Pharmaceutics

21 pages, 9795 KiB

Open AccessArticle

Physicochemical Characterization and Oral Bioavailability of Curcumin–Phospholipid Complex Nanosuspensions Prepared Based on Microfluidic System

by Bo Zhang, Wenjing Guo, Zhenyu Chen, Yaxin Chen, Ruining Zhang, Minchen Liu, Jian Yang and Jiquan Zhang

Pharmaceutics 2025, 17(3), 395; https://doi.org/10.3390/pharmaceutics17030395 - 20 Mar 2025

Viewed by 396

Abstract

Background: Curcumin has been proved to have promising prospects in the fields of anti-inflammation, antibacterial, anti-oxidation, and neuroprotection. However, its poor water solubility and stability in strong acid, as well as fast metabolism, lead to low bioavailability, making it difficult to develop [...] Read more.

Background: Curcumin has been proved to have promising prospects in the fields of anti-inflammation, antibacterial, anti-oxidation, and neuroprotection. However, its poor water solubility and stability in strong acid, as well as fast metabolism, lead to low bioavailability, making it difficult to develop further. This study aimed to improve the bioavailability of curcumin by using microfluidic preparation technology. Methods: Using a self-built microfluidic system, polyvinylpyrrolidone K30 and sodium dodecyl sulfate were used as stabilizers to further prepare curcumin–phospholipid complex nanoparticles (CPC-NPs) on the basis of curcumin–phospholipid complex (CPC). The CPC-NPs were characterized and evaluated by X-ray powder diffraction (XRD), differential scanning caborimetry (DSC), dynamic light scattering, and transmission electron microscopy (TEM). Blood samples were collected from rats after oral administration of curcumin, CPC, curcumin nanoparticles (CUR-NPs), and CPC-NPs, respectively. The pharmacokinetics were analyzed by enzymatic digestion and HPLC. Results: The optimized CPC-NPs had a particle size of 71.19 ± 1.37 nm, a PDI of 0.226 ± 0.047, and a zeta potential of −38.23 ± 0.89 mV, which showed a spherical structure under TEM and good stability within 5 days at 4 °C and 25 °C. It was successfully characterized by XRD combined with DSC, indicating the integrational state of curcumin–soy lecithin and conversion to an amorphous form. The results of the pharmacokinetic study showed that the C_max of curcumin, CUR-NPs, CPC, and CPC-NPs were 133.60 ± 28.10, 270.23 ± 125.42, 1894.43 ± 672.65, and 2163.87 ± 777.36 ng/mL, respectively; the AUC_0–t of curcumin, CUR-NPs, CPC, and CPC-NPs were 936.99 ± 201.83, 1155.46 ± 340.38, 5888.79 ± 1073.32, and 9494.28 ± 1863.64 ng/mL/h. Conclusions: CPC-NPs prepared by microfluidic technology had more controllable quality than that of traditional preparation and showed superior bioavailability compared with free drug, CPC, and CUR-NPs. Pharmacodynamic evaluation of anti-inflammatory, anti-oxidation, and neuroprotection needs to be confirmed in follow-up studies. Full article

(This article belongs to the Special Issue Synthesis of Microfluidic-Based Nanoparticles and Their Potential Applications in Drug Delivery Systems)

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57 pages, 1992 KiB

Open AccessReview

The 20th Anniversary of Pegaptanib (MacugenTM), the First Approved Aptamer Medicine: History, Recent Advances and Future Prospects of Aptamers in Therapy

by Miklós Bege, Rasha Ghanem Kattoub and Anikó Borbás

Pharmaceutics 2025, 17(3), 394; https://doi.org/10.3390/pharmaceutics17030394 - 20 Mar 2025

Viewed by 621

Abstract

In addition to classic small-molecule drugs and modern protein-based biologics, an intriguing class of medicines is the therapeutic oligonucleotides. Most approved drugs in this category are antisense oligomers or those acting via RNA interference, both of which use base hybridization. Aptamers, also known [...] Read more.

In addition to classic small-molecule drugs and modern protein-based biologics, an intriguing class of medicines is the therapeutic oligonucleotides. Most approved drugs in this category are antisense oligomers or those acting via RNA interference, both of which use base hybridization. Aptamers, also known as chemical antibodies form a smaller, yet equally interesting group of oligonucleotides that can recognize a wide range of molecular targets. Despite their high potential, only two aptamers have been approved to date, pegaptanib (MacugenTM) and avacincaptad pegol (IzervayTM), both for the treatment of age-related macular degeneration (AMD). Targeting vascular endothelial growth factor (VEGF), which plays an important role in the pathogenesis of many eye diseases, pegaptanib emerged as the first anti-VEGF agent and was used in various indications, further inspiring the development of other anti-VEGF therapies. In this review, we summarize the history of the first approved aptamer medicine, pegaptanib. We describe its chemistry and track its development from the earliest stages to the preclinical phase, clinical trials, and eventual regulatory approval. Additionally, we evaluate its position among other therapeutic agents and provide a comprehensive overview of pegaptanib’s efficacy, safety, and cost-effectiveness, comparing these aspects with those of monoclonal antibodies with similar indications, bevacizumab and ranibizumab. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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15 pages, 2644 KiB

Open AccessArticle

Harnessing Silver Nanoclusters to Combat Staphylococcus aureus in the Era of Antibiotic Resistance

by Julieta Chiappero, Gustavo A. Monti, Diego F. Acevedo, Natalia S. Paulucci and Edith I. Yslas

Pharmaceutics 2025, 17(3), 393; https://doi.org/10.3390/pharmaceutics17030393 - 20 Mar 2025

Viewed by 426

Abstract

Background/Objectives: In the race to develop new antibiotics to combat multidrug-resistant bacteria, particularly the ESKAPE pathogens which pose a significant threat to public health, silver nanoclusters (AgNCs) have emerged as a promising alternative. This article focuses on the potential of novel silver [...] Read more.

Background/Objectives: In the race to develop new antibiotics to combat multidrug-resistant bacteria, particularly the ESKAPE pathogens which pose a significant threat to public health, silver nanoclusters (AgNCs) have emerged as a promising alternative. This article focuses on the potential of novel silver nanoclusters as an antimicrobial agent against Staphylococcus aureus, a high-priority pathogen known for its ability to cause persistent nosocomial infections and develop protective biofilms. Methods: In this study, we successfully synthesized AgNCs at pH 7 using an eco-friendly photoreduction method with poly acrylic acid (PAA) and poly methacrylic acid (PMAA) as stabilizers. This methodology produced fluorescent AgNCs, demonstrating their stability in aqueous solutions for at least three months and highlighting the effectiveness of PAA and PMAA as stabilizing agents. The AgNCs were incubated with S. aureus suspension, and the antimicrobial capability at different concentrations and times of incubation were determined. Also, the AgNCs hemocompatibility was studied by exposing the clusters to rat blood cells. Results: The in vitro assays revealed that AgNCs capping with PAA or PMAA has antimicrobial activity in low doses (the determination of minimum inhibitory concentration (MIC): 0.2 µg/mL, and the determination of minimum bactericidal concentration (MBC): 2 µg/mL) and without cytotoxicity (hemolysis less than 10%) to rat blood cells until 1 µg/mL. In the presence of both AgNCs (5 µg/mL), bacterial growth was completely inhibited within just 3 h. Conclusions: The findings of this study highlight the potential of silver nanoclusters as effective antimicrobial agents against S. aureus. Their stability, low toxicity, and rapid bactericidal activity make them promising candidates for further development in antimicrobial applications. Full article

(This article belongs to the Special Issue Conjugated Polymer Nanoparticles: Innovative Designs for Photodynamic and Photothermal Therapy in Cancer and Bacterial Infections—Preclinical Evaluation and Beyond)

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19 pages, 11762 KiB

Open AccessArticle

Ciprofloxacin-Loaded Spray-Dried Lactose Particles: Formulation Optimization and Antibacterial Efficacy

by Sai Liu, Simon Gaisford and Gareth R. Williams

Pharmaceutics 2025, 17(3), 392; https://doi.org/10.3390/pharmaceutics17030392 - 20 Mar 2025

Viewed by 302

Abstract

Background/Objectives: Bacterial infections in the oral cavity and outer ear require effective and targeted drug delivery systems. This study details the production of drug-loaded lactose microparticles, with the aim of creating antibiotic formulations for ultimate use in combatting oral and outer ear [...] Read more.

