Pharmaceutics

17 pages, 4180 KiB

Open AccessArticle

A Sponge-like Polysaccharide from Pine Pollen: Structural Features and Therapeutic Potential in DNCB-Induced Atopic Dermatitis Models

by Zhuoya Qiu, Mengru Zhang, Haitao Du, Yi Wang, Xuekun Shao, Jialei Fu, Ping Wang and Cheng Wang

Pharmaceutics 2025, 17(8), 1058; https://doi.org/10.3390/pharmaceutics17081058 - 14 Aug 2025

Abstract

Objectives: Atopic dermatitis (AD) is a long-term, recurring inflammatory skin condition characterized by impaired epidermal barrier function and abnormal immune system regulation. Pine pollen has traditionally been used for dermatological treatments, though its active components remain unclear. The primary objective of this study [...] Read more.

Objectives: Atopic dermatitis (AD) is a long-term, recurring inflammatory skin condition characterized by impaired epidermal barrier function and abnormal immune system regulation. Pine pollen has traditionally been used for dermatological treatments, though its active components remain unclear. The primary objective of this study was to pinpoint the active constituents of pine pollen and elucidate its therapeutic effects against AD. Methods: The safety concentration ranges and protective efficacy of nine pine pollen constituents against 2,4-dinitrochlorobenzene (DNCB)-induced HaCaT cell damage were evaluated using the CCK-8 assay. Furthermore, models of DNCB-induced damage were established both in vitro (HaCaT cells) and in vivo (BALB/c mice) to explore the protective effects of the key functional component. Results: Our findings identified pine pollen polysaccharides (PPPS) as the principal bioactive constituent, characterized by a unique infrared absorption spectral profile and a sponge-like architecture with three-dimensional interconnected porous networks. In vitro, PPPS inhibited DNCB-induced decreases in cell viability, morphological abnormalities, oxidative stress, and apoptosis. In vivo, PPPS alleviated DNCB-induced skin lesions by attenuating epidermal hyperplasia, suppressing mast cell infiltration, inhibiting cell apoptosis, and downregulating the expression of IL-4 and IL-17A. Conclusions: This study provides evidence that PPPS from pine pollen can alleviate epidermal damage in AD, offering a novel therapeutic strategy for AD treatment. Full article

(This article belongs to the Special Issue Recent Advances in Pharmaceutical Applications of Functionalized Polysaccharides and Their Derivatives, 2nd Edition)

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17 pages, 999 KiB

Open AccessArticle

Preclinical Assessment of a Metformin–Melatonin Combination: Antinociceptive Synergism

by Marcia Yvette Gauthereau-Torres, Jenny Selene Martínez-Guillen, Claudia Cervantes-Durán, Carmen Judith Gutiérrez-García, Daniel Godínez-Hernández, Asdrúbal Aguilera Méndez and Luis Fernando Ortega-Varela

Pharmaceutics 2025, 17(8), 1057; https://doi.org/10.3390/pharmaceutics17081057 - 14 Aug 2025

Abstract

Background/Objectives: Pain is a growing public health concern worldwide, and the use of combinations of drugs can improve their analgesic effects while minimizing their adverse effects. Drugs such as metformin (antidiabetic) and melatonin (sleep regulator) have analgesic potential in combination. In this study, [...] Read more.

