiotechnology in Cancer)

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