Pharmaceutics

13 pages, 1116 KB

Open AccessArticle

A Four-Layer Numerical Model for Transdermal Drug Delivery: Parameter Optimization and Experimental Validation Using a Franz Diffusion Cell

by Fjola Jonsdottir, O. I. Finsen, B. S. Snorradottir and S. Sigurdsson

Pharmaceutics 2025, 17(10), 1333; https://doi.org/10.3390/pharmaceutics17101333 (registering DOI) - 14 Oct 2025

Abstract

Background/Objectives: A mechanistic understanding of transdermal drug delivery relies on accurately capturing the layered structure and barrier function of the skin. This study presents a four-layer numerical model that explicitly includes the donor compartment, stratum corneum (SC), viable skin (RS), and receptor compartment. [...] Read more.

Background/Objectives: A mechanistic understanding of transdermal drug delivery relies on accurately capturing the layered structure and barrier function of the skin. This study presents a four-layer numerical model that explicitly includes the donor compartment, stratum corneum (SC), viable skin (RS), and receptor compartment. Methods: The model is based on Fickian diffusion and incorporates interfacial partitioning and mass transfer resistance. It is implemented using the finite element method in MATLAB and calibrated through nonlinear least-squares optimization against experimental data from Franz diffusion cell studies using porcine skin. Validation was performed using receptor concentration profiles over time and final drug content in the SC and RS layers, assessed via tape stripping and residual skin analysis. Results: The model provided excellent agreement with experimental data. For diclofenac, the optimized partition coefficient at the SC–RS interface was close to unity, indicating minimal interfacial discontinuity and that a simplified three-layer model may be sufficient for this compound. Conclusions: The proposed four-layer framework provides a physiologically informed and generalizable platform for simulating transdermal drug delivery. It enables spatial resolution, mechanistic interpretation, and flexible adaptation to other drugs and formulations, particularly those with significant interfacial effects or limited lipophilicity. Full article

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

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20 pages, 448 KB

Open AccessReview

Therapeutic and Formulation Innovations in the Management of Canine Otitis Externa

by Yunmei Song, Sangseo Kim, Songhita Mukhopadhyay, Souha H. Youssef, Jin Quan Eugene Tan, Emily Josephine Weir, Stephen W. Page and Sanjay Garg

Pharmaceutics 2025, 17(10), 1332; https://doi.org/10.3390/pharmaceutics17101332 (registering DOI) - 14 Oct 2025

Abstract

Canine Otitis Externa (COE) is a challenging otological disorder in dogs which causes significant irritation and discomfort. This comprehensive review provides an extensive analysis of COE with emphasis on the fundamentals of the condition, starting with the basic anatomy of the canine external [...] Read more.

Canine Otitis Externa (COE) is a challenging otological disorder in dogs which causes significant irritation and discomfort. This comprehensive review provides an extensive analysis of COE with emphasis on the fundamentals of the condition, starting with the basic anatomy of the canine external ear canal, followed by pathophysiology and diagnosis of COE. Furthermore, novel therapeutic interventions, formulation considerations, and challenges, with the perspective of future directions in the field of COE management, are described. Diagnostic models, including clinical examination, cytology, and susceptibility tests, are presented to provide an overview of the processes involved in detecting and selecting appropriate therapies for the management of COE. Moreover, this paper describes the limitations of current therapies with considerations for the selection of alternative novel treatments such as aromatherapy, acupuncture, bacteriophages, nutraceuticals, and nanomedicines. This review places particular emphasis on the pharmaceutical formulation of topical products used for COE treatment. Various factors, including osmotic pressure, safety profile, viscosity, bioadhesion, and formulation pH, must be considered when developing topical preparations. These parameters are critical in formulation development to enhance therapeutic outcomes and minimise potential side effects. Finally, potential advancements in COE management are highlighted, including the integration of microbial genomics and the significance of managing the microbiota. Overall, this review serves as a valuable resource for those interested in the future of topical treatment of COE by providing a deep understanding of diagnostic, therapeutic, and medical interventions for effective management. Full article

(This article belongs to the Special Issue Innovations in Drug Delivery, Pharmacometrics, and Clinical Studies in Veterinary Medicine)

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26 pages, 1856 KB

Open AccessReview

Extracellular Vesicles and Nanoparticles in Regenerative and Personalised Medicine: Diagnostic and Therapeutic Roles—A Narrative Review

by Elena Silvia Bernad, Ingrid-Andrada Vasilache, Robert Leonard Bernad, Lavinia Hogea, Dragos Ene, Florentina Duica, Bogdan Tudora, Sandor Ianos Bernad, Marius Lucian Craina, Loredana Mateiovici and Răzvan Ene

Pharmaceutics 2025, 17(10), 1331; https://doi.org/10.3390/pharmaceutics17101331 - 14 Oct 2025

Abstract

Background: Degenerative, metabolic and oncologic diseases are scarcely amenable to the complete reconstruction of tissue structure and functionalities using common therapeutic modalities. On the nanoscale, extracellular vesicles (EVs) and nanoparticles (NPs) have emerged as attractive candidates in regenerative and personalised medicine. However, EV [...] Read more.

Background: Degenerative, metabolic and oncologic diseases are scarcely amenable to the complete reconstruction of tissue structure and functionalities using common therapeutic modalities. On the nanoscale, extracellular vesicles (EVs) and nanoparticles (NPs) have emerged as attractive candidates in regenerative and personalised medicine. However, EV transfection is hindered by its heterogeneity and low yield, while NPs suffer from cytotoxicity, immunogenicity, and long-term safety issues. Scope of Review: This review synthesises data from over 180 studies as part of a narrative synthesis, critically evaluating the disease-specific utility, mechanistic insights, and translational obstacles. The focus is laid on comparative cytotoxicity profiles, the capacities of hybrid EV–NP systems to circumvent mutual shortcomings, and the increasing impact of artificial intelligence (AI) on predictive modelling, as well as toxicity appraisal and manufacturing. Key Insights: EVs have inherent biocompatibility, immune evasive and organotropic signalling functions; NPs present structural flexibility, adjustable physicochemical properties, and industrial scalability. Common molecular pathways for NP toxicity, such as ROS production, MAPK and JAK/STAT activation, autophagy, and apoptosis, are significant biomarkers for regulatory platforms. Nanotechnological and biomimetic nanocarriers incorporate biological tropism with engineering control to enhance therapeutic efficacy, as well as their translational potential. AI approaches can support rational drug design, promote reproducibility across laboratories, and meet safe-by-design requirements. Conclusions: The intersection of EVs, NPs and AI signifies a turning point in regenerative nanomedicine. To advance this field, there is a need for convergence on experimental protocols, the adoption of mechanistic biomarkers, and regulatory alignment to ensure reproducibility and clinical competence. If realised, these endeavours will not only transition nanoscale medicament design from experimental constructs into reliable and patient-specific tools for clinical trials, but we also have the strong expectation that they could revolutionise future treatments of challenging human disorders. Full article

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

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22 pages, 2797 KB

Open AccessArticle

Carbon Dots with Tunable Charge as Mucus-Penetrating Gene Carriers

by Samuel Arca, Clea Witjaksono, Françoise Pons and Luc Lebeau

Pharmaceutics 2025, 17(10), 1330; https://doi.org/10.3390/pharmaceutics17101330 - 14 Oct 2025

Abstract

Background/Objectives: Local delivery of gene therapy products through the airways shows great promise for the treatment of a number of serious lung diseases, but its effectiveness is hampered by the mucus layer protecting the lung epithelium in the trachea and bronchi. Methods: To [...] Read more.