Background/Objectives: Pain is a growing public health concern worldwide, and the use of combinations of drugs can improve their analgesic effects while minimizing their adverse effects. Drugs such as metformin (antidiabetic) and melatonin (sleep regulator) have analgesic potential in combination. In this study, we evaluated the pharmacological interaction between metformin and melatonin when orally administered in a rat model, using the formalin test. Methods: Female Wistar rats (220–350 g) were injected with 50 µL of 1% formalin in the dorsal surface of the right hind paw. Formalin produces pain-related flinching behavior, and antinociception was evaluated as the reduction in this response. The percentage of the antinociceptive effect was determined after the oral administration of metformin (30–1000 mg/kg), melatonin (10–150 mg/kg), and their combination (MMC). To establish the nature of the interaction, isobolographic analysis was performed in a fixed-dose ratio (0.5:0.5), based on the effective dose 50 (ED₅₀) values for each drug: metformin (947.46 ± 242.60 mg/kg) and melatonin (126.86 ± 37.98 mg/kg). To evaluate the mechanism of action, the receptor antagonist for metformin compound C (dorsomorphin) for AMPK inhibition, MT1 and MT2 melatonin receptor antagonists (4-P-PDOT, luzindole), and an opioid antagonist (naloxone) were employed. The rotarod test was used to evaluate the safety profile of the combination. Results: The metformin–melatonin combination significantly reduced the number of flinches in the second phase of the formalin test. The theoretical ED₅₀ for the combination (ED₅₀ T) was 537.15 ± 122.76 mg/kg. Experimentally, the ED₅₀ (ED₅₀ E) was significantly lower (360.83 ± 23.36 mg/kg), indicating a synergistic interaction for the combination involving opioidergic pathways, MT2 receptors, and AMPK activation. Conclusions: Oral metformin–melatonin coadministration could provide a therapeutic alternative for inflammatory pain. Full article

(This article belongs to the Special Issue Emerging Drugs and Formulations for Pain Treatment)

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14 pages, 1678 KiB

Open AccessArticle

Encapsulation of Therapeutic, Low-Molecular-Weight Chemokines Using a Single Emulsion, Microfluidic, Continuous Manufacturing Process

by Julie A. Kobyra, Michael Pezzillo, Elizabeth R. Bentley, Stephen C. Balmert, Charles Sfeir and Steven R. Little

Pharmaceutics 2025, 17(8), 1056; https://doi.org/10.3390/pharmaceutics17081056 - 14 Aug 2025

Abstract

Background/Objectives: Controlled release systems, such as polymeric microparticles (MPs), have emerged as a promising solution to extend the bioavailability and reduce dosing frequency for biologic drugs; however, the formulation of these systems to encapsulate highly sensitive, hydrophilic biologic drugs within hydrophobic polymers remains [...] Read more.

Background/Objectives: Controlled release systems, such as polymeric microparticles (MPs), have emerged as a promising solution to extend the bioavailability and reduce dosing frequency for biologic drugs; however, the formulation of these systems to encapsulate highly sensitive, hydrophilic biologic drugs within hydrophobic polymers remains a nontrivial task. Although scalable manufacturing and FDA approval of single emulsion processes encapsulating small molecules has been achieved, scaling more complex double emulsion processes to encapsulate hydrophilic biologics remains more challenging. Methods: Here, we demonstrate that two hydrophilic, low-molecular-weight, recombinant chemokines, CCL22 and CCL2, can be encapsulated in poly(lactic-co-glycolic acid) (PLGA) MPs using a single emulsion method where the proteins are dissolved in an organic solvent during formulation. Results: As expected, we observed some differences in release kinetics from single emulsion MPs compared to double emulsion MPs, which traditionally have been used to encapsulate proteins. Single emulsion MPs exhibited a substantially reduced initial burst. Importantly, protein released from single emulsion CCL22-MPs also retained biological activity, as determined by a cell-based functional assay. Decreasing particle size or changing the polymer end group from PLGA-COOH to PLGA-OH increased the initial burst from single emulsion MPs, demonstrating tunability of release kinetics for protein-loaded, single emulsion MPs. Finally, to improve scalability and enable more precise control over MP formulations, the single emulsion process was adapted to a microfluidic, continuous manufacturing system, and the resulting MPs were evaluated similarly. Conclusions: Altogether, this study demonstrates the feasibility of using a single emulsion encapsulation method for at least some protein biologics. Full article