Background/Objectives: Bacterial infections in the oral cavity and outer ear require effective and targeted drug delivery systems. This study details the production of drug-loaded lactose microparticles, with the aim of creating antibiotic formulations for ultimate use in combatting oral and outer ear bacterial infections. Methods: Lactose particles were prepared via spray drying and optimized with varying ciprofloxacin (cipro) loadings to maximize the drug content. The particles were characterized to evaluate their performance in terms of physicochemical properties, drug-loading efficiency, drug-release kinetics, and antibacterial activity. Results: The resulting particles exhibited spherical morphology, efficient cipro loading (in the range of 1.1−52.9% w/w) and rapid cipro release within 5 h (achieving 70−81% release). In addition, they demonstrated effective concentration-dependent antibacterial activity against gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa, with bacterial growth effectively inhibited for more than 24 h when particle concentrations reached the minimum inhibitory concentration. Conclusions: These findings highlight the potential of spray-dried cipro loaded lactose particles as an efficient approach for localized antibacterial treatment, offering a promising solution for managing bacterial infections in the oral cavity and outer ear. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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16 pages, 6558 KiB

Open AccessArticle

Simvastatin-Loaded Chitosan-Functionalized PLGA Nanoparticles: Characterization and Use in Intimal Hyperplasia Therapy

by Ashley A. Peters, Chanpreet Kaur, Maleen Cabe, Kelly A. Langert, Kristopher Maier and Vivian Gahtan

Pharmaceutics 2025, 17(3), 391; https://doi.org/10.3390/pharmaceutics17030391 - 20 Mar 2025

Viewed by 391

Abstract

Background: Statins have beneficial pleiotropic effects, including reducing intimal hyperplasia (IH), but off-target effects remain a concern. Here, we tested the hypothesis that chitosan-functionalized polymeric nanoparticles (NPs) loaded with simvastatin (SL-cNPs) would (1) readily associate with endothelial cells (ECs) and vascular smooth [...] Read more.

Background: Statins have beneficial pleiotropic effects, including reducing intimal hyperplasia (IH), but off-target effects remain a concern. Here, we tested the hypothesis that chitosan-functionalized polymeric nanoparticles (NPs) loaded with simvastatin (SL-cNPs) would (1) readily associate with endothelial cells (ECs) and vascular smooth muscle cells (VSMCs); (2) affect EC and VSMC function; and (3) reduce IH compared to systemic simvastatin. Methods: Human aortic ECs and VSMCs were cultured with fluorescently labeled SL-cNPs. The association of SL-cNPs was assessed by immunostaining and flow cytometry. The effect of SL-cNPs, empty cNPs (E-cNPs), and free simvastatin on cells was determined using qRT-PCR for RhoA and RhoB. Carotid artery balloon-injured rats were treated intraoperatively with intraluminal saline, E-cNPs, low- or high-dose SL-cNPs, periadventitial high-dose SL-cNPs, or with pre- and post-operative oral simvastatin plus intraoperative intraluminal saline or low-dose SL-cNPs. Rats were euthanized (day 14) and IH was quantified. Results: SL-cNPs readily associated with ECs and VSMCs. Low- and high-dose SL-cNPs induced significant increases in EC and VSMC RhoA gene expression. High-dose SL-cNPs induced a significant increase in EC RhoB expression, while free simvastatin and low- and high-dose SL-cNPs significantly increased RhoB expression in VSMCs. In vivo, oral simvastatin plus intraluminal SL-cNPs significantly reduced IH compared to controls. Conclusions: cNPs can be used as a vehicle to locally deliver statins to vascular cells. However, other NP formulations may be preferential for IH reduction given only the combination of oral simvastatin and SL-cNPs effectively reduced IH. Full article

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

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44 pages, 3282 KiB

Open AccessReview

The Future of Medicine: How 3D Printing Is Transforming Pharmaceuticals

by Jurga Bernatoniene, Jolita Stabrauskiene, Jurga Andreja Kazlauskaite, Urte Bernatonyte and Dalia Marija Kopustinskiene

Pharmaceutics 2025, 17(3), 390; https://doi.org/10.3390/pharmaceutics17030390 - 19 Mar 2025

Viewed by 1111

Abstract

Three-dimensional printing technology is transforming pharmaceutical manufacturing by shifting from conventional mass production to additive manufacturing, with a strong emphasis on personalized medicine. The integration of bioinks and AI-driven optimization is further enhancing this innovation, enabling drug production with precise dosages, tailored drug-release [...] Read more.

Three-dimensional printing technology is transforming pharmaceutical manufacturing by shifting from conventional mass production to additive manufacturing, with a strong emphasis on personalized medicine. The integration of bioinks and AI-driven optimization is further enhancing this innovation, enabling drug production with precise dosages, tailored drug-release profiles, and unique multi-drug combinations that respond to individual patient needs. This advancement is significantly impacting healthcare by accelerating drug development, encouraging innovative pharmaceutical designs, and enhancing treatment efficacy. Traditional pharmaceutical manufacturing follows a one-size-fits-all approach, which often fails to meet the specific requirements of patients with unique medical conditions. In contrast, 3D printing, coupled with bioink formulations, allows for on-demand drug production, reducing dependency on large-scale manufacturing and storage. AI-powered design and process optimization further refine dosage forms, printability, and drug release mechanisms, ensuring precision and efficiency in drug manufacturing. These advancements have the potential to lower overall healthcare costs while improving patient adherence to medication regimens. This review explores the potential, challenges, and environmental benefits of 3D pharmaceutical printing, positioning it as a key driver of next-generation personalized medicine. Full article

(This article belongs to the Special Issue Customized Pharmaceutics: Innovations for Diverse Populations)

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19 pages, 1651 KiB

Open AccessReview

Nanotechnology-Based Therapies for Preventing Post-Surgical Adhesions

by Zi Yi Teo, Samyuktha Dhanalakshmi Senthilkumar and Dinesh Kumar Srinivasan

Pharmaceutics 2025, 17(3), 389; https://doi.org/10.3390/pharmaceutics17030389 - 19 Mar 2025

Viewed by 443

Abstract

Adhesions are the body’s natural response to various inflammatory causes, with surgery being the most common cause. However, the formation of postoperative adhesions can lead to significant complications, including intestinal obstruction and chronic pain. To prevent such postoperative complications associated with adhesions, developing [...] Read more.

Adhesions are the body’s natural response to various inflammatory causes, with surgery being the most common cause. However, the formation of postoperative adhesions can lead to significant complications, including intestinal obstruction and chronic pain. To prevent such postoperative complications associated with adhesions, developing effective strategies for adhesion prevention has been a major focus of research. Currently, several therapeutic models have been developed to achieve this objective. These include pharmaceuticals, inert polymers, functional biomaterials, and nanotherapeutics. Among the various strategies developed, nanotherapeutics, though still in its early stages, has shown promise as a potential approach. Other therapeutic models are associated with adverse side effects and complications related to their application. On the other hand, nanotherapeutic models are able to overcome the limitations of the other strategies and provide their own set of unique advantages. Hence, nanotherapeutics represents a promising area for further research. Further efforts should be made to refine existing nanotherapeutics for clinical application while also addressing associated safety and ethical concerns related to their use in medical practice. Therefore, this article aims to review the various nanotherapeutic approaches developed for the prevention of postoperative adhesions, explore their regulatory pathways, and discuss associated safety and ethical concerns. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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31 pages, 4979 KiB

Open AccessReview

Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles

by Yuan Zou, Jing Zhang, Longmin Chen, Qianqian Xu, Sheng Yao and Hong Chen

Pharmaceutics 2025, 17(3), 388; https://doi.org/10.3390/pharmaceutics17030388 - 18 Mar 2025

Viewed by 986

Abstract

Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently [...] Read more.

Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood–brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases. Full article

(This article belongs to the Special Issue Advances in Oral Delivery of Lipid Nanoparticles for Treating Inflammatory Diseases)

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33 pages, 592 KiB

Open AccessReview

Progress in Gene Therapy for Hereditary Tyrosinemia Type 1

by Helen Thomas and Robert C. Carlisle

Pharmaceutics 2025, 17(3), 387; https://doi.org/10.3390/pharmaceutics17030387 - 18 Mar 2025

Viewed by 572

Abstract

Hereditary Tyrosinemia Type-1 (HT1), an inherited error of metabolism caused by a mutation in the fumarylacetoacetate hydrolase gene, is associated with liver disease, severe morbidity, and early mortality. The use of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) has almost eradicated the acute HT1 symptoms and childhood mortality. [...] Read more.

Hereditary Tyrosinemia Type-1 (HT1), an inherited error of metabolism caused by a mutation in the fumarylacetoacetate hydrolase gene, is associated with liver disease, severe morbidity, and early mortality. The use of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) has almost eradicated the acute HT1 symptoms and childhood mortality. However, patient outcomes remain unsatisfactory due to the neurocognitive effects of NTBC and the requirement for a strict low-protein diet. Gene therapy (GT) offers a potential single-dose cure for HT1, and there is now abundant preclinical data showing how a range of vector-nucleotide payload combinations could be used with curative intent, rather than continued reliance on amelioration. Unfortunately, there have been no HT1-directed clinical trials reported, and so it is unclear which promising pre-clinical approach has the greatest chance of successful translation. Here, to fill this knowledge gap, available HT1 preclinical data and available clinical trial data pertaining to liver-directed GT for other diseases are reviewed. The aim is to establish which vector-payload combination has the most potential as a one-dose HT1 cure. Analysis provides a strong case for progressing lentiviral-based approaches into clinical trials. However, other vector-payload combinations may be more scientifically and commercially viable, but these options require additional investigation. Full article

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

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11 pages, 861 KiB

Open AccessArticle

Altered Pharmacokinetics of Ropivacaine in Patients Undergoing Laparoscopic Major Hepatectomy

by Jun Zhang, Hongyuan Lv, Jiliang Shen, Zhichao Ai, Minjun Liu, Xiaorui Liu, Tieshuai Liu, Bo Shen, Hong Yu and Xin Yu

Pharmaceutics 2025, 17(3), 386; https://doi.org/10.3390/pharmaceutics17030386 - 18 Mar 2025

Viewed by 303

Abstract

Background/Objectives: Ropivacaine is primarily metabolized by the liver. High doses of ropivacaine, combined with altered pharmacokinetics due to hepatectomy, raise concerns about potential drug toxicity. We investigated the impact of LMH (laparoscopic major hepatectomy) on the pharmacokinetics of high-dose ropivacaine. Methods: Ten patients [...] Read more.

Background/Objectives: Ropivacaine is primarily metabolized by the liver. High doses of ropivacaine, combined with altered pharmacokinetics due to hepatectomy, raise concerns about potential drug toxicity. We investigated the impact of LMH (laparoscopic major hepatectomy) on the pharmacokinetics of high-dose ropivacaine. Methods: Ten patients undergoing LMH received a BD-TAP (bilateral dual transversus abdominis plane) block with a high dose of ropivacaine (3 mg·kg⁻¹ in 60 mL). Plasma concentrations of total and free ropivacaine and AAG (alpha-1 acid glycoprotein) levels were measured. Liver volumes were calculated using three-dimensional liver reconstruction technology. Results: The peak total ropivacaine concentration occurred 45 min after the block, reaching 2031.5 (876.0) ng·mL⁻¹, with a tendency to exceed the toxicity threshold in patients with a CFLV (cut functional liver volume) exceeding 199.24 mL or a CFLV/TFLV (total functional liver volume) ratio surpassing 18.61%. The peak free ropivacaine concentration, 111.5 (31.3) ng·mL⁻¹, was observed 90 min after the block, potentially exceeding the toxicity threshold when CFLV exceeded 452.33 mL or the CFLV/TFLV ratio was greater than 42.16%. Plasma AAG levels increased approximately 1.5 times within 24 h, from 1519.7 (422.6) μg·mL⁻¹ preoperatively to 2253.6 (460.4) μg·mL⁻¹ postoperatively, effectively reducing the toxicity risk associated with free ropivacaine. Conclusions: Preoperative administration of high-dose ropivacaine can be safely utilized in patients undergoing major hepatectomy. The increased plasma AAG concentration due to surgical stress reduces free ropivacaine levels, enhancing patient tolerance to the drug. The CFLV and CFLV/TFLV ratio may be supplementary indicators for predicting ropivacaine toxicity. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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21 pages, 5965 KiB

Open AccessArticle

Enhancing the Oral Bioavailability of Glutathione Using Innovative Analogue Approaches

by Naibo Yin, Paul W. R. Harris, Mengyang Liu, Jianguo Sun, Guanyu Chen, Jingyuan Wen and Margaret A. Brimble

Pharmaceutics 2025, 17(3), 385; https://doi.org/10.3390/pharmaceutics17030385 - 18 Mar 2025

Viewed by 899

Abstract

Background: Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. Methods: This study synthesised [...] Read more.

Background: Glutathione (GSH) is an essential antioxidant that protects against oxidative stress, but its oral bioavailability is below 1% due to enzymatic degradation and poor gastrointestinal absorption. Improving the oral bioavailability of GSH could significantly enhance its therapeutic efficacy. Methods: This study synthesised GSH analogues with chemical modifications to improve bioavailability. Seven GSH derivatives were designed: three analogues with altered stereochemistry (1.62, 1.63, and 1.64) and three N-methylated derivatives (1.65, 1.70, and 1.71), alongside a native GSH (1.61). The analogues were synthesised via Fmoc-solid-phase peptide synthesis, and they were characterised using reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionisation mass spectrometry (ESI-MS), Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR) spectroscopy. Their toxicity was assessed on Caco-2 cells for viability, and their antioxidant activity was assessed on UVA-irradiated fibroblast cells, enzymatic resistance, and interactions with GSH-metabolising enzymes. Results: Among the tested analogues, the N-methylated cysteine Compound (1.70) emerged as the most promising candidate. Compound 1.70 demonstrated superior resistance to enzymatic degradation, as well as showing enhanced cell viability and improved antioxidant activity. In vivo studies revealed a 16.8-fold increase in plasma half-life (t½) and a 16.1-fold increase in oral bioavailability compared to native GSH. Conclusions: Chemical modification strategies, particularly the N-methylation of GSH, present a viable approach to enhancing oral bioavailability. Compound 1.70 showed significant potential for therapeutic applications, warranting further investigation and development in clinical settings. Full article

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

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20 pages, 3630 KiB

Open AccessArticle

Evaluating Manganese-Doped Magnetic Nanoflowers for Biocompatibility and In Vitro Magnetic Hyperthermia Efficacy

by Andreea-Elena Petru, Cristian Iacovita, Ionel Fizeșan, Roxana Dudric, Ionut-Valentin Crestin, Constantin Mihai Lucaciu, Felicia Loghin and Bela Kiss

Pharmaceutics 2025, 17(3), 384; https://doi.org/10.3390/pharmaceutics17030384 - 18 Mar 2025

Viewed by 435

Abstract

Background/Objectives: Magnetic hyperthermia (MH) has emerged as a promising alternative to conventional cancer treatments, offering targeted tumor destruction with minimal damage to healthy tissues. In this study, we synthesized manganese-doped magnetic nanoflowers (Mn-NFs) using a polyol-mediated approach to enhance heating efficiency and [...] Read more.