Background/Objectives: Local delivery of gene therapy products through the airways shows great promise for the treatment of a number of serious lung diseases, but its effectiveness is hampered by the mucus layer protecting the lung epithelium in the trachea and bronchi. Methods: To overcome this barrier, we engineered carbon dots (CDs) with mucus penetrating properties. Results: The CDs were synthesized by solvothermal treatment of citric acid and branched polyethyleneimine, and functionalized with maleamic acid groups to create cationic mucoinert nanoparticles with tunable charge. We characterized their interactions with a mucus model through turbidity and transport measurements, and assessed their impact on the viscoelastic properties of the biopolymer. We then demonstrated that the carriers are effective at delivering pDNA to a variety of cell models in vitro. In particular, mucus-producing Calu-3 cells cultured at the air–liquid interface (ALI) were used as a discriminating model to evaluate intracellular delivery of the genetic cargo through a thick layer of mucus at the cell surface. Conclusions: The functionalization of CDs with maleamic acid groups resulted in a 1000- to 10,000-fold increase in transfection efficiency in the mucus-producing model, offering new opportunities for lung gene therapy. Full article

(This article belongs to the Special Issue Application of Nanomaterials in Pulmonary Drug Delivery)

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20 pages, 4947 KB

Open AccessArticle

Engineered Liposomal Delivery of Human ACE2 Across the Blood–Brain Barrier Attenuated Neurogenic Hypertension

by Yue Shen, Richard Nii Lante Lamptey, Gowthami Reddy Mareddy, Bivek Chaulagain, Jagdish Singh and Chengwen Sun

Pharmaceutics 2025, 17(10), 1329; https://doi.org/10.3390/pharmaceutics17101329 - 14 Oct 2025

Abstract

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf [...] Read more.

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article

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

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20 pages, 652 KB

Open AccessReview

Short Peptides as Excipients in Parenteral Protein Formulations: A Mini Review

by Dorian Migoń, Zbigniew Jaremicz and Wojciech Kamysz

Pharmaceutics 2025, 17(10), 1328; https://doi.org/10.3390/pharmaceutics17101328 - 13 Oct 2025

Abstract

Biopharmaceutical medicines represent one of the most dynamic sectors of the pharmaceutical industry, with therapeutic proteins forming the largest and most important group. Their structural complexity and inherent sensitivity to chemical and physical stressors, however, continue to pose major challenges for formulation development [...] Read more.

Biopharmaceutical medicines represent one of the most dynamic sectors of the pharmaceutical industry, with therapeutic proteins forming the largest and most important group. Their structural complexity and inherent sensitivity to chemical and physical stressors, however, continue to pose major challenges for formulation development and long-term stability. Short peptides have emerged as a promising yet underutilized class of excipients for protein-based drug products. Their modular architecture allows for precise tuning of physicochemical properties such as polarity, charge distribution, and hydrogen-bonding potential, thereby offering advantages over single amino acids. Experimental studies indicate that short peptides can serve multiple functions: stabilizers, antioxidants, viscosity-lowering agents, and as lyo/cryoprotectants or bulking agents in lyophilized formulations. Notably, the relatively small and chemically defined space of short peptides—approximately 400 possible dipeptides and 8000 tripeptides—makes them particularly amenable to systematic screening and computational modeling. This enables rational identification of candidates with tailored excipient functions. This review summarizes current knowledge on the use of short peptides as excipients in parenteral protein formulations, with a focus on their functional versatility and potential for rational design in future development. Full article

(This article belongs to the Section Biopharmaceutics)

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48 pages, 1661 KB

Open AccessReview

Unique Features and Collateral Immune Effects of mRNA-LNP COVID-19 Vaccines: Plausible Mechanisms of Adverse Events and Complications

by János Szebeni

Pharmaceutics 2025, 17(10), 1327; https://doi.org/10.3390/pharmaceutics17101327 - 13 Oct 2025

Abstract

A reassessment of the risk-benefit balance of the two lipid nanoparticle (LNP)-based vaccines, Pfizer’s Comirnaty and Moderna’s Spikevax, is currently underway. While the FDA has approved updated products, their administration is recommended only for individuals aged 65 years or older and for those [...] Read more.

A reassessment of the risk-benefit balance of the two lipid nanoparticle (LNP)-based vaccines, Pfizer’s Comirnaty and Moderna’s Spikevax, is currently underway. While the FDA has approved updated products, their administration is recommended only for individuals aged 65 years or older and for those aged 6 months or older who have at least one underlying medical condition associated with an increased risk of severe COVID-19. Among other factors, this change in guidelines reflect an expanded spectrum and increased incidence of adverse events (AEs) and complications relative to other vaccines. Although severe AEs are relatively rare (occurring in < 0.5%) in vaccinated individuals, the sheer scale of global vaccination has resulted in millions of vaccine injuries, rendering post-vaccination syndrome (PVS) both clinically significant and scientifically intriguing. Nevertheless, the cellular and molecular mechanisms of these AEs are poorly understood. To better understand the phenomenon and to identify research needs, this review aims to highlight some theoretically plausible connections between the manifestations of PVS and some unique structural properties of mRNA-LNPs. The latter include (i) ribosomal synthesis of the antigenic spike protein (SP) without natural control over mRNA translation, diversifying antigen processing and presentation; (ii) stabilization of the mRNA by multiple chemical modification, abnormally increasing translation efficiency and frameshift mutation risk; (iii) encoding for SP, a protein with multiple toxic effects; (iv) promotion of innate immune activation and mRNA transfection in off-target tissues by the LNP, leading to systemic inflammation with autoimmune phenomena; (v) short post-reconstitution stability of vaccine nanoparticles contributing to whole-body distribution and mRNA transfection; (vi) immune reactivity and immunogenicity of PEG on the LNP surface increasing the risk of complement activation with LNP disintegration and anaphylaxis; (vii) GC enrichment and double proline modifications stabilize SP mRNA and prefusion SP, respectively; and (viii) contaminations with plasmid DNA and other organic and inorganic elements entailing toxicity with cancer risk. The collateral immune anomalies considered are innate immune activation, T-cell- and antibody-mediated cytotoxicities, dissemination of pseudo virus-like hybrid exosomes, somatic hypermutation, insertion mutagenesis, frameshift mutation, and reverse transcription. Lessons from mRNA-LNP vaccine-associated AEs may guide strategies for the prediction, prevention, and treatment of AEs, while informing the design of safer next-generation mRNA vaccines and therapeutics. Full article

(This article belongs to the Special Issue Development of Nucleic Acid Delivery System)

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29 pages, 1315 KB

Open AccessReview

Targeting the Eye: RNA-Based Therapies, Interferences, and Delivery Strategies

by Mohammed S. Abdel-Raziq Hassan, Cheng Zhong, Fatma Hassan and S. Kevin Li

Pharmaceutics 2025, 17(10), 1326; https://doi.org/10.3390/pharmaceutics17101326 - 13 Oct 2025

Abstract

Recent advances in molecular biology have led to the development of RNA-based therapeutics, offering significant promise for treating various eye diseases. Current RNA therapeutics include RNA aptamers, antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and messenger RNA (mRNA) that can target specific genetic [...] Read more.

Recent advances in molecular biology have led to the development of RNA-based therapeutics, offering significant promise for treating various eye diseases. Current RNA therapeutics include RNA aptamers, antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and messenger RNA (mRNA) that can target specific genetic and molecular pathways involved in eye disorders. In addition to their potential in therapy, RNA technologies have also provided tools for mechanistic studies to improve the understanding of eye diseases, expanding the possibilities of RNA-based treatments. Despite the utility of RNA in studying eye disease mechanisms and its potential in disease treatment, only a few RNA-based therapies have been approved for posterior eye diseases. This paper reviews RNA interference and related ocular delivery and posterior eye diseases, focusing on the use of RNA aptamers, siRNA, short hairpin RNA (shRNA), and microRNA (miRNA). Approaches using RNA to advance our understanding of eye diseases and disease treatments, particularly in the posterior segment of the eye, are discussed. It is concluded that RNA therapeutics offer a novel approach to treating a variety of eye diseases by targeting their molecular causes. siRNA, shRNA, miRNA, and ASO can directly silence disease-driving genes, while RNA aptamers bind to specific targets. Although many RNA-based therapies are still in experimental stages, they hold promise for conditions such as age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, and inherited retinal disorders. Effective delivery methods and long-term safety are key challenges that need to be addressed for these treatments to become widely available. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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27 pages, 1204 KB

Open AccessReview

Orally Dispersible Swallowed Topical Corticosteroids in Eosinophilic Esophagitis: A Paradigm Shift in the Management of Esophageal Inflammation

by Alberto Barchi, Marina Girelli, Antonio Ventimiglia, Francesco Vito Mandarino, Silvio Danese, Sandro Passaretti, Mona-Rita Yacoub, Serena Nannipieri, Ambra Federica Ciliberto, Luca Albarello, Alessandra Bartolucci, Edoardo Vespa and Giuseppe Dell’Anna