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

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31 pages, 6995 KiB

Open AccessArticle

Dual-Cross-Linked Alginate Hydrogels as a Strategy to Improve the Antifungal Properties of Posaconazole

by Katarzyna Sosnowska, Marta Szekalska, Ewelina Piktel, Robert Bucki, Eliza Wolska, Iwona Misztalewska-Turkowicz, Karolina Halina Markiewicz, Agnieszka Zofia Wilczewska and Katarzyna Winnicka

Pharmaceutics 2025, 17(8), 1055; https://doi.org/10.3390/pharmaceutics17081055 - 14 Aug 2025

Abstract

Background/Objectives: Despite the continuous development of medicine, the treatment of dermatological fungal infections is difficult due to their chronic nature, recurrence, and resistance of some pathogens to standard therapies. In order to improve the effectiveness of treatment, not only are new active [...] Read more.

Background/Objectives: Despite the continuous development of medicine, the treatment of dermatological fungal infections is difficult due to their chronic nature, recurrence, and resistance of some pathogens to standard therapies. In order to improve the effectiveness of treatment, not only are new active substances with antifungal activity synthesized, but new, unconventional carriers are also developed for substances already used. Methods: Therefore, the focus of this research was to evaluate the possibility of using a combination of two cross-linking techniques for sodium alginate ionic cross-linking with Zn²⁺ ions and electrostatic interaction with ε-poly-L-lysine. The pharmaceutical properties, antifungal activity against Candida strains, and compatibility with human fibroblasts of the designed hydrogels were assessed. Results: It was shown that the double cross-linking process increased the viscosity of the developed hydrogels, improved bioadhesive properties to hairless mice skin, and provided an extended release profile of the active substance. In addition, obtained formulations were characterized by improved antifungal effect against C. albicans, C. krusei, and C. parapsilosis. Prepared hydrogels expressed biocompatibility with human fibroblasts. Conclusions: Dual-cross-linked alginate hydrogels are a promising dermatological formulation that might improve the efficacy of posaconazole in the treatment of antifungal infections. Full article

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

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19 pages, 4026 KiB

Open AccessArticle

Synthesis of Terminal-Alkylated PEGs with Imine Spacer to Form Iminium Mono-Ion Complexes for pDNA Delivery into Skeletal Muscle

by Riku Oba, Yoko Endo-Takahashi, Yoichi Negishi and Shoichiro Asayama

Pharmaceutics 2025, 17(8), 1054; https://doi.org/10.3390/pharmaceutics17081054 - 13 Aug 2025

Abstract

Background/Objectives: To design the pDNA delivery carrier for delivery into skeletal muscle, a total of twelve terminal-alkylated PEGs (Cx-I-PEGy) with four alkyl groups of different carbon numbers (Cx: x = 4, 8, 12, 16) modified via an imine spacer at the ends of [...] Read more.

Background/Objectives: To design the pDNA delivery carrier for delivery into skeletal muscle, a total of twelve terminal-alkylated PEGs (Cx-I-PEGy) with four alkyl groups of different carbon numbers (Cx: x = 4, 8, 12, 16) modified via an imine spacer at the ends of three methoxy PEGs of different molecular weights (PEGy: y = 500, 2k, 5k) have been synthesized. Methods: Among them, four Cx-I-PEG5k formed an imine-mediated complex formation with pDNA, as assessed by agarose gel electrophoresis, defined as an iminium mono-ion complex (I-MIC) without multivalent electrostatic interaction by minimizing potential toxic cations. Results: Most resulting I-MICs maintained the flexible structure of pDNA and promoted the binding to pDNA. The expression of pDNA by intramuscular injection with the resulting I-MICs was the highest by using I-MICs with C4-I-PEG5k and was observed extensively by the in vivo imaging system (IVIS). Conclusions: These results suggest that the I-MICs with C4-I-PEG5k are promising for pDNA transfection into skeletal muscle, offering the alkyl iminium for the pDNA binding group to demonstrate the factor of pDNA’s flexible structure as one of the key parameters for in vivo local pDNA transfection. Full article