Background/Objectives: Magnetic hyperthermia (MH) has emerged as a promising alternative to conventional cancer treatments, offering targeted tumor destruction with minimal damage to healthy tissues. In this study, we synthesized manganese-doped magnetic nanoflowers (Mn-NFs) using a polyol-mediated approach to enhance heating efficiency and biocompatibility for MH applications. Our objective was to evaluate their structural, magnetic, and in vitro hyperthermic properties to determine their potential for lung cancer therapy. Methods: Mn-NFs, with the general formula MnxFe₃-xO₄ (x = 0, 0.3, 0.5, 0.7), were synthesized via a one-step polyol method and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), and vibrating sample magnetometry (VSM). Their heating efficiency was assessed through specific absorption rate (SAR) measurements in aqueous and solid environments under an alternating magnetic field (AMF). Cytocompatibility was evaluated using the Alamar Blue assay on A549 lung carcinoma cells. Cellular uptake was quantified via a colorimetric iron determination method, while in vitro MH efficacy was tested by subjecting Mn-NF-loaded A549 cells to AMF exposure at different field strengths and nanoparticle concentrations. Results: Mn-NFs exhibited a flower-like morphology with enhanced magnetic properties, achieving high SAR values, particularly in immobilized conditions. Cytotoxicity assays confirmed high biocompatibility at relevant doses, with Mn-NFs of x = 0.3 showing optimal cellular uptake. MH studies demonstrated significant cancer cell death at AMF intensities of around 30 kA/m, with increased effectiveness following static magnetic field pre-alignment. Conclusions: The results highlight Mn-NFs, particularly those with a Mn content of x = 0.3, as promising candidates for MH-based lung cancer therapy, combining high heating efficiency, biocompatibility, and effective intracellular uptake. Further studies are needed to validate their therapeutic potential in vivo. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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28 pages, 1047 KiB

Open AccessReview

Advances in Liposomal Interleukin and Liposomal Interleukin Gene Therapy for Cancer: A Comprehensive Review of Preclinical Studies

by Eman A. Kubbara, Ahmed Bolad and Husam Malibary

Pharmaceutics 2025, 17(3), 383; https://doi.org/10.3390/pharmaceutics17030383 - 18 Mar 2025

Viewed by 691

Abstract

Background: Preclinical studies on liposomal interleukin (IL) therapy demonstrate considerable promise in cancer treatment. This review explores the achievements, challenges, and future potential of liposomal IL encapsulation, focusing on preclinical studies. Methods: A structured search was conducted using the PubMed and Web of [...] Read more.

Background: Preclinical studies on liposomal interleukin (IL) therapy demonstrate considerable promise in cancer treatment. This review explores the achievements, challenges, and future potential of liposomal IL encapsulation, focusing on preclinical studies. Methods: A structured search was conducted using the PubMed and Web of Science databases with the following search terms and Boolean operators: (“liposomal interleukin” OR “liposome-encapsulated interleukin”) AND (“gene therapy” OR “gene delivery”) AND (“cancer” OR “tumor” OR “oncology”) AND (“pre-clinical studies” OR “animal models” OR “in vitro studies”. Results: Liposomal IL-2 formulations are notable for enhancing delivery and retention at tumor sites. Recombinant human interleukin (rhIL-2) adsorbed onto small liposomes (35–50 nm) substantially reduces metastases in murine models. Hepatic metastasis models demonstrate superior efficacy of liposomal IL-2 over free IL-2 by enhancing immune responses, particularly in the liver. Localized delivery strategies, including nebulized liposomal IL-2 in canine pulmonary metastases and intrathoracic administration in murine sarcoma models, reduce systemic toxicity while promoting immune activation and tumor regression. Liposomal IL gene therapy, delivering cytokine genes directly to tumor sites, represents a notable advancement. Combining IL-2 gene therapy with other cytokines, including IL-6 or double-stranded RNA adjuvants, synergistically enhances macrophage and T-cell activation. Liposomal IL-4, IL-6, and IL-21 therapies show potential across various tumor types. Pairing liposomal IL-2 with chemotherapy or immune agents improves remission and survival. Innovative strategies, including PEGylation and ligand-targeted systems, optimize delivery, release, and therapeutic outcomes. Conclusions: Utilizing immune-stimulatory ILs through advanced liposomal delivery and gene therapy establishes a strong foundation for advancing cancer immunotherapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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16 pages, 2318 KiB

Open AccessArticle

Physiologically Based Biopharmaceutics Model of Apixaban for Biopharmaceutics Risk Assessment

by Paulo Paixão, Zvonimir Petric and José A. G. Morais

Pharmaceutics 2025, 17(3), 382; https://doi.org/10.3390/pharmaceutics17030382 - 18 Mar 2025

Viewed by 417

Abstract

Background/Objectives: This study applies a Physiologically Based Biopharmaceutics Modeling (PBBM) framework to predict the bioavailability (BA) and bioequivalence (BE) of apixaban, a borderline BCS Class III/IV drug. It investigates how formulation factors, such as particle size, granulation method, and dissolution conditions, affect apixaban’s [...] Read more.

Background/Objectives: This study applies a Physiologically Based Biopharmaceutics Modeling (PBBM) framework to predict the bioavailability (BA) and bioequivalence (BE) of apixaban, a borderline BCS Class III/IV drug. It investigates how formulation factors, such as particle size, granulation method, and dissolution conditions, affect apixaban’s in vivo behavior under fasting conditions. Methods: A PBBM approach was developed by integrating physicochemical, formulation, and drug-related parameters to simulate dissolution and absorption using a middle-out strategy for combining in silico, in vitro, and in vivo data. The Noyes–Whitney equation was used to predict dissolution influenced by particle size, granulation type, and in vitro dissolution conditions. This information was added to a compartmental absorption model of the gastrointestinal track connected to a classical compartmental model characterizing apixaban’s disposition. Results: The study validated the apixaban PBBM predictions by comparing simulated and observed pharmacokinetic profiles across several doses and immediate release formulations (solution and tablets) administered through the oral route. Results demonstrated acceptable prediction accuracy for BA and BE under various conditions. The model’s simulations identified a dissolution safe space, enabling regulatory and development insights into acceptable formulation characteristics. Conclusions: These findings highlight the potential of PBBM in streamlining drug development, reducing clinical studies, and supporting regulatory decisions. Specifically, for apixaban, the study demonstrated that particle sizes below 120 µm ensure BE with reference formulations, while formulations with faster dissolution rates, such as smaller particle sizes, align closely with BCS biowaiver criteria. This research emphasizes PBBM as a valuable tool for optimizing drug quality and lifecycle management. Full article

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

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20 pages, 3414 KiB

Open AccessReview

Oral Bioavailability Enhancement of Anti-Cancer Drugs Through Lipid Polymer Hybrid Nanoparticles

by Saud Almawash

Pharmaceutics 2025, 17(3), 381; https://doi.org/10.3390/pharmaceutics17030381 - 17 Mar 2025

Viewed by 603

Abstract

Cancer is considered as the second leading cause of death worldwide. Chemotherapy, radiotherapy, immunotherapy, and targeted drug delivery are the main treatment options for treating cancers. Chemotherapy drugs are either available for oral or parenteral use. Oral chemotherapy, also known as chemotherapy at [...] Read more.

Cancer is considered as the second leading cause of death worldwide. Chemotherapy, radiotherapy, immunotherapy, and targeted drug delivery are the main treatment options for treating cancers. Chemotherapy drugs are either available for oral or parenteral use. Oral chemotherapy, also known as chemotherapy at home, is more likely to improve patient compliance and convenience. Oral anti-cancer drugs have bioavailability issues associated with lower aqueous solubility, first-pass metabolism, poor intestinal permeability and drug absorption, and degradation of the drug throughout its journey in the gastrointestinal tract. A highly developed carrier system known as lipid polymer hybrid nanoparticles (LPHNs) has been introduced. These nanocarriers enhance drug stability, solubility, and absorption, and reduce first-pass metabolism. Consequently, this will have a positive impact on oral bioavailability enhancement. This article provides an in-depth analysis of LPHNs as a novel drug delivery system for anti-cancer agents. It discusses an overview of the limited bioavailability of anti-cancer drugs, their reasons and consequences, LPHNs based anti-cancer drug delivery, conventional and modern preparation methods as well as their drug loading and entrapment efficiencies. In addition, this article also gives an insight into the mechanistic approach to oral bioavailability enhancement, potential applications in anti-cancer drug delivery, limitations, and future prospects of LPHNs in anti-cancer drug delivery. Full article

(This article belongs to the Special Issue New Technology for Prolonged Drug Release, 2nd Edition)

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21 pages, 1518 KiB

Open AccessArticle

Design of Experiment Approach for Enhancing the Dissolution Profile and Robustness of Loratadine Tablet Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate

by Alhasan A. Jabbar, Israa Al-Ani, Ramadan I. Al-Shdefat, Nadia Ghazal, Anwar Jaffal and Mohamed H. Fayed

Pharmaceutics 2025, 17(3), 380; https://doi.org/10.3390/pharmaceutics17030380 - 17 Mar 2025

Viewed by 427

Abstract

Background: Formulating poorly water-soluble drugs poses significant challenges due to their limited solubility and bioavailability. Loratadine (LTD), classified as a BCS II molecule, exhibits notably low solubility, leading to reduced bioavailability. Objective: This study aims to enhance the dissolution rate of LTD through [...] Read more.