Pharmaceutics 2025, 17(10), 1325; https://doi.org/10.3390/pharmaceutics17101325 - 13 Oct 2025

Abstract

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease of the esophagus within the type 2 inflammatory spectrum, characterized by progressive tissue remodeling driven by uncontrolled inflammation. Its incidence and prevalence are rising sharply, likely reflecting environmental triggers acting on genetic and epigenetic susceptibility. [...] Read more.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease of the esophagus within the type 2 inflammatory spectrum, characterized by progressive tissue remodeling driven by uncontrolled inflammation. Its incidence and prevalence are rising sharply, likely reflecting environmental triggers acting on genetic and epigenetic susceptibility. Therapeutic options have expanded rapidly, with recent approvals of new topical steroidal formulations together with biologic compounds. Proton pump inhibitors (PPIs), older swallowed topical corticosteroid (STC), and dietary interventions remain in use but are limited by suboptimal adherence and treatment discontinuation. This has driven a shift toward advanced orally dispersible STCs formulations—most notably budesonide orally dispersible tablets (BOT), budesonide oral suspension (BOS), and fluticasone orally dispersible tablets (FOT). BOT, the most extensively studied, achieves high rates of histologic and clinical remission, with favorable safety and superior adherence compared to earlier STCs formulations. This comprehensive overview focuses on following key research findings and novelty aspects of new treatments: (a) optimized esophageal targeting through orally dispersible or viscous formulations of STC, enhancing mucosal contact time and improving drug delivery to affected tissues compared to older formulations; (b) robust evidence for both induction and maintenance rates of remission, with data extending up to nearly 2 years and showing stable efficacy across clinical, histologic, and endoscopic endpoints; (c) effectiveness in STC-refractory patients, with BOT showing benefit even in those previously unresponsive to older STC formulations. This review synthesizes evidence of steroid therapy in EoE, from pharmacological aspects to clinical efficacy from randomized trials and emerging real-world studies, highlighting its impact on EoE management and outlining future therapeutic directions. Full article

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

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3 pages, 972 KB

Open AccessCorrection

Correction: Mandal et al. Modified Linear Peptides Effectively Silence STAT-3 in Breast Cancer and Ovarian Cancer Cell Lines. Pharmaceutics 2023, 15, 666

by Dindyal Mandal, Sandeep Lohan, Muhammad Imran Sajid, Abdulelah Alhazza, Rakesh Kumar Tiwari, Keykavous Parang and Hamidreza Montazeri Aliabadi

Pharmaceutics 2025, 17(10), 1324; https://doi.org/10.3390/pharmaceutics17101324 - 13 Oct 2025

Abstract

In the original publication [...] Full article

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

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20 pages, 5106 KB

Open AccessArticle

Phase I Clinical Study with the GRPR-Antagonist [^99mTc]Tc-DB8 for SPECT Imaging of Prostate Cancer: Does the Injected Peptide Mass Make a Difference?

by Anna Orlova, Anastasia Rybina, Anna Medvedeva, Roman Zelchan, Olga Bragina, Liubov Tashireva, Maria Larkina, Ruslan Varvashenya, Nadejda Lushnikova, Panagiotis Kanellopoulos, Theodosia Maina, Berthold A. Nock, Vladimir Tolmachev and Vladimir Chernov

Pharmaceutics 2025, 17(10), 1323; https://doi.org/10.3390/pharmaceutics17101323 - 12 Oct 2025

Viewed by 42

Abstract

Background/Objectives: The gastrin-releasing peptide receptor (GRPR) shows high-density expression in prostate cancer (PCa), especially in the early stages of the disease. The introduction of a safe radiotracer for assessing GRPR-expression in PCa may serve as an alternative or complementary tracer to PSMA-directed [...] Read more.

Background/Objectives: The gastrin-releasing peptide receptor (GRPR) shows high-density expression in prostate cancer (PCa), especially in the early stages of the disease. The introduction of a safe radiotracer for assessing GRPR-expression in PCa may serve as an alternative or complementary tracer to PSMA-directed probes for patients with insufficient PSMA expression. In the present study, the tolerability and safety, biodistribution, and dosimetry of the new GRPR-targeting radiopeptide [^99mTc]Tc-DB8 were investigated for the first time in male PCa patients. A mass escalation study was performed, aiming to improve tumor-to-background contrast and, thereby, to enhance diagnostic accuracy. Methods: Sixteen male patients were enrolled in a single-center diagnostic open-label exploratory Phase I clinical trial. Patients were administered a single intravenous injection of 40, 80, or 120 µg of [^99mTc]Tc-DB8 peptide (n = 5–6) and underwent whole-body planar imaging (anterior and posterior) 2, 4, 6, and 24 h post-injection (pi) and SPECT-CT acquisition 2, 4, and 6 h pi. Results: Administration of [^99mTc]Tc-DB8 was well tolerated at all tested peptide masses. The effective dose did not differ significantly between the injected peptide mass and was 0.005 ± 0.003 mSv/MBq. High activity uptake was observed in the pancreas and kidneys, which 3-fold decreased with an increasing injected peptide mass from 40 to 120 µg. The activity uptake in primary tumors did not differ significantly between cohorts injected with different peptide masses [SUV_max 1.65–9.96]. The tumor-to-muscle ratios increased with time and were the highest for the cohort injected with 120 µg of peptide, 7.2 ± 3.1 (4.64-11-25) at 4 h pi. Conclusions: Single intravenous administration of [^99mTc]Tc-DB8, for visualization of GRPR expression in PCa using SPECT imaging was well tolerated in a peptide mass range of 40–120 µg. An injected peptide mass of 80–120 µg/patient and SPECT acquisition 2–4 h pi were found to be optimal for further clinical studies due to the significantly lower activity accumulation in the pancreas and kidneys. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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21 pages, 1300 KB

Open AccessReview

Cancer Cell Membrane-Coated NPs as a Biomimetic Strategy for Precision Tumor Therapy

by Junyi Lin, Wei Li, Alaa R. Aboushanab and Jingjing Sun

Pharmaceutics 2025, 17(10), 1322; https://doi.org/10.3390/pharmaceutics17101322 - 11 Oct 2025

Viewed by 211

Abstract

Cancer treatment remains challenging due to the complexity of the tumor microenvironment, which promotes tumor heterogeneity and contributes to the development of multidrug resistance, ultimately hindering drug delivery and reducing therapeutic efficacy. In recent years, biomimetic nanocarriers have emerged as promising tools to [...] Read more.

Cancer treatment remains challenging due to the complexity of the tumor microenvironment, which promotes tumor heterogeneity and contributes to the development of multidrug resistance, ultimately hindering drug delivery and reducing therapeutic efficacy. In recent years, biomimetic nanocarriers have emerged as promising tools to address these challenges. Among them, cancer cell membrane (CCM)-coated nanoparticles (CCM-NPs) have attracted increasing attention due to their unique advantages, including homologous targeting, prolonged circulation mediated by self-recognition, and enhanced tumor penetration. Moreover, CCM-NPs can serve as versatile platforms for tumor vaccines by leveraging their inherent tumor-associated antigens and immunomodulatory potential. By leveraging CCMs to functionalize NPs, researchers have developed innovative approaches to improve drug delivery, enhance tumor immunotherapy, and optimize cancer vaccine efficacy. Despite these advancements, a comprehensive review summarizing the latest progress in CCM-based biomimetic nanocarriers for tumor treatment is lacking. This review integrates recent advances in CCM-NPs for targeted drug delivery and cancer vaccination, and discusses their fabrication, characterization, mechanisms and applications across multiple cancer types, which provides timely insights to guide their future development in precision tumor therapy. Full article

(This article belongs to the Special Issue Innovative Drug Delivery Strategies for Targeted Cancer Immunotherapy)

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24 pages, 2142 KB

Open AccessReview

Advances in Nasal Biopharmaceutics to Support Product Development and Therapeutic Needs

by Ben Forbes, Lucy Goodacre, Alison B. Lansley, Andrew R. Martin, Helen Palmer, Claire Patterson, Chris Roe and Regina Scherließ

Pharmaceutics 2025, 17(10), 1321; https://doi.org/10.3390/pharmaceutics17101321 - 11 Oct 2025

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Abstract

Background/Objectives: Nasal biopharmaceutics is the scientific understanding of product and patient factors that determine the rate and extent of drug exposure following nasal administration. The authors considered whether current biopharmaceutics tools are fit for the current and future needs of nasal product development [...] Read more.