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

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13 pages, 1914 KiB

Open AccessArticle

Therapeutic pCRISPRi Delivery to Lung Squamous Cell Carcinoma by Combining Nanobubbles and Ultrasound

by Taiki Yamaguchi, Yoko Endo-Takahashi, Takumi Amano, Arina Ihara, Tetsushi Sakuma, Takashi Yamamoto, Takuya Fukazawa and Yoichi Negishi

Pharmaceutics 2025, 17(8), 1053; https://doi.org/10.3390/pharmaceutics17081053 - 13 Aug 2025

Abstract

Background/Objectives: Lung squamous cell carcinoma (SCC), a major subtype of non-small cell lung cancer, remains a significant clinical challenge due to a scarcity of actionable molecular targets and the limited effectiveness of current targeted therapies. Emerging treatment strategies inhibit the gene expression [...] Read more.

Background/Objectives: Lung squamous cell carcinoma (SCC), a major subtype of non-small cell lung cancer, remains a significant clinical challenge due to a scarcity of actionable molecular targets and the limited effectiveness of current targeted therapies. Emerging treatment strategies inhibit the gene expression of lineage survival oncogenes such as ΔNp63 and SOX2. CRISPR interference (CRISPRi) is a promising method to downregulate these genes; however, the efficacy depends on effective delivery. Here, we focused on the delivery system using nanobubbles (NBs) and ultrasound (US) for site-specific CRISPRi delivery to SCC. We evaluated the therapeutic efficacy of plasmid-based CRISPRi (pCRISPRi) targeting SOX2 or ΔNp63 using intratumoral pCRISPRi/NBs injections followed by US. Methods: A mixture of NBs and pCRISPRi was injected directly into the tumors and exposed to US-induced cavitation to facilitate pCRISPRi uptake. Tumor volume was measured every other day, and apoptosis was assessed by TUNEL assay. Results: In a lung SCC xenograft model, NBs/US-mediated pCRISPRi delivery induced apoptosis and significantly suppressed tumor growth. Conclusions: These findings suggest that US-guided, NB-facilitated delivery of pCRISPRi can locally suppress lineage survival oncogenes and trigger tumor cell death, representing a promising targeted therapy for lung SCC. Additionally, this platform could be adapted to other cancers by targeting alternative factors. Full article

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

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24 pages, 2186 KiB

Open AccessArticle

Drug Metabolism and Pharmacokinetic Evaluation of a Novel RNase H2 Inhibitor for the Treatment of Triple-Negative Breast Cancer

by Yang Wang, Huan Xie, Jing Ma, Ting Du, Song Gao, Yuan Chen, Shiaw-Yih Lin and Dong Liang

Pharmaceutics 2025, 17(8), 1052; https://doi.org/10.3390/pharmaceutics17081052 - 13 Aug 2025

Abstract

Objectives: A thorough understanding of pharmacokinetics and metabolism is critical during early drug development. This study investigates the absorption, distribution, metabolism, and excretion (ADME) profile of R14, a novel compound, using a combination of in vitro and in vivo approaches. Methods: In vitro [...] Read more.

Objectives: A thorough understanding of pharmacokinetics and metabolism is critical during early drug development. This study investigates the absorption, distribution, metabolism, and excretion (ADME) profile of R14, a novel compound, using a combination of in vitro and in vivo approaches. Methods: In vitro studies included Caco-2 permeability assays, metabolic stability evaluations in liver microsomes and hepatocytes, and identification of CYP isoforms responsible for R14 metabolism. In vivo pharmacokinetic and metabolic profiling was conducted in rats following oral administration. R14 was quantified using UHPLC-MS/MS. Metabolites were identified using high-resolution UHPLC- QTOF MS/MS, and relative exposure was estimated using peak area-derived AUCs. Results: R14 exhibited low oral bioavailability (13.4%) and high systemic clearance (2.63 L/h/kg), indicating high hepatic extraction. A total of 21 plasma and 38 urine metabolites were identified. Major metabolic pathways included initial hydroxylation and hydrogenation, followed by sequential methylation and Phase II conjugations (glucuronidation and sulfation). Key metabolites (M3, M4, M22, M38) accounted for the majority of systemic exposure. Less than 1% of the unchanged drug was excreted in urine, confirming extensive metabolism. Notably, discrepancies between in vitro and in vivo metabolite profiles suggested rapid further transformation of initial metabolites in vivo, which were not fully captured in vitro. Conclusions: This study demonstrates an efficient and integrated strategy for early-phase ADME characterization. The combined use of in vitro assays and in vivo studies, guided by advanced analytical techniques, provides a robust framework for understanding drug metabolism. These findings can inform drug optimization and help minimize risks in later stages of development. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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14 pages, 1261 KiB