Background: Formulating poorly water-soluble drugs poses significant challenges due to their limited solubility and bioavailability. Loratadine (LTD), classified as a BCS II molecule, exhibits notably low solubility, leading to reduced bioavailability. Objective: This study aims to enhance the dissolution rate of LTD through the utilization of the wet granulation process using Tocopheryl polyethylene glycol 1000 succinate (TPGS). Methods: A Design-of-Experiment methodology was adopted to investigate and optimize the formulation variables for preparing an oral delivery system of LTD with improved dissolution properties. The levels of TPGS (2–6% w/w), as a surfactant, and sodium starch glycolate (SSG; 2–8% w/w), as a super-disintegrant, were established as independent variables in the formulations. Loratadine was granulated in the presence of TPGS, and the resultant granules were subsequently compressed into tablets. The granules and tablets produced were then subjected to characterization. Results: ANOVA analysis indicated that both TPGS and SSG had a significant (p < 0.05) influence on the critical characteristics of the obtained granules and tablets, with TPGS showing a particularly notable effect. The optimal concentrations of TPGS and SSG for the development of LTD tablets with the necessary quality attributes were identified as 5.0% w/w and 2.0% w/w, respectively, through optimization utilizing the desirability function. The tablets produced at these optimized concentrations displayed favorable properties concerning their mechanical strength (5.72 ± 0.32 KP), disintegration time (7.11 ± 1.08 min.), and release profile (86.21 ± 1.61%). Conclusions: In conclusion, incorporating TPGS in the granulation process shows promise in improving the dissolution profile of poorly water-soluble drugs and demonstrated formulation robustness. Full article

(This article belongs to the Special Issue Advances in Analysis and Modeling of Solid Drug Product)

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28 pages, 3411 KiB

Open AccessReview

Clinical Applications of Targeted Nanomaterials

by Ankesh Kumar, SK Shahvej, Pankaj Yadav, Unnati Modi, Amit K. Yadav, Raghu Solanki and Dhiraj Bhatia

Pharmaceutics 2025, 17(3), 379; https://doi.org/10.3390/pharmaceutics17030379 - 17 Mar 2025

Viewed by 1699

Abstract

Targeted nanomaterials are at the forefront of advancements in nanomedicine due to their unique and versatile properties. These include nanoscale size, shape, surface chemistry, mechanical flexibility, fluorescence, optical behavior, magnetic and electronic characteristics, as well as biocompatibility and biodegradability. These attributes enable their [...] Read more.

Targeted nanomaterials are at the forefront of advancements in nanomedicine due to their unique and versatile properties. These include nanoscale size, shape, surface chemistry, mechanical flexibility, fluorescence, optical behavior, magnetic and electronic characteristics, as well as biocompatibility and biodegradability. These attributes enable their application across diverse fields, including drug delivery. This review explores the fundamental characteristics of nanomaterials and emphasizes their importance in clinical applications. It further delves into methodologies for nanoparticle programming alongside discussions on clinical trials and case studies. We discussed some of the promising nanomaterials, such as polymeric nanoparticles, carbon-based nanoparticles, and metallic nanoparticles, and their role in biomedical applications. This review underscores significant advancements in translating nanomaterials into clinical applications and highlights the potential of these innovative approaches in revolutionizing the medical field. Full article

(This article belongs to the Special Issue Functional Nanomaterials in Pharmaceutics: Current Uses and Potential Applications)

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17 pages, 1724 KiB

Open AccessReview

Applications of Cyclodextrin-Based Drug Delivery Systems in Inflammation-Related Diseases

by Zelan Dai, Huijuan Yang, Peng Yin, Xingkang Liu, Ling Zhang, Youwei Dou and Shibo Sun

Pharmaceutics 2025, 17(3), 378; https://doi.org/10.3390/pharmaceutics17030378 - 17 Mar 2025

Viewed by 516

Abstract

Currently, inflammation diseases are one of the leading causes of mortality worldwide. The therapeutic drugs for inflammation are mainly steroidal and non-steroidal anti-inflammatory drugs. However, the use of these anti-inflammatory drugs over a prolonged period is prone to causing serious side effects. Accordingly, [...] Read more.

Currently, inflammation diseases are one of the leading causes of mortality worldwide. The therapeutic drugs for inflammation are mainly steroidal and non-steroidal anti-inflammatory drugs. However, the use of these anti-inflammatory drugs over a prolonged period is prone to causing serious side effects. Accordingly, it is particularly critical to design an intelligent target-specific drug delivery system to control the release of drugs in order to mitigate the side effects of anti-inflammatory drugs without limiting their activity. Meanwhile, cyclodextrin-based nano-delivery systems have garnered significant attention in contemporary pharmaceutical research owing to their capacity to enhance drug bioavailability, enable site-specific targeted accumulation, prolong the systemic circulation duration, facilitate synergistic therapeutic outcomes, and exhibit superior biocompatibility profiles. It is worth noting that cyclodextrin-based drug delivery systems show great potential in inflammation-related diseases. However, few studies have systematically reviewed their design strategies and application advancements. Here, we summarize the structural and chemical modification strategies of cyclodextrins, as well as cyclodextrin-based drug delivery systems and their applications in inflammation-related diseases. In summary, the aim is to provide a bit of insight into the development of cyclodextrin-based drug delivery systems for inflammation-related diseases. Full article

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

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19 pages, 5818 KiB

Open AccessArticle

PK/PD of Positively Charged ADC in Mice

by Hsuan-Ping Chang, Huyen Khanh Le, Shufang Liu and Dhaval K. Shah

Pharmaceutics 2025, 17(3), 377; https://doi.org/10.3390/pharmaceutics17030377 - 17 Mar 2025

Viewed by 2115

Abstract

Background/Objectives: Antibody–drug conjugates (ADCs) show significant promise in oncology but often suffer from a narrow therapeutic window. Introducing a positive charge on the antibody is one proposed strategy to enhance tumor distribution and efficacy of ADC. Accordingly, this study evaluates the pharmacokinetics [...] Read more.

Background/Objectives: Antibody–drug conjugates (ADCs) show significant promise in oncology but often suffer from a narrow therapeutic window. Introducing a positive charge on the antibody is one proposed strategy to enhance tumor distribution and efficacy of ADC. Accordingly, this study evaluates the pharmacokinetics (PK) and pharmacology of an ADC developed using a positively charged (+5) version of anti-HER2 antibody trastuzumab conjugated with vc-MMAE linker-payload. Methods: A positively charged variant of trastuzumab was generated and conjugated to vc-MMAE. In vitro cytotoxicity assays were performed in cell lines with varying HER2 expression levels: N87 (high), MCF-7 (low), and MDA-MB-468 (non-expressing). In vivo biodistribution of wild-type (WT) and positively charged (+5) ADC was investigated in plasma, tumors, liver, and spleen. A pilot efficacy and toxicity study was also conducted in N87 tumor-bearing mice. Results: The charged ADC showed differential potency and PK behavior compared to the WT ADC. The charged ADC had similar potency in N87 cells but demonstrated ~20-fold and ~60-fold higher potency in MCF-7 and MDA-MB-468 cells. Plasma exposures of all the analytes were found to be reduced following the administration of charged ADC. However, total antibody exposure was found to increase in liver, spleen, and low antigen-expressing MCF-7 tumors. Tumor payload exposures were found to be significantly reduced for the charged ADCs, but liver and spleen displayed higher peak concentrations and increased tissue-to-plasma exposure ratios for the payload, suggesting preferential distribution of ADC with high drug–antibody ratio (DAR) to liver and spleen. Consistent with reduced tumor exposures, charged ADC showed lower efficacy in N87 tumor-bearing mice. No overt toxicity was observed for the charged ADC. Conclusions: Our findings suggest that while positively charged ADCs may be more potent in vitro, their efficacy in vivo may be compromised due to altered PK behavior. Thus, introducing a positive charge into the antibody framework may not be a viable strategy for improving the therapeutic potential of ADCs. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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12 pages, 11239 KiB

Open AccessArticle

Burst-Free Sustained Release of Proteins from Thermal Gelling Polymer Solutions

by Yuxing Zhang, Xixi Zou, Qiran Du, Xiaotao Dong, Uday Kumar Chinta, Ruyue Yu, Fei Wu and Tuo Jin

Pharmaceutics 2025, 17(3), 376; https://doi.org/10.3390/pharmaceutics17030376 - 16 Mar 2025

Viewed by 527

Abstract

Objectives: Thermo-gelling hydrophilic polymers like PLGA–PEG–PLGA are known as injectable sustained-release depots for biologics, but they face challenges due to the occurrence of severe burst release. This study aimed to develop a strategy to avoid the initial burst release by pre-encapsulating proteins [...] Read more.