Background/Objectives: Nasal biopharmaceutics is the scientific understanding of product and patient factors that determine the rate and extent of drug exposure following nasal administration. The authors considered whether current biopharmaceutics tools are fit for the current and future needs of nasal product development and regulation. Methods: The limitations of current methods were critically assessed, unmet needs were highlighted, and key questions were posed to guide future directions in biopharmaceutics research. Results: The emergence of physiologically based biopharmaceutics models for nasal delivery has the potential to drive the scientific understanding of nasal delivery. Simulations can guide formulation and device development, inform dose selection and generate mechanistic insights. Developments in modeling need to be complemented by advances in experimental systems, including the use of realistic or idealized nasal casts to estimate the regional deposition of nasal sprays and refined in vitro cell culture models to study nasal drug absorption and the influence of mucus. Similarly, improvements are needed to address the practicalities of using animals in non-clinical studies of nasal drug delivery, and greater clinical use of gamma scintigraphy/magnetic resonance imaging is recommended to measure the delivery and nasal retention of different formulations in humans. Conclusions: Nasal drug delivery is a rapidly growing field and requires advances in nasal biopharmaceutics to support product innovation. Key needs are (i) validated clinically relevant critical product attributes for product performance and (ii) established links between how patients administer the product and where in the nose it deposits and dissolves in order to act or be absorbed, leading to its desired clinical effect. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments, 3rd Edition)

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10 pages, 1043 KB

Open AccessCommunication

Preliminary In Vivo Ocular Tolerance Assessment of a Cefuroxime Sodium Suspension in Self-Emulsifying Oil

by Katarzyna Krzemińska, Eliza Wolska, Juliusz Chorążewicz and Małgorzata Sznitowska

Pharmaceutics 2025, 17(10), 1320; https://doi.org/10.3390/pharmaceutics17101320 - 11 Oct 2025

Viewed by 140

Abstract

Cefuroxime sodium (CEF) is a second-generation cephalosporin that remains unstable in an aqueous environment. The answer to this low stability may be self-emulsifying oils, which are isotropic mixtures of oil and surfactants, in which the stability of CEF has already been proven. Self-emulsifying [...] Read more.

Cefuroxime sodium (CEF) is a second-generation cephalosporin that remains unstable in an aqueous environment. The answer to this low stability may be self-emulsifying oils, which are isotropic mixtures of oil and surfactants, in which the stability of CEF has already been proven. Self-emulsifying oils are well known for their ability to enhance the solubility and bioavailability of lipophilic drugs. This research presents a preliminary in vivo study of an innovative approach to develop eye drops in the form of a self-emulsifying oil (SEO) containing suspended water-labile antibiotic cefuroxime sodium. Such a concept has never been explored before. Upon contact with tear fluid, the preparation rapidly forms an emulsion, allowing for the rapid dissolution of the antibiotic. The aim of the study was to assess the tolerability of such eye drops. CEF (5% w/w) was suspended in SEO carriers, prepared by dissolving surfactants (Tween 20; 5% w/w) in Miglyol. The in vivo evaluation was conducted on rabbits after two once-a-day applications of the eye drops. The study demonstrated the safety of both the SEO-placebo and the SEO containing suspended CEF. The formulations did not affect the appearance of the cornea and iris. During the observations, only changes in the conjunctiva of the eye were noted, which manifested as conjunctival hyperemia. The result of the Draize test was an average of 3.3 points out of 110 possible points, which classifies the CEF-SEO suspension as minimally irritating. Full article

(This article belongs to the Special Issue Advances in Emulsifying Drug Delivery Systems)

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21 pages, 3438 KB

Open AccessArticle

Research on Enhancing the Solubility and Bioavailability of Canagliflozin Using Spray Drying Techniques with a Quality-by-Design Approach

by Ji Ho Lee, Seong Uk Choi, Tae Jong Kim, Na Yoon Jeong, Hyun Seo Paeng and Kyeong Soo Kim

Pharmaceutics 2025, 17(10), 1319; https://doi.org/10.3390/pharmaceutics17101319 - 11 Oct 2025

Viewed by 92

Abstract

Objectives: The objective of this study was to enhance the solubility and bioavailability of canagliflozin (CFZ) using a spray drying technique with a Quality-by-Design (QbD) approach. Methods: The formulation of CFZ-loaded solid dispersions (CFZ-SDs) was optimized using a Box–Behnken design (BBD) [...] Read more.

Objectives: The objective of this study was to enhance the solubility and bioavailability of canagliflozin (CFZ) using a spray drying technique with a Quality-by-Design (QbD) approach. Methods: The formulation of CFZ-loaded solid dispersions (CFZ-SDs) was optimized using a Box–Behnken design (BBD) with three factors at three levels, resulting in a total of fifteen experiments, including three central point replicates. The design space was determined using the BBD, and the optimized CFZ-SD was evaluated for reproducibility, morphology, and physical properties and subjected to in vitro and in vivo tests. Results: The optimal values for each X factor were identified using a response optimization tool, achieving a yield (Y1) of 62.8%, a solubility (Y2) of 9941 μg/mL, and a particle size (Y3) of 5.89 μm, all of which were within the 95% prediction interval (PI). Additionally, amorphization induced by spray drying was confirmed for the optimized CFZ-SD using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) analyses. In in vitro dissolution tests, the final dissolution rate of the CFZ-SD increased 3.58-fold at pH 1.2 and 3.84-fold at pH 6.8 compared to an Invokana^® tablet. In addition, relative to CFZ, it showed an 8.67-fold and 8.85-fold increase at pH 1.2 and pH 6.8, respectively. The in vivo pharmacokinetic behavior of CFZ and the CFZ-SD was evaluated in Sprague–Dawley rats following oral administration at a dose of 5 mg/kg. The AUC of the CFZ-SD increased 1.9-fold compared to that of CFZ. Conclusions: In this study, a solid dispersion (SD) formulation of CFZ, a BCS class IV SGLT2 inhibitor, was developed and optimized using a QbD approach to enhance solubility and oral bioavailability. Full article

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

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27 pages, 6020 KB

Open AccessArticle

Engineered Nanobody-Bearing Extracellular Vesicles Enable Precision Trop2 Knockdown in Resistant Breast Cancer

by Jassy Mary S. Lazarte, Mounika Aare, Sandeep Chary Padakanti, Arvind Bagde, Aakash Nathani, Zachary Meeks, Li Sun, Yan Li and Mandip Singh

Pharmaceutics 2025, 17(10), 1318; https://doi.org/10.3390/pharmaceutics17101318 - 11 Oct 2025

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Abstract

Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims [...] Read more.

Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims to develop an enhanced way of targeting Trop2 expression in tumors and blocking it using extracellular vesicles (EVs) bioengineered to express a nanobody sequence against Trop2 (NB60 E). Methods: Here, a plasmid construct was designed to express the Trop2 sequence, NB60, flanked with HA tag and myc epitope and a PDGFR transmembrane domain in the C-terminal region, and was transfected into HEK293T cells for EVs isolation. The potency of NB60 E to knock down Trop2 in letrozole-resistant breast cancer cells (LTLT-Ca and MDA-MB-468 cells) was initially investigated. Thereafter, the effects of NB60 E on the cell viability and downstream signaling pathway of Trop2 via MTT assay and Western blotting were determined. Lastly, we also examined whether NB60 E treatment in Jurkat T cells affects IL-6, TNF-α, and IL-2 cytokine production by enzyme-linked immunosorbent assay (ELISA). Results: Results revealed treatment with NB60 E significantly reduced surface Trop2 expression across both cell lines by 23.5 ± 1.5% in MDA-MB-468, and 61.5 ± 1.5% in LTLT-Ca, relative to the HEK293T-derived control EVs (HEK293T E). NB60 E treatment resulted in a marked reduction in LTLT-Ca cell viability by 52.8 ± 0.9% at 48 h post-treatment. This was accompanied by downregulation of key oncogenic signaling molecules: phosphorylated ERK1/2 (p-ERK 1/2) decreased by 30 ± 4%, cyclin D1 by 67 ± 11%, phosphorylated STAT3 (p-STAT3) by 71.8 ± 1.6%, and vimentin by 40.8 ± 1.4%. ELISA analysis revealed significant decreases in IL-6 (−57.5 ± 1.5%, 7.4 ± 0.35 pg/mL) and TNF-α (−32.1 ± 0.3%, 6.1 ± 1.2 pg/mL) levels, coordinated by an increase in IL-2 secretion (22.1 ± 2.7%, 49.2 ± 1.1 pg/mL). Quantitative analysis showed marked reductions in the number of nodes (−45 ± 4.4%), junctions (−55 ± 3.5%), and branch points (−38 ± 1.2%), indicating suppression of angiogenic capacity. In vivo experiment using near-infrared Cy7 imaging demonstrated rapid and tumor-selective accumulation of NB60 E within 4 h post-administration, followed by efficient systemic clearance by 24 h. The in vivo results demonstrate the effectiveness of NB60 E in targeting Trop2-enriched tumors while being efficiently cleared from the system, thus minimizing off-target interactions with normal cells. Lastly, Trop2 expression in LTLT-Ca tumor xenografts revealed a significant reduction of 41.0 ± 4% following NB60 E treatment, confirming efficient targeted delivery. Conclusions: We present a first-in-field NB60 E-grafted EV therapy that precisely homes to Trop2-enriched breast cancers, silences multiple growth-and-invasion pathways, blocks angiogenesis, and rewires cytokine crosstalk, achieving potent antitumor effects with self-clearing, biomimetic carriers. Our results here show promising potential for the use of NB60 E as anti-cancer agents, not only for letrozole-resistant breast cancer but also for other Trop2-expressing cancers. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Targeted Delivery)

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2 pages, 402 KB

Open AccessCorrection

Correction: Si et al. Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment. Pharmaceutics 2020, 12, 1079

by Yingnan Si, JiaShiung Guan, Yuanxin Xu, Kai Chen, Seulhee Kim, Lufang Zhou, Renata Jaskula-Sztul and X. Margaret Liu

Pharmaceutics 2025, 17(10), 1317; https://doi.org/10.3390/pharmaceutics17101317 - 11 Oct 2025

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Abstract

In the original publication [...] Full article

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22 pages, 1393 KB

Open AccessArticle

Metrological Evaluation of Metopimazine HPLC Assay: ISO-GUM and Monte Carlo Simulation Approaches

by Hasnaa Haidara, Eman A. Assirey, Taoufiq Saffaj and Bouchaib Ihssane

Pharmaceutics 2025, 17(10), 1316; https://doi.org/10.3390/pharmaceutics17101316 - 10 Oct 2025

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Abstract

Background: Measurement uncertainty (MU) is a crucial parameter for ensuring the reliability of analytical methods and the validity of results, as required by ISO 17025:2017. Its estimation is particularly critical for quality control laboratories, where compliance decisions are based on a rigorous [...] Read more.

Background: Measurement uncertainty (MU) is a crucial parameter for ensuring the reliability of analytical methods and the validity of results, as required by ISO 17025:2017. Its estimation is particularly critical for quality control laboratories, where compliance decisions are based on a rigorous interpretation of uncertainties. Methods: In this study, we evaluated the uncertainty associated with an HPLC-UV method for the determination of Metopimazine (MPZ) in a pharmaceutical form, applying two complementary approaches: The ISO-GUM (Guide to the Expression of Uncertainty in Measurement) top-down approach and the Monte Carlo Simulation (MCS). Results: The results of both approaches showed excellent agreement, thus validating the robustness of the evaluation. The analysis of uncertainty sources revealed that the accuracy of the sample volume (V_Sample) and the calibration standard (C_x) were the dominant contributors, representing 39.9% and 36.2% of the total uncertainty, respectively. Combined, these two factors accounted for 76.1% of the variability, underscoring their critical impact on the assay’s precision. The expanded uncertainty (k = 2, 95% confidence level) was determined to be (99.41 ± 0.69)%, reflecting the method’s reproducibility. Conclusions: These results highlight the importance of rigorously controlling calibration standard preparation, sample volume, and repeatability conditions to optimize the reliability of the assay. Full article

(This article belongs to the Special Issue Advances in the Preparation and Technology of Pharmaceutical Solid Dosage Forms)

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31 pages, 1047 KB

Open AccessReview

Translational Advances in Lipid Nanoparticle Drug Delivery Systems for Cancer Therapy: Current Status and Future Horizons

by Hari Krishnareddy Rachamala

Pharmaceutics 2025, 17(10), 1315; https://doi.org/10.3390/pharmaceutics17101315 - 10 Oct 2025

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Abstract

Lipid nanoparticles/liposomes (LNPs) represent a highly adaptable nanocarrier system that has gained significant traction in oncology for both therapeutic and diagnostic (theranostic) purposes. Their structural flexibility, biocompatibility, and capacity to encapsulate diverse therapeutic agents ranging from chemotherapeutics to nucleic acids and imaging tracers [...] Read more.

Lipid nanoparticles/liposomes (LNPs) represent a highly adaptable nanocarrier system that has gained significant traction in oncology for both therapeutic and diagnostic (theranostic) purposes. Their structural flexibility, biocompatibility, and capacity to encapsulate diverse therapeutic agents ranging from chemotherapeutics to nucleic acids and imaging tracers have enabled targeted cancer treatment with improved efficacy and reduced systemic toxicity. This review critically examines liposome-based platforms across a broad spectrum of cancers, including melanoma, lung, colorectal, liver, breast, ovarian, pancreatic, brain tumors, sarcoma, neuroblastoma, and leukemia. It outlines recent advances in ligand-mediated targeting, pH- and temperature-responsive release systems, and multifunctional LNPs capable of delivering combined therapeutic and imaging payloads. Moreover, the review discusses preclinical outcomes, current clinical trial status, and the challenges hindering clinical translation. By integrating recent innovations and emphasizing translational potential, this work highlights the pivotal role of LNPs in advancing precision cancer therapeutics and diagnostics. Full article

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

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35 pages, 9436 KB

Open AccessArticle

Coated Zein Polymeric Nanoparticles Loaded with Amlodipine as a Repurposed Antibacterial Ocular Cure for MRSA-Induced Infection: Optimization, In Vitro, Ex Vivo, and In Vivo Assessments

by Alaa S. Eita, Amna M. A. Makky, Asem Anter and Islam A. Khalil

Pharmaceutics 2025, 17(10), 1314; https://doi.org/10.3390/pharmaceutics17101314 - 10 Oct 2025

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Abstract

Background: Amlodipine besylate (AML) is recognized as a calcium channel blocker curative for hypertension. However, the drug emerged recently as an antibacterial cure that competently prevails over resistant strains. Methods: Incorporating amlodipine into zein nanoparticles was employed to innovate a suitable carrier for [...] Read more.

Background: Amlodipine besylate (AML) is recognized as a calcium channel blocker curative for hypertension. However, the drug emerged recently as an antibacterial cure that competently prevails over resistant strains. Methods: Incorporating amlodipine into zein nanoparticles was employed to innovate a suitable carrier for loading and targeting deep corneal infection. The Box–Behnken design was adopted to produce various formulations of amlodipine-loaded zein nanoparticles (AML-ZNs) with diversity in composition concentration (% w/v), comprising zein, Labrafac, and poloxamer 407. Results: Relying on the optimization criterion, the chosen preference formulation concentration (% w/v) consists of 2.068 for zein, 0.75 for Labrafac, and 1.0 for Poloxamer. Morphological micrography of AML-ZNs showed regular spherical particles in the nanometric scale, and physicochemical characterization procedures confirmed system suitability. While tracking eyedrop optimum features, sodium alginate was selected for coating nanoparticles to improve stability and system viscosity. Both pH and sterility were also considered and maintained. Comparative studies were conducted pre- and post-coating, and the assessed features for the final selected formulation were 349.9 ± 5.8 nm, 0.2186 ± 0.0271, −55.45 ± 1.84 mV, 81.293 ± 0.9%, and 19.3 ± 0.19 cp for size, PDI, surface charge, entrapment, and viscosity, respectively. The AML-ZNs-Alg formulation demonstrates a more controlled pattern of release of roughly 40% of the drug released after 48 h, while the permeation profile shows 37 ± 3.52% permeated after 24 h, confirmed visually. In vitro microbial assay alongside the corneal in vivo microbial and histological pathology evaluation proved the efficacy of amlodipine as an antibacterial agent. Conclusions: These findings highlighted that the prepared AML-ZNs-Alg eyedrop can be a promising system as an antibacterial therapy. Full article

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

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31 pages, 1024 KB

Open AccessReview

Polymer-Based Scaffolds Incorporating Selected Essential Oil Components for Wound Healing: A Review

by Vuyolwethu Khwaza and Opeoluwa O. Oyedeji

Pharmaceutics 2025, 17(10), 1313; https://doi.org/10.3390/pharmaceutics17101313 - 9 Oct 2025

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Abstract

Background: The treatment of wounds remains a significant clinical challenge, particularly in chronic and infected wounds, where delayed healing often results in complications. Recent advances in biomaterials have highlighted the potential of polymer-based scaffolds as promising platforms for wound management due to their [...] Read more.