Open AccessArticle

Promising Protocol for In Vivo Experiments with Betulin

by Pavel Šiman, Aleš Bezrouk, Alena Tichá, Hana Kozáková, Tomáš Hudcovic, Otto Kučera and Mohamed Niang

Pharmaceutics 2025, 17(8), 1051; https://doi.org/10.3390/pharmaceutics17081051 - 13 Aug 2025

Abstract

Background/Objectives: Betulin is a promising agent in many areas of medicine and is being investigated, particularly in the field of cancer. However, in in vivo experiments, its water insolubility becomes a significant obstacle. This study describes a promising method for the administration [...] Read more.

Background/Objectives: Betulin is a promising agent in many areas of medicine and is being investigated, particularly in the field of cancer. However, in in vivo experiments, its water insolubility becomes a significant obstacle. This study describes a promising method for the administration of betulin in in vivo experiments and the determination of betulin levels in organ samples. Methods: Betulin was first dissolved in ethanol, and this solution was then mixed with acylglycerols, followed by evaporation of the ethanol. Olive oil and food-grade lard were determined to be suitable lipids for noninvasive application per os. A method for processing the organs of experimental animals for betulin determination was developed. Determination of betulin levels in blood is also likely the only viable option for use in future clinical studies and practice. Results: The maximum amount of betulin usable (i.e., absorbable by organisms) in olive oil (10 mg/mL), suppository mass (6 mg/mL), food lard (4 mg/mL), and cocoa butter (2 mg/mL) carriers was found microscopically. A specific distribution of betulin concentration in the organs of experimental animals (Wistar rats) after a weekly diet containing betulin was discovered. The blood was shown to be particularly advantageous, as it allows continuous monitoring of betulin levels in the body. In these pilot experiments, a statistically significant (p < 0.001) synergistic effect of betulin on solid Ehrlich adenocarcinoma tumors was observed when betulin was combined with cytostatic Namitecan (NMRI mice). The high-purity betulin used in this study is very stable even under fluctuating storage conditions. Conclusions: Our study suggests that both the method of betulin administration and the proposed analytical procedure could greatly increase the reliability and reproducibility of in vivo studies, as well as future preclinical and clinical studies on the effects of betulin and potentially other similar water-insoluble triterpenoids on living organisms. Full article

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

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20 pages, 1650 KiB

Open AccessReview

Maillard Reaction-Derived Carbon Nanodots: Food-Origin Nanomaterials with Emerging Functional and Biomedical Potential

by Gréta Törős and József Prokisch

Pharmaceutics 2025, 17(8), 1050; https://doi.org/10.3390/pharmaceutics17081050 - 13 Aug 2025

Abstract

The Maillard reaction (MR), a non-enzymatic interaction between reducing sugars and amino compounds, plays a pivotal role in developing the flavor, color, and aroma of thermally processed foods. Beyond its culinary relevance, the MR gives rise to a structurally diverse array of compounds, [...] Read more.