Objectives: Thermo-gelling hydrophilic polymers like PLGA–PEG–PLGA are known as injectable sustained-release depots for biologics, but they face challenges due to the occurrence of severe burst release. This study aimed to develop a strategy to avoid the initial burst release by pre-encapsulating proteins in polysaccharide microparticles through an aqueous–aqueous emulsion mechanism, thereby enhancing therapeutic retention and linear release kinetics. Methods: Five model proteins (G-CSF, GM-CSF, IGF-1, FVIII, BSA) were encapsulated in dextran microparticles, using an organic solvent-free aqueous–aqueous emulsion method. These particles were dispersed in a 23% (w/w) PLGA–PEG–PLGA solution and injected into a 37 °C release buffer to form a gel depot. The in vitro release profiles were quantified using ELISA and MicroBCA assays over 9–42 days. The bioactivity of the proteins was validated using cell proliferation assays (NFS-60, TF-1, MCF-7) and chromogenic kits. The in vivo pharmacokinetics of the FVIII-loaded formulations were evaluated in Sprague–Dawley rats (n = 5/group) over 28 days. Results: Protein-loaded dextran particles retained their structural integrity within the hydrogel and exhibited minimal burst release (≤5% within 30 min vs. >25% for free proteins). Sustained near-linear release profiles were observed for all the proteins, with complete release by day 9 (G-CSF, GM-CSF, BSA) or day 42 (FVIII). Rats administered with the thermal gel with FVIII–dextran particles showed a significantly lower peak plasma concentration (C_max: 88.25 ± 30.21 vs. 132.63 ± 66.67 ng/mL) and prolonged therapeutic coverage (>18 days vs. 15 days) compared to those administered with the thermal gel with the FVIII solution. The bioactivity of the released proteins remained at ≥90% of the native forms. Conclusions: Pre-encapsulation in dextran microparticles effectively mitigates burst release from thermosensitive hydrogels, while preserving protein functionality. Full article

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

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32 pages, 3475 KiB

Open AccessReview

Revolutionizing Drug Delivery: The Impact of Advanced Materials Science and Technology on Precision Medicine

by Mohamed El-Tanani, Shakta Mani Satyam, Syed Arman Rabbani, Yahia El-Tanani, Alaa A. A. Aljabali, Ibrahim Al Faouri and Abdul Rehman

Pharmaceutics 2025, 17(3), 375; https://doi.org/10.3390/pharmaceutics17030375 - 15 Mar 2025

Cited by 1 | Viewed by 1270

Abstract

Recent progress in material science has led to the development of new drug delivery systems that go beyond the conventional approaches and offer greater accuracy and convenience in the application of therapeutic agents. This review discusses the evolutionary role of nanocarriers, hydrogels, and [...] Read more.

Recent progress in material science has led to the development of new drug delivery systems that go beyond the conventional approaches and offer greater accuracy and convenience in the application of therapeutic agents. This review discusses the evolutionary role of nanocarriers, hydrogels, and bioresponsive polymers that offer enhanced drug release, target accuracy, and bioavailability. Oncology, chronic disease management, and vaccine delivery are some of the applications explored in this paper to show how these materials improve the therapeutic results, counteract multidrug resistance, and allow for sustained and localized treatments. The review also discusses the translational barriers of bringing advanced materials into the clinical setting, which include issues of biocompatibility, scalability, and regulatory approval. Methods to overcome these challenges include surface modifications to reduce immunogenicity, scalable production methods such as microfluidics, and the harmonization of regulatory systems. In addition, the convergence of artificial intelligence (AI) and machine learning (ML) is opening new frontiers in material science and personalized medicine. These technologies allow for predictive modeling and real-time adjustments to optimize drug delivery to the needs of individual patients. The use of advanced materials can also be applied to rare and underserved diseases; thus, new strategies in gene therapy, orphan drugs development, and global vaccine distribution may offer new hopes for millions of patients. Full article

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

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18 pages, 2091 KiB

Open AccessArticle

N-(9-Acridinyl) Amino Acid Derivatives: Synthesis and In Vitro Evaluation of Anti-Toxoplasma gondii Activity

by Đorđe Zlatković, Vladimir Dobričić, Jelena Srbljanović, Olivera Lijeskić, Neda Bauman, Vladimir Ćirković and Tijana Štajner

Pharmaceutics 2025, 17(3), 374; https://doi.org/10.3390/pharmaceutics17030374 - 15 Mar 2025

Viewed by 489

Abstract

Background/Objectives: Acridine, an aromatic heterocyclic compound, serves as a basis for the synthesis of potent bioactive derivatives, displaying a broad spectrum of biological activity, such as antibacterial, antitumor, and antiparasitic activity. With the ability to undergo various types of electrophilic substitutions, introducing [...] Read more.

Background/Objectives: Acridine, an aromatic heterocyclic compound, serves as a basis for the synthesis of potent bioactive derivatives, displaying a broad spectrum of biological activity, such as antibacterial, antitumor, and antiparasitic activity. With the ability to undergo various types of electrophilic substitutions, introducing different side chains could lead to compounds being active towards various and potentially multiple biotargets. Toxoplasma gondii, a ubiquitous protozoan parasite with worldwide distribution, poses a major health threat, particularly in immunocompromised patients and fetuses. Current treatment options for toxoplasmosis are scarce, with notable limitations, especially regarding side myelotoxicity and inactivity towards T. gondii cysts, causing a need for novel drug candidates. The aim of this study was to evaluate selected N-(9-acrydinil) amino acid derivatives as potential anti-T. gondii agents. Methods: Synthesis of new derivatives was performed using a two-step method, with the initial mixing of 9-chloroacridine with methanol and sodium alkoxide solution and subsequent adding of appropriate amino acids. Cytotoxicity of the tested compounds was evaluated on the Vero cell line using a MTT assay, while their anti-T. gondii activity was investigated using T. gondii RH strain tachyzoites. Results: CC₅₀ values of the derivatives ranged from 41.72 to 154.10 µM. Anti-T. gondii activity, displayed as a reduction in the number of viable tachyzoites compared to the untreated control, ranged from 0 to 33.3%. One of the derivatives displayed activity comparable to the standard treatment option while retaining acceptable cytotoxicity. Esterification, presence of aromatic substituents and the length of the amino acid side chain were identified as key factors that affect both toxicity and activity of these derivatives. Conclusions: Promising results obtained throughout this study provide guidelines for further structural modifications of N-(9-acrydinil) amino acid derivatives in order to synthesize drug candidates competitive to standard treatment options for toxoplasmosis. Full article

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

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20 pages, 3849 KiB

Open AccessArticle

Leveraging Omeprazole PBPK/PD Modeling to Inform Drug–Drug Interactions and Specific Recommendations for Pediatric Labeling

by Amira Soliman, Leyanis Rodriguez-Vera, Ana Alarcia-Lacalle, Leandro F. Pippa, Saima Subhani, Viera Lukacova, Jorge Duconge, Natalia V. de Moraes and Valvanera Vozmediano

Pharmaceutics 2025, 17(3), 373; https://doi.org/10.3390/pharmaceutics17030373 - 14 Mar 2025

Viewed by 789

Abstract

Background/Objectives: Omeprazole is widely used for managing gastrointestinal disorders like GERD, ulcers, and H. pylori infections. However, its use in pediatrics presents challenges due to drug interactions (DDIs), metabolic variability, and safety concerns. Omeprazole’s pharmacokinetics (PK), primarily influenced by CYP2C19 metabolism, is affected [...] Read more.