Background: The treatment of wounds remains a significant clinical challenge, particularly in chronic and infected wounds, where delayed healing often results in complications. Recent advances in biomaterials have highlighted the potential of polymer-based scaffolds as promising platforms for wound management due to their ability to mimic the extracellular matrix, support tissue regeneration, and provide a moist environment conducive to healing. Objectives: This review aims to provide a comprehensive overview of the recent progress in the design and application of polymer-based scaffolds loaded with essential oil (EO) components, emphasizing their role in promoting effective wound healing. Methods: Relevant literature on polymeric scaffolds and EO-based bioactive agents was systematically reviewed, focusing on studies that investigated the biological activities, fabrication techniques, and therapeutic performance of EO-loaded scaffolds in wound management. Results: Findings from recent studies indicate that EO components, particularly monoterpenoids such as thymol, carvacrol, and eugenol, exhibit remarkable antimicrobial, anti-inflammatory, antioxidant, and analgesic properties that accelerate wound healing. When incorporated into polymer matrices, these components enhance scaffold biocompatibility, antimicrobial efficacy, and tissue regeneration capacity through synergistic interactions. Conclusions: The integration of essential oil components into polymeric scaffolds represents a promising strategy for developing multifunctional wound dressings. Such systems combine the structural advantages of polymers with the therapeutic benefits of EOs, offering an effective platform for accelerating healing and preventing wound infections. Full article

(This article belongs to the Special Issue Advances in Drug Delivery Systems for the Treatment of Chronic Wound Healing)

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24 pages, 9190 KB

Open AccessArticle

Targeting Glycolysis with 2-Deoxy-D-Glucose and Lysosomal Integrity with L-Leucyl-L-Leucine Methyl Ester as Antimelanoma Strategy

by Milica Kosic, Mihajlo Bosnjak, Milos Mandic, Ljubica Vucicevic, Maja Misirkic Marjanovic, Sofie Espersen Poulsen and Ljubica Harhaji-Trajkovic

Pharmaceutics 2025, 17(10), 1312; https://doi.org/10.3390/pharmaceutics17101312 - 9 Oct 2025

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Abstract

Background/Objectives: Melanoma cells enhance glycolysis and expand lysosomes to support energy metabolism, proliferation, and metastasis. However, lysosomal membrane permeabilization (LMP) causes cathepsin leakage into cytosol triggering cytotoxicity. This study investigated the antimelanoma effect of 2-deoxy-D-glucose (2DG), an inhibitor of glycolytic enzyme hexokinase-2, [...] Read more.

Background/Objectives: Melanoma cells enhance glycolysis and expand lysosomes to support energy metabolism, proliferation, and metastasis. However, lysosomal membrane permeabilization (LMP) causes cathepsin leakage into cytosol triggering cytotoxicity. This study investigated the antimelanoma effect of 2-deoxy-D-glucose (2DG), an inhibitor of glycolytic enzyme hexokinase-2, in combination with cathepsin C-dependent LMP inducer L-leucyl-L-leucine methyl ester (LLOMe) and cathepsin C-independent LMP-inducers mefloquine and siramesine. Methods: The viability of A375 and B16 melanoma cells and primary fibroblasts was measured by crystal violet. Apoptosis, necrosis, and LMP were assessed by flow cytometry; caspase activation, mitochondrial depolarization, superoxide production, and energy metabolism were analyzed by fluorimetry, and expression of cathepsins and hexokinase-2 was evaluated by immunoblot. Appropriate inhibitors, antioxidant, and energy boosters were used to confirm cell death type and mechanism. Results: LLOMe triggered LMP, mitochondrial depolarization, and mitochondrial superoxide production, while suppressing oxidative phosphorylation. 2DG suppressed glycolysis and, together with LLOMe, synergized in ATP depletion, caspase activation, and mixed apoptosis and necrosis in A375 cells. Inhibitors of lysosomal acidification, cysteine cathepsins, and caspases, as well as antioxidant and energy boosters, reduced 2DG+LLOMe-induced toxicity. Cathepsins B, C, and D were lower, while hexokinase-2 was higher in A375 cells than fibroblasts. Accordingly, 2DG exhibited lower while LLOMe exhibited higher toxicity against fibroblasts than A375 and B16 cells. However, mefloquine and siramesine induced stronger LMP in A375 cells than in fibroblasts and showed melanoma-selective toxicity when combined with 2DG. Conclusions: 2DG-mediated glycolysis inhibition in combination with lysosomal destabilization induced by mefloquine and siramesine, but not with non-selectively toxic LLOMe, may be promising antimelanoma strategy. Full article

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

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24 pages, 4100 KB

Open AccessArticle

Comparative In Vitro Evaluation of Buccal Films, Microcapsules, and Liposomal Systems for Naringin and Citrus × paradisi L. Peel Extract: Effects of Encapsulation Strategy and Compound Origin on Release Profiles

by Jolita Stabrauskiene, Mindaugas Marksa and Jurga Bernatoniene

Pharmaceutics 2025, 17(10), 1311; https://doi.org/10.3390/pharmaceutics17101311 - 9 Oct 2025

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Abstract

Background/Objectives: Citrus × paradisi Macfad., Rutaceae. peel is a rich source of naringin (NR), but its poor solubility and low bioavailability limit applications. This study aimed to improve NR delivery by comparing microencapsulation, liposomal microencapsulation, and buccal films containing either pure NR [...] Read more.

Background/Objectives: Citrus × paradisi Macfad., Rutaceae. peel is a rich source of naringin (NR), but its poor solubility and low bioavailability limit applications. This study aimed to improve NR delivery by comparing microencapsulation, liposomal microencapsulation, and buccal films containing either pure NR or grapefruit peel extract. Methods: Four spray-dried powder formulations—spray-dried NR (NS), liposomal NR (NLS), spray-dried extract (ES), and liposomal extract (ELS)—were produced using maltodextrin, β-cyclodextrin, and HPMC as wall materials. Buccal films (EP1, EP2, NP1, NP2) were prepared via solvent casting with HPMC, alginate (ALG), or polyvinyl alcohol (PVA). All samples were evaluated for solubility, moisture content, mucoadhesion, and in vitro release under simulated gastric, intestinal, and salivary conditions. Results: NR powders had the highest absolute solubility (306.42 ± 10.34 µg/mL), whereas ELS showed the lowest due to low loading. However, relative to theoretical NR content, ELS achieved the highest dissolution efficiency (55.3%), followed by NLS (42.7%), outperforming NS (5.6%) and ES (91.8%) in sustained release potential. Dual encapsulation (NLS, ELS) slowed gastric release and maintained intestinal delivery, while non-liposomal powders released rapidly. In buccal films, NP2 (NR + PVA) showed the highest release (69.97 ± 3.01 µg/mL; 40.9% efficiency) and strongest mucoadhesion (0.47 N·s). Extract-based films had lower absolute NR release but higher relative efficiency to content, likely due to co-extracted compounds enhancing wettability and matrix erosion. Conclusions: Liposomal microencapsulation improves relative dissolution efficiency and sustains intestinal release, while PVA-based buccal films enhance both release and mucoadhesion. Polymer choice and active ingredient composition are critical for optimising oral delivery of NR. These results demonstrate the potential of the proposed systems in the pharmaceutical or dietary supplement field, especially in improving the oral delivery of poorly soluble flavonoids. A graphical summary is included, visually summarising the main formulation strategies and results. Full article

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

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26 pages, 3302 KB

Open AccessReview

Improving In Vitro–In Vivo Correlation (IVIVC) for Lipid-Based Formulations: Overcoming Challenges and Exploring Opportunities

by Arnaud Bourderi-Cambon, Khaled Fadhlaoui, Ghislain Garrait, Emmanuelle Lainé, Imen Dhifallah, Manon Rossano, Philippe Caisse and Eric Beyssac

Pharmaceutics 2025, 17(10), 1310; https://doi.org/10.3390/pharmaceutics17101310 - 9 Oct 2025

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Abstract

Lipid-based formulations (LBFs) play a crucial role in enhancing the oral bioavailability of poorly water-soluble drugs by leveraging lipid digestion and solubilization processes. However, developing robust in vitro–in vivo correlations (IVIVCs) for LBFs presents unique challenges due to the complex interplay of digestion, [...] Read more.