The Maillard reaction (MR), a non-enzymatic interaction between reducing sugars and amino compounds, plays a pivotal role in developing the flavor, color, and aroma of thermally processed foods. Beyond its culinary relevance, the MR gives rise to a structurally diverse array of compounds, including a novel class of fluorescent nanomaterials known as carbon nanodots (CNDs). These Maillard-derived CNDs, although primarily incidental in food systems, exhibit physicochemical characteristics—such as aqueous solubility, biocompatibility, and tunable fluorescence—that are similar to engineered CNDs currently explored in biomedical fields. While CNDs synthesized through hydrothermal or pyrolytic methods are well-documented for drug delivery and imaging applications, no studies to date have demonstrated the use of Maillard-derived CNDs specifically in drug delivery. This review examines the chemistry of the Maillard reaction, the formation mechanisms and characteristics of food-based CNDs, and their potential functional applications in food safety, bioactivity, and future biomedical use. Additionally, it critically evaluates the health implications of Maillard reaction products (MRPs), including both beneficial antioxidants and harmful by-products such as advanced glycation end-products (AGEs). This integrated perspective highlights the dual role of MR in food quality and human health, while identifying key research gaps needed to harness the full potential of food-origin nanomaterials. Full article

(This article belongs to the Topic Challenges and Opportunities in Drug Delivery Research, 2nd Edition)

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21 pages, 3228 KiB

Open AccessArticle

CUSP06, a Novel CDH6-Targeted Antibody-Drug Conjugate, Demonstrates Antitumor Efficacy in Multiple CDH6-Expressing Human Cancer Models

by Wei Lu, Jing Shi, Wentao Zhang, Nicole Covino, Amy Penticoff, Robert Phillips, John Cogswell, Laurie Tatalick, Stephanie Pasas-Farmer, Jianjian Zhang, Caiwei Chen, Yixuan Wang, Huiyan Shi, Shuhui Liu, Xun Meng and Eric Slosberg

Pharmaceutics 2025, 17(8), 1049; https://doi.org/10.3390/pharmaceutics17081049 - 13 Aug 2025

Abstract

Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in [...] Read more.

Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in ovarian cancer, renal cell carcinoma, as well as, less frequently, cholangiocarcinoma, uterine serous carcinoma, glioma, lung, pancreatic and thyroid cancers. The characteristic of limited expression in normal tissues, high expression in tumor tissues, and rapid internalization upon antibody binding makes CDH6 a well-suited antibody-drug conjugate (ADC) target. Methods: We developed a novel CDH6-targeting ADC, CUSP06, consisting of a proprietary humanized antibody selective for CDH6, a protease cleavable linker, and an exatecan payload, with a drug-to-antibody ratio (DAR) of 8. We further characterized the pharmacological activities of CUSP06 in multiple in vitro and in vivo models. Results: CUSP06 was selectively bound to cell surface CDH6 and was efficiently internalized into CDH6-positive ovarian cancer cells, and led to the induction of DNA damage and apoptosis of CDH6-positive cancer cells. CUSP06 exhibited strong antiproliferative activity against several CDH6-positive cancer cell lines and demonstrated strong bystander cell killing effect in the cell mixing experiments in vitro. CUSP06 exhibits excellent in vivo antitumor efficacy in CDH6-high or -low cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) models from human ovarian, renal and uterine cancers, as well as cholangiocarcinoma. CUSP06 demonstrated a favorable safety profile in GLP-compliant toxicology studies in Sprague Dawley rats and cynomolgus monkeys. Conclusions: The preclinical data highlighted the therapeutic potential of CUSP06 in multiple CDH6-positive human cancers. Full article

(This article belongs to the Special Issue Advancements and Innovations in Antibody Drug Conjugates)

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24 pages, 12879 KiB

Open AccessArticle

Evaluation of Sterilized Bioactive-Glass-Coated Magnetic Nanoparticles: Physicochemical Integrity and Biological Compatibility After Gamma Irradiation

by João Gabriel Acioli de Siqueira, Ângela Leão Andrade, Rodrigo Ribeiro de Andrade, Pedro Igor Macário Viana, Lucas Resende Dutra Sousa, Paula Melo de Abreu Vieira, Gabriel Maia Vieira, Tatiane Cristine Silva de Almeida, Maximiliano Delany Martins, Samantha Roberta Machado de Oliveira, Flaviano dos Santos Martins, Marcelo Barbosa de Andrade, Rosana Zacarias Domingues, Alfredo Miranda de Goes, Guilherme Mattos Jardim Costa and Thalita Marcolan Valverde