Background/Objectives: Omeprazole is widely used for managing gastrointestinal disorders like GERD, ulcers, and H. pylori infections. However, its use in pediatrics presents challenges due to drug interactions (DDIs), metabolic variability, and safety concerns. Omeprazole’s pharmacokinetics (PK), primarily influenced by CYP2C19 metabolism, is affected by ontogenetic changes in enzyme expression, complicating dosing in children. Methods: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for omeprazole and its metabolites to predict age-related variations in metabolism and response. Results: The PBPK model successfully predicted exposure to parent and metabolites in adults and pediatrics, incorporating competitive and mechanism-based inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites. By accounting for age-dependent metabolic pathways, the model enabled priori predictions of omeprazole exposure in different age groups. Linking PK to the pharmacodynamics (PD) model, we described the impact of age-related physiological changes on intragastric pH, the primary outcome for proton pump inhibitors efficacy. Conclusions: The PBPK-PD model allowed for the virtual testing of dosing scenarios, providing an alternative to clinical studies in pediatrics where traditional DDI studies are challenging. This approach offers valuable insights for accurate dosing recommendations in pediatrics, accounting for age-dependent variability in metabolism, and underscores the potential of PBPK modeling in guiding pediatric drug development. Full article

(This article belongs to the Special Issue Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling and Applications)

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26 pages, 2862 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations

by Celeste Vallejo, Cameron Meaney, Lara Clemens, Kyunghee Yang, Viera Lukacova and Haiying Zhou

Pharmaceutics 2025, 17(3), 372; https://doi.org/10.3390/pharmaceutics17030372 - 14 Mar 2025

Viewed by 602

Abstract

Background/Objectives: Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus^® to simulate plasma and liver concentrations in patient populations after administration of either infliximab, ipilimumab, or [...] Read more.

Background/Objectives: Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus^® to simulate plasma and liver concentrations in patient populations after administration of either infliximab, ipilimumab, or nivolumab. Methods: The models include distribution and clearance mechanisms specific to large molecules, FcRn binding dynamics, and target-mediated drug disposition (TNF-α for infliximab, CTLA-4 for ipilimumab, and PD-1 for nivolumab). Results: The PBPK model for each large molecule was able to reproduce observed plasma concentration data in patient populations, including patients with rheumatoid arthritis and patients with solid tumors. Liver concentrations were predicted to be between 10% and 23% of the plasma concentrations for each of the three drugs, aligning with previously reported results. This lends further validity to the PBPK models and their ability to accurately predict hepatic concentrations in the absence of direct tissue measurements. Conclusions: These results can be used to drive liver toxicity predictions using the quantitative systems toxicology model, BIOLOGXsym™, which integrates hepatic interstitial concentrations with in vitro mechanistic toxicity data to predict the extent of liver toxicity for biologics. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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19 pages, 5257 KiB

Open AccessArticle

Development and Evaluation of Fluconazole Co-Crystal for Improved Solubility and Mechanical Properties

by Ritu Rathi, Inderbir Singh, Tanikan Sangnim and Kampanart Huanbutta

Pharmaceutics 2025, 17(3), 371; https://doi.org/10.3390/pharmaceutics17030371 - 14 Mar 2025

Viewed by 546

Abstract

Background: Fluconazole (FLZ) is a broad-spectrum anti-fungal drug presenting poor flowability, mechanical properties, and limited aqueous solubility. These issues pose challenges for the handling and manufacturing of dosage forms of FLZ. The current research aimed to develop fluconazole co-crystal (CC) for improving [...] Read more.

Background: Fluconazole (FLZ) is a broad-spectrum anti-fungal drug presenting poor flowability, mechanical properties, and limited aqueous solubility. These issues pose challenges for the handling and manufacturing of dosage forms of FLZ. The current research aimed to develop fluconazole co-crystal (CC) for improving its aqueous solubility, flowability, and mechanical properties. (2) Methods: The fluconazole benzoic acid (FLZ-BA) co-crystal was prepared using the solvent evaporation technique. The prepared co-crystal was characterized for drug content, solubility, anti-fungal activity, dissolution, and stability. DSC (Differential Scanning Calorimetry), PXRD (Powder X-Ray Diffraction), SEM (Scanning Electron Microscopy), and FTIR (Fourier Transmission Infrared) spectroscopy were carried out to confirm the co-crystal formation. The co-crystal was further evaluated for their flow characteristics and mechanical properties via CTC (compressibility, tabletability, and compactibility), Heckel, and Kawakita analysis. (3) Results: The CC showed 69.51% drug content and 13-fold greater aqueous solubility than pure FLZ. The DSC thermogram showed a sharp endothermic peak between the parent components, a distinct PXRD pattern was observed, and the SEM analysis revealed a different morphology, confirming the formation of co-crystal (new crystalline form). The CC showed immediate drug release and was found to more stable, and less hygroscopic than FLZ alone. The CC revealed better flowability, tabletability (tensile strength), compressibility, and compactibility. Moreover, Heckel and Kawakita analysis indicated the co-crystal to deform plastically, favoring improved compression. (4) Conclusions: The immediate drug release capabilities, improved hygroscopic stability, solubility, better antifungal activity, and flowability make FLZ-BA co-crystal a suitable candidate for the preparation of an immediate drug release dosage form. The study also revealed the application of co-crystal for improving the flowability and mechanical properties. Full article

(This article belongs to the Special Issue Recent Advances in Cocrystal and Nano-Cocrystal Technologies for Pharmaceutical and Nutraceutical Applications)

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28 pages, 21909 KiB

Open AccessArticle

Improved Photodynamic Therapy of Hepatocellular Carcinoma via Surface-Modified Protein Nanoparticles

by Ahmed M. Abdelsalam, Amir Balash, Shaimaa M. Khedr, Muhammad Umair Amin, Konrad H. Engelhardt, Eduard Preis and Udo Bakowsky

Pharmaceutics 2025, 17(3), 370; https://doi.org/10.3390/pharmaceutics17030370 - 14 Mar 2025

Cited by 1 | Viewed by 555

Abstract

Background: Photodynamic therapy (PDT) has evolved as a reliable therapeutic modality for cancer. However, the broad application of the technique is still limited because of poor bioavailability and the non-selective distribution of photosensitizers within host tissues. Herein, zein, a natural corn protein, was [...] Read more.

Background: Photodynamic therapy (PDT) has evolved as a reliable therapeutic modality for cancer. However, the broad application of the technique is still limited because of poor bioavailability and the non-selective distribution of photosensitizers within host tissues. Herein, zein, a natural corn protein, was functionalized with glycyrrhetinic acid (GA) and polyethylene glycol (Z-PEG-GA) as a targeting platform for liver cancer cells. Parietin, as novel photosensitizer, was successfully encapsulated into zein via nanoprecipitation and used for the therapy of hepatocellular carcinoma. Methods: The in vitro phototoxicity of Z-PEG-GA nanoparticles and their non-functionalized control (Z-PEG) were assessed against hepatocellular carcinoma (HepG2 cells) and the In vivo biodistribution was determined in an adult male CD-1 Swiss albino mice model. Results: The formulated Z-PEG and Z-PEG-GA showed spherical shapes with average sizes of 82.8 and 94.7 nm for unloaded nanoparticles, respectively, and 109.7 and 111.5 nm for loaded nanoparticles carrying more than 70% of parietin, and Quantum yield measurements show that parietin’s photodynamic potential is conserved. Moreover, parietin-loaded Z-PEG-GA exhibited three-fold higher toxicity against liver cancer cells than its non-functionalized control and attained more than an eleven-fold enhancement in the generated intracellular reactive oxygen species (ROS) at a 9 J/cm² radiant exposure. The generated intracellular ROS led to mitochondrial disruption and the release of cytochrome c. In vivo biodistribution studies revealed that fluorescence signals of Z-PEG-GA can persist in the excised animal liver for up to 24 h post-administration. Conclusions: Consequently, tailored zein can hold great potential for delivering several hydrophobic photosensitizers in anticancer PDT. Full article