Lipid-based formulations (LBFs) play a crucial role in enhancing the oral bioavailability of poorly water-soluble drugs by leveraging lipid digestion and solubilization processes. However, developing robust in vitro–in vivo correlations (IVIVCs) for LBFs presents unique challenges due to the complex interplay of digestion, permeation, and dynamic solubilization. This article reviews the construction of IVIVC in the context of LBFs, highlighting the limitations of traditional methods and the need for tailored approaches. It examines the in vitro tools commonly employed for LBF characterization, such as USP dissolution tests, lipolysis assays, and combined models, and discusses their relevance to in vivo performance prediction. The review also explores the sources of in vivo data essential for validating IVIVC and describes the most popular in silico tools for predicting in vivo performance, focusing on lipid-based formulations. This work aims to pave the way for more effective and adaptable IVIVC methodologies for lipid-based drug delivery systems. Full article

(This article belongs to the Special Issue Optimizing Pharmacokinetics Through Formulation Science and Technology)

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36 pages, 4341 KB

Open AccessReview

Physiological Barriers to Nucleic Acid Therapeutics and Engineering Strategies for Lipid Nanoparticle Design, Optimization, and Clinical Translation

by Yerim Kim, Jisu Park, Jaewon Choi, Minse Kim, Gyeongsu Seo, Jeongeun Kim, Jeong-Ann Park, Kwang Suk Lim, Suk-Jin Ha and Hyun-Ouk Kim

Pharmaceutics 2025, 17(10), 1309; https://doi.org/10.3390/pharmaceutics17101309 - 8 Oct 2025

Viewed by 504

Abstract

Lipid nanoparticles are a clinically validated platform for delivering nucleic acids, but performance is constrained by multiscale physiological barriers spanning circulation, vascular interfaces, extracellular matrices, cellular uptake, and intracellular trafficking. This review links composition–structure–function relationships for ionizable lipids, helper phospholipids, cholesterol, and PEG-lipids [...] Read more.

Lipid nanoparticles are a clinically validated platform for delivering nucleic acids, but performance is constrained by multiscale physiological barriers spanning circulation, vascular interfaces, extracellular matrices, cellular uptake, and intracellular trafficking. This review links composition–structure–function relationships for ionizable lipids, helper phospholipids, cholesterol, and PEG-lipids to systemic fate, endothelial access, endosomal escape, cytoplasmic stability, and nuclear transport. We outline strategies for tissue and cell targeting, including hepatocyte ligands, immune and tumor selectivity, and selective organ targeting through compositional tuning, together with approaches that modulate escape using pH-responsive chemistries or fusion-active peptides and polymers. We further examine immunomodulatory co-formulation, route and schedule effects on biodistribution and immune programming, and manufacturing and stability levers from microfluidic mixing to lyophilization. Across these themes, we weigh trade-offs between stealth and engagement, potency and tolerability, and potency and manufacturability, noting that only a small fraction of endosomes supports productive release and that protein corona variability and repeat dosing can reshape tropism and clearance. Convergence of standardized assays for true cytosolic delivery, biomarker-guided patient selection, and robust process controls will be required to extend LNP therapeutics beyond the liver while sustaining safety, access, and scale. Full article

(This article belongs to the Special Issue Recent Advances in Non-Viral Vectors for Gene Therapy and Gene Delivery)

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33 pages, 2345 KB

Open AccessArticle

Formulation and Testing of Alginate Microbeads Containing Salvia officinalis Extract and Prebiotics

by Krisztina Bodnár, Pálma Fehér, Zoltán Ujhelyi, Ádám Haimhoffer, Boglárka Papp, Dávid Sinka, Csongor Freytag, Eszter Fidrus, Krisztina Szarka, Gábor Kardos, Fruzsina Nacsa, Ildikó Bácskay and Liza Józsa

Pharmaceutics 2025, 17(10), 1308; https://doi.org/10.3390/pharmaceutics17101308 - 8 Oct 2025

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Abstract

Background/Objectives: This study aimed to develop an advanced oral delivery platform for Salvia officinalis (S. officinalis) extract by co-encapsulating it with inulin and pectin in alginate-based microbeads, formulated via ionic gelation. Methods: The microbeads were comprehensively characterized, including the [...] Read more.

Background/Objectives: This study aimed to develop an advanced oral delivery platform for Salvia officinalis (S. officinalis) extract by co-encapsulating it with inulin and pectin in alginate-based microbeads, formulated via ionic gelation. Methods: The microbeads were comprehensively characterized, including the assessment of morphology, particle size, encapsulation efficiency, swelling behavior, in vitro dissolution, and enzymatic stability, and Caco-2 cell-based assays for cytocompatibility, permeability, and transepithelial electrical resistance. Antioxidant capacity and anti-inflammatory effects were also evaluated. Results: The resulting microbeads (~275 µm) achieved > 90% encapsulation efficiency and exhibited pronounced swelling (~90%). The release of S. officinalis constituents displayed pH sensitivity, with sustained release in simulated intestinal fluid, alongside significant enhancement of enzymatic stability. Encapsulation led to markedly improved permeability of bioactive compounds across Caco-2 monolayers, attributable to reversible modulation of tight junctions. Encapsulated extract retained potent antioxidant activity and significantly reduced pro-inflammatory cytokines. The formulation, across various concentrations, further promoted the growth and viability of Lactobacillus strains. Conclusions: Collectively, these findings demonstrate that alginate–inulin–pectin microbeads provide a multifunctional system for stabilizing S. officinalis extract, enabling controlled release, enhanced intestinal absorption, and maintained bioefficacy. Importantly, the formulation also promoted Lactobacillus viability, indicating a prebiotic effect and offering considerable potential for improved oral therapeutic applications. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds in Micro- and Nanocarriers)

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22 pages, 2533 KB

Open AccessArticle

DST-3, a Novel Modified Cryptotanshinone, Protects Against Pulmonary Fibrosis via Inhibiting STAT3/Smad Signaling Pathway and Improves Bioavailability

by Ruoqing Guan, Xiangjun He, Yuxing Dai, Guangye Huang, Zhaoyun Xue, Jianwen Chen and Peiqing Liu

Pharmaceutics 2025, 17(10), 1307; https://doi.org/10.3390/pharmaceutics17101307 - 8 Oct 2025

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Abstract

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive loss of lung function and poor prognosis. Cryptotanshinone (CTS), a small-molecule compound extracted from Salvia miltiorrhiza, possesses diverse pharmacological activities but suffers from poor oral bioavailability, which restricts its [...] Read more.