Pharmaceutics 2025, 17(8), 1048; https://doi.org/10.3390/pharmaceutics17081048 - 12 Aug 2025

Abstract

Background/Objectives: Gamma irradiation is a promising terminal sterilization method for nanoparticle-based biomedical systems. However, its potential effects on the physicochemical properties and biological performance of multifunctional nanomaterials must be carefully evaluated. This study aimed to assess the structural integrity, sterility, and cytocompatibility [...] Read more.

Background/Objectives: Gamma irradiation is a promising terminal sterilization method for nanoparticle-based biomedical systems. However, its potential effects on the physicochemical properties and biological performance of multifunctional nanomaterials must be carefully evaluated. This study aimed to assess the structural integrity, sterility, and cytocompatibility of magnetic nanoparticles (MNPs) and bioactive-glass-coated magnetic nanoparticles (MNPBGs), both based on magnetite (Fe₃O₄), after gamma irradiation. Methods: MNPs and MNPBGs were synthesized and subjected to gamma irradiation at 25 kGy, with additional doses explored in preliminary evaluations. Physicochemical characterizations were performed using XRD, TEM, SAED, and Raman spectroscopy. FTIR analyses were conducted on bioactive glass (BG) controls without magnetite. Sterility was evaluated via microbiological assays. Cytocompatibility and nitric oxide (NO) production were assessed using RAW 264.7 macrophages and Saos-2 osteosarcoma cells. Prussian blue staining was used to evaluate cellular uptake. Results: Gamma irradiation preserved the crystal structure, morphology, and size distribution of the nanoparticles. FTIR revealed only minor changes in the silicate network of BG, such as reduced intensity and slight shifting of Si-O-Si and Si-O-NBO bands, indicating limited radiation-induced structural rearrangement without affecting the material’s stability or cytocompatibility. Microbiological assays confirmed complete inhibition of microbial growth. All irradiated samples exhibited high cytocompatibility, with MNPBGs demonstrating enhanced biological responses. Notably, MNPBGs induced a more pronounced NO production in macrophages. Cellular uptake of nanoparticles by Saos-2 cells remained unaffected after irradiation. Conclusions: Gamma irradiation at 25 kGy is an effective sterilization strategy that maintains the structural and functional integrity of MNPs and MNPBGs. These findings support their safe use in sterile biomedical applications, particularly for bone-related therapies involving immunomodulation and drug delivery, with potential relevance for cancer treatment strategies such as osteosarcoma. Full article

(This article belongs to the Special Issue Cutting-Edge Drug Delivery and Nanomedicine: Innovations in Hybrid Systems, Theranostics and Targeted Therapies)

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23 pages, 2039 KiB

Open AccessArticle

Enhancing Chemical Stability and Bioavailability of Aneratrigine Capsules via Dry Granulation: Addressing Stability Challenges in Sodium Bicarbonate-Containing Formulations for Clinical Development

by Kwan-Ik Cha, Ga-Eon Kim, Ji-Hyung Seol, Dong-Woo Kim and Seungbeom Lee

Pharmaceutics 2025, 17(8), 1047; https://doi.org/10.3390/pharmaceutics17081047 - 12 Aug 2025

Abstract

Background: Aneratrigine, a potent selective Nav1.7 inhibitor, faced challenges in developing a clinically viable oral formulation due to its poor aqueous solubility in acidic gastric conditions (0.06 mg/mL at pH 1.2), leading to limited bioavailability in Phase 1 studies. Methods: To address [...] Read more.