(This article belongs to the Special Issue Recent Advances in Polymeric Nanoparticle-Based Drug Delivery System for Cancer Therapy)

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1 pages, 395 KiB

Open AccessCorrection

Correction: Kuskov et al. Amphiphilic Poly-N-vinylpyrrolidone Nanoparticles as Carriers for Nonsteroidal, Anti-Inflammatory Drugs: Pharmacokinetic, Anti-Inflammatory, and Ulcerogenic Activity Study. Pharmaceutics 2022, 14, 925

by Andrey Kuskov, Dragana Nikitovic, Aikaterini Berdiaki, Mikhail Shtilman and Aristidis Tsatsakis

Pharmaceutics 2025, 17(3), 369; https://doi.org/10.3390/pharmaceutics17030369 - 14 Mar 2025

Viewed by 272

Abstract

Error in Figure [...] Full article

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27 pages, 3833 KiB

Open AccessArticle

The Influence of Indisulam on Human Immune Effector Cells: Is a Combination with Immunotherapy Feasible?

by Lisa Arnet, Lisabeth Emilius, Annett Hamann, Maria Carmo-Fonseca, Carola Berking, Jan Dörrie and Niels Schaft

Pharmaceutics 2025, 17(3), 368; https://doi.org/10.3390/pharmaceutics17030368 - 14 Mar 2025

Viewed by 529

Abstract

Background: As a modulator of pre-mRNA splicing, the anti-cancer agent indisulam can induce aberrantly spliced neoantigens, enabling immunologic anti-tumor activity. Consequently, combining indisulam with immunotherapy is expected to be a promising novel approach in cancer therapy. However, a prerequisite for such a combination [...] Read more.

Background: As a modulator of pre-mRNA splicing, the anti-cancer agent indisulam can induce aberrantly spliced neoantigens, enabling immunologic anti-tumor activity. Consequently, combining indisulam with immunotherapy is expected to be a promising novel approach in cancer therapy. However, a prerequisite for such a combination is that immune effector cells remain functional and unharmed by the chemical. Methods: To ensure the immunocompetence of human immune effector cells is maintained, we investigated the influence of indisulam on ex vivo-isolated T cells and monocyte-derived dendritic cells (moDCs) from healthy donors. We used indisulam concentrations from 0.625 µM to 160 µM and examined the impact on the following: (i) the activation of CD4⁺ and CD8⁺ T cells by CD3-crosslinking and via a high-affinity TCR, (ii) the cytotoxicity of CD8⁺ T cells, (iii) the maturation process of moDCs, and (iv) antigen-specific CD8⁺ T cell priming. Results: We observed dose-dependent inhibitory effects of indisulam, and substantial inhibition occurred at concentrations around 10 µM, but the various functions of the immune system exhibited different sensitivities. The weaker activation of T cells via CD3-crosslinking was more sensitive than the stronger activation via the high-affinity TCR. T cells remained capable of killing tumor cells after treatment with indisulam up to 40 µM, but T cell cytotoxicity was impaired at 160 µM indisulam. While moDC maturation was also rather resistant, T cell priming was almost completely abolished at a concentration of 10 µM. Conclusions: These effects should be considered in possible future combinations of immunotherapy with the mRNA splicing inhibitor indisulam. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy, 2nd Edition)

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26 pages, 3935 KiB

Open AccessArticle

Nasal Administration of a Nanoemulsion Based on Methyl Ferulate and Eugenol Encapsulated in Chitosan Oleate: Uptake Studies in the Central Nervous System

by Giada Botti, Laura Catenacci, Alessandro Dalpiaz, Luca Randi, Maria Cristina Bonferoni, Sara Perteghella, Sarah Beggiato, Luca Ferraro, Barbara Pavan and Milena Sorrenti

Pharmaceutics 2025, 17(3), 367; https://doi.org/10.3390/pharmaceutics17030367 - 13 Mar 2025

Viewed by 549

Abstract

Background/Objectives: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new [...] Read more.

Background/Objectives: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new nasal formulation based on a nanoemulsion (NE) for the jointed brain-targeting of eugenol and methyl ferulate (Fer-Me, i.e., a Fer-lipidized derivative maintaining the parent compound anti-oxidative properties). NE was obtained using chitosan oleate, a surfactant combining mucoadhesive and absorption-enhancing properties with stabilizing effects on the dispersion of eugenol, used as a Fer-Me vehicle. Methods: The nasal formulation was obtained by spontaneous emulsification processes; cell viability and uptake studies were performed on an in vitro model of respiratory mucosa (RPMI 2650 cells). After intravenous and nasal administrations, the pharmacokinetic profiles of eugenol and Fer-Me in rats’ bloodstreams and cerebrospinal fluid (CSF) were analyzed via HPLC-UV analysis. Results: The NE dispersed-phase mean diameter was 249.22 ± 32.78 nm; Fer-Me and eugenol loading in NE was about 1 and 2 mg/mL, respectively. NE increased the uptake of loaded compounds by mucosal cells. Following intravenous administration, the Fer-Me plasma half-life was 10.08 ± 0.37 min, and a negligible ability of the compound to permeate in the CSF, compared to eugenol, was observed. NE nasal administration allowed us to sensibly increase the Fer-Me brain-targeting and prolong the eugenol permanence in the CSF. Conclusions: This nasal formulation appears promising to overcome Fer and eugenol pharmacokinetic issues. The possible translational relevance of the present findings is discussed. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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22 pages, 1826 KiB

Open AccessReview

Nanomanaging Chronic Wounds with Targeted Exosome Therapeutics

by Anita Yadav, Anu Sharma, Mohini Moulick and Subhadip Ghatak

Pharmaceutics 2025, 17(3), 366; https://doi.org/10.3390/pharmaceutics17030366 - 13 Mar 2025

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Abstract

Chronic wounds pose a significant healthcare challenge, impacting millions of patients worldwide and burdening healthcare systems substantially. These wounds often occur as comorbidities and are prone to infections. Such infections hinder the healing process, complicating clinical management and proving recalcitrant to therapy. The [...] Read more.

Chronic wounds pose a significant healthcare challenge, impacting millions of patients worldwide and burdening healthcare systems substantially. These wounds often occur as comorbidities and are prone to infections. Such infections hinder the healing process, complicating clinical management and proving recalcitrant to therapy. The environment within the wound itself poses challenges such as lack of oxygen, restricted blood flow, oxidative stress, ongoing inflammation, and bacterial presence. Traditional systemic treatment for such chronic peripheral wounds may not be effective due to inadequate blood supply, resulting in unintended side effects. Furthermore, topical applications are often impervious to persistent biofilm infections. A growing clinical concern is the lack of effective therapeutic modalities for treating chronic wounds. Additionally, the chemically harsh wound microenvironment can reduce the effectiveness of treatments, highlighting the need for drug delivery systems that can deliver therapies precisely where needed with optimal dosages. Compared to cell-based therapies, exosome-based therapies offer distinct advantages as a cell-free approach for chronic wound treatment. Exosomes are of endosomal origin and enable cell-to-cell communications, and they possess benefits, including biocompatibility and decreased immunogenicity, making them ideal vehicles for efficient targeting and minimizing off-target damage. However, exosomes are rapidly cleared from the body, making it difficult to maintain optimal therapeutic concentrations at wound sites. The hydrogel-based approach and development of biocompatible scaffolds for exosome-based therapies can be beneficial for sustained release and prolong the presence of these therapeutic exosomes at chronic wound sites. Engineered exosomes have been shown to possess stability and effectiveness in promoting wound healing compared to their unmodified counterparts. Significant progress has been made in this field, but further research is essential to unlock their clinical potential. This review seeks to explore the benefits and opportunities of exosome-based therapies in chronic wounds, ensuring sustained efficacy and precise delivery despite the obstacles posed by the wound environment. Full article

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

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Pharmaceutics, Volume 17, Issue 3 (March 2025) – 119 articles

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