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive loss of lung function and poor prognosis. Cryptotanshinone (CTS), a small-molecule compound extracted from Salvia miltiorrhiza, possesses diverse pharmacological activities but suffers from poor oral bioavailability, which restricts its clinical development, particularly in pulmonary fibrosis. DST-3, a newly synthesized derivative of CTS, was designed to overcome these limitations. Methods: The antifibrotic effects of DST-3 were investigated in a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice through lung function assessment, histopathological evaluation, hydroxyproline quantification, and cytokine profiling. In vitro, TGF-β1-stimulated MRC5 fibroblasts were employed to explore the mechanism of action, focusing on STAT3/Smad signaling via Western blotting and molecular binding assays. Furthermore, a validated HPLC–MS/MS method was developed for DST-3, and its pharmacokinetic profile was characterized in Sprague–Dawley rats and compared with that of CTS. Results: DST-3 markedly attenuated pulmonary fibrosis in vivo, as evidenced by improved lung function, reduced collagen deposition, and decreased proinflammatory cytokine levels. In vitro, DST-3 inhibited TGF-β1-induced fibroblast activation by directly binding to STAT3 and suppressing STAT3/Smad signaling. Pharmacokinetic analysis demonstrated that, compared with CTS, DST-3 exhibited more rapid absorption, a higher peak plasma concentration, a greater area under the curve (AUC), improved hepatic metabolic stability, and enhanced lung tissue exposure. Conclusions: Our study demonstrates that DST-3 exerts potent antifibrotic effects in vivo and in vitro, primarily through STAT3 pathway inhibition. Its improved pharmacokinetic characteristics further support its potential as a promising candidate for the treatment of pulmonary fibrosis. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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23 pages, 5760 KB

Open AccessArticle

Effect of Crosslinking Using Heat on the Physicochemical Features of Bsa–Capsaicin Nanoparticles

by Lino Sánchez-Segura, Silvio Zaina, Angela F. Kú-González, José Alfredo Guzmán-López, Laura E. Zavala-García and Mercedes G. López

Pharmaceutics 2025, 17(10), 1306; https://doi.org/10.3390/pharmaceutics17101306 - 8 Oct 2025

Viewed by 311

Abstract

Background/Objectives: The synthesis of protein nanoparticles (NPs) using the coacervation method is influenced by critical parameters. The use of glutaraldehyde limits the pharmacological applications of NPs in humans due to the potential toxicity of residual aldehydes that remain after the purification of [...] Read more.

Background/Objectives: The synthesis of protein nanoparticles (NPs) using the coacervation method is influenced by critical parameters. The use of glutaraldehyde limits the pharmacological applications of NPs in humans due to the potential toxicity of residual aldehydes that remain after the purification of the nanoparticles. The aim was to assess heat effect as a crosslinking agent for the synthesis of bovine serum albumin (BSA)–capsaicin nanoparticles and its effect on the physicochemical characteristics of nanoparticles. Results: The initial concentrations of BSA and capsaicin in the formulation were directly correlated with the amount of BSA that was transformed into nanoparticles and the loaded capsaicin (r = 0.97, p = 0.0003 and r = 0.95, p = 0.0003), respectively. Furthermore, the morphometric parameters of nanoparticles were affected by the increase in capsaicin concentration, but not by temperature. The nanoparticles increased in dimensions and showed a loss of shape due to coalescence between nanoparticles. The ζ-potential decreased with the increase in the concentration of capsaicin added. This effect compromised the stability of the nanoparticles; on the other hand, molecular interactions were observed between hydrophobic residues of phenylalanine and tyrosine in BSA and the hydrophobic moiety of capsaicin. At the same time, BSA nanoparticles showed a potential for disassembling and delivering the payload capsaicin, which caused an antisteatotic effect in the liver of a murine model. Conclusions: heat (70 °C) can replace crosslinking agents, such as glutaraldehyde. This property is particularly useful when an aldehyde-free synthesis of BSA nanoparticles is needed. Full article

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

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30 pages, 1628 KB

Open AccessReview

RNA Therapeutics: Delivery Problems and Solutions—A Review

by Natalia Pozdniakova, Evgenii Generalov, Alexei Shevelev and Olga Tarasova

Pharmaceutics 2025, 17(10), 1305; https://doi.org/10.3390/pharmaceutics17101305 - 7 Oct 2025

Viewed by 783

Abstract

RNA-based therapeutics offer transformative potential for treating devastating diseases. However, current RNA delivery technologies face significant hurdles, including inefficient tissue targeting, insufficient selectivity, and severe side effects, leading to the termination of many clinical trials. This review critically assesses the landscape of RNA-derived [...] Read more.

RNA-based therapeutics offer transformative potential for treating devastating diseases. However, current RNA delivery technologies face significant hurdles, including inefficient tissue targeting, insufficient selectivity, and severe side effects, leading to the termination of many clinical trials. This review critically assesses the landscape of RNA-derived medicines, examining world-renowned mRNA vaccines (Spikevax, BNT162b2/Comirnaty) and RNA-based therapeutics like Miravirsen (anti-miR-122). It details the composition and clinical trial results of numerous modified short RNA drugs (e.g., siRNAs, miRNA mimetics/inhibitors) targeting various conditions. Prospects for RNA-based medicines are analysed for diseases with substantial societal impact, such as cancer, autoimmune disorders, and infectious diseases, with a focus on evolving delivery methods, including lipid nanoparticles, viral vectors, and exosomes. RNA-mediated macrophage reprogramming emerges as a promising strategy, potentially enhancing both delivery and clinical efficacy. This review highlights that while approved RNA therapies primarily target rare diseases due to delivery limitations, novel approaches in RNA modification, targeted delivery systems, and enhanced understanding of molecular mechanisms are crucial for expanding their application to prevalent diseases and unlocking their full therapeutic potential. Full article

(This article belongs to the Special Issue RNA-Based Vaccines and Therapeutics)

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18 pages, 4627 KB

Open AccessArticle

The Potential of Thymus zygis L. (Thyme) Essential Oil Coating in Preventing Vulvovaginal Candidiasis on Intrauterine Device (IUD) Strings

by Gulcan Sahal, Hanife Guler Donmez, Herman J. Woerdenbag, Abbas Taner and Mehmet Sinan Beksac

Pharmaceutics 2025, 17(10), 1304; https://doi.org/10.3390/pharmaceutics17101304 - 7 Oct 2025

Viewed by 349

Abstract

Background/Objectives: Fungal colonization and biofilm formation on intrauterine device (IUD) strings are known to contribute to recurrent infections and decreased contraceptive efficacy. This study aims to develop a novel approach to prevent Candida reservoir and biofilm formation on IUD strings, thereby lowering the [...] Read more.

Background/Objectives: Fungal colonization and biofilm formation on intrauterine device (IUD) strings are known to contribute to recurrent infections and decreased contraceptive efficacy. This study aims to develop a novel approach to prevent Candida reservoir and biofilm formation on IUD strings, thereby lowering the risk of IUD-associated vulvovaginal candidiasis (VVC). Methods: Cervicovaginal samples were collected from human cervix using a sterile cytobrush, avoiding microbial contamination. Cytological examination using the Papanicolaou method was performed to detect the presence of Candida. The antifungal effect of the essential oils (EOs) was determined by broth dilution and disk diffusion methods. Antifungal and biofilm inhibitory effects of Thymus zygis (Tz) EO-coated IUD strings were determined by agar diffusion and crystal violet binding assays, while fungal growth on the coated strings was assessed using Scanning Electron Microscopy (SEM) and Energy-Dispersive X-ray (EDX) analysis. Results: Tz EO exhibited significantly lower minimum inhibitory concentration (MIC ≤ 0.06 µL/mL) and minimum fungicidal concentration (MFC = 0.24 µL/mL) values compared to Melaleuca alternifolia (Ma) EO (MIC > 0.24 µL/mL, MFC = 1.95 µL/mL), along with larger zones of inhibition (ZOI) against both Candida albicans (110.0 ± 6.0 mm vs. 91.3 ± 7.0 mm) and Candida glabrata (84.0 ± 13.1 mm vs. 50.0 ± 9.2 mm), indicating a stronger antifungal potential. On IUD strings coated with 4% (40 μL/g) Tz EO in hypromellose ointment, the biofilm formation of both C. albicans and C. glabrata strains was inhibited by 58.9% and 66.7%, respectively, as confirmed by SEM and EDX. Conclusions: Tz EO-coated IUD strings effectively inhibit Candida growth, suggesting a promising natural strategy to reduce recurrent IUD-associated fungal infections. However, before these results can be translated to clinical practice, additional research is needed. Future investigations may encompass an extended number of Candida isolates, stability and release studies of the EO in relation to the formulation, toxicity to vaginal mucosa, epithelial cells and sperm motility, and the effect on vaginal microbiotia. Full article

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

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Pharmaceutics, Volume 17, Issue 10 (October 2025) – 96 articles

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