Background: Aneratrigine, a potent selective Nav1.7 inhibitor, faced challenges in developing a clinically viable oral formulation due to its poor aqueous solubility in acidic gastric conditions (0.06 mg/mL at pH 1.2), leading to limited bioavailability in Phase 1 studies. Methods: To address this, a capsule formulation containing sodium bicarbonate (NaHCO₃) was developed to enhance dissolution via in situ pH modulation. However, production-scale wet granulation led to stability issues, such as capsule content discoloration and excessive degradant formation, attributed to NaHCO₃ decomposition under thermal and moisture stress. This raised the content pH and triggered degradation products not seen in initial compatibility tests. Consequently, dry granulation was adopted to minimize heat and moisture exposure. Results: The dry granulation process proved scalable, maintaining chemical integrity across laboratory (1.5 kg), pilot (5.4 kg), and commercial (25.9 kg) batches. The optimized formulation showed enhanced stability (total impurities < 0.05%) and improved dissolution (>80% at 30 min, pH 4.0). Conclusions: This work establishes a robust manufacturing platform that overcomes stability challenges in alkalizer-containing formulations, facilitating the successful advancement of aneratrigine to Phase 2a and providing a model for developing heat- and moisture-sensitive compounds. Full article

(This article belongs to the Special Issue Emerging Drugs and Formulations for Pain Treatment)

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22 pages, 722 KiB

Open AccessSystematic Review

Laser Interventions for Intraoral Halitosis: A Systematic Review of Randomized Controlled Trials

by Rafał Wiench, Jakub Fiegler-Rudol, Natalia Zięba and Maciej Misiołek

Pharmaceutics 2025, 17(8), 1046; https://doi.org/10.3390/pharmaceutics17081046 - 12 Aug 2025

Abstract

Background: This systematic review evaluated the efficacy of laser therapies and antimicrobial photodynamic therapy (aPDT) for the treatment of intraoral halitosis by synthesizing randomized controlled trials. Methods: A comprehensive search of the PubMed, Embase, Scopus, and Cochrane Library databases identified 14 [...] Read more.

Background: This systematic review evaluated the efficacy of laser therapies and antimicrobial photodynamic therapy (aPDT) for the treatment of intraoral halitosis by synthesizing randomized controlled trials. Methods: A comprehensive search of the PubMed, Embase, Scopus, and Cochrane Library databases identified 14 eligible RCTs. Results: Laser-based interventions, including diode lasers and Er,Cr:YSGG lasers, and aPDT using photosensitizers such as methylene blue, toluidine blue, and Bixa orellana (annatto), effectively reduced volatile sulfur compound levels and associated bacterial populations compared to traditional methods like tongue scraping and antiseptic rinses. Combination treatments consistently demonstrated superior short-term efficacy, although treatment outcomes often declined after 7–14 days, indicating the necessity for repeated sessions or adjunctive oral hygiene measures. Conclusions: Methodological heterogeneity across studies regarding laser parameters, photosensitizer types, and outcome measurements highlighted the need for standardized protocols. Future research should focus on multicenter trials with extended follow-up and standardized microbiological evaluations to further validate these promising treatments and integrate them effectively into clinical practice. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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17 pages, 2895 KiB

Open AccessArticle

Anti-Neuroinflammation Effect of Standardized Ethanol Extract of Leaves of Perilla frutescens var. acuta on Aβ-Induced Alzheimer’s Disease-like Mouse Model

by Hyunji Kwon, Jihye Lee, Eunhong Lee, Somin Moon, Eunbi Cho, Jieun Jeon, A Young Park, Joon-Ho Hwang, Gun Hee Cho, Haram Kong, Mi-Houn Park, Sung-Kyu Kim, Dong Hyun Kim and Ji Wook Jung

Pharmaceutics 2025, 17(8), 1045; https://doi.org/10.3390/pharmaceutics17081045 - 12 Aug 2025

Abstract

Background/Objectives: Perilla frutescens var. acuta Kudo, a member of the Lamiaceae family, has been previously reported to reduce neuroinflammation and potentially decrease Aβ plaque accumulation in 5XFAD mice. In this study, we aimed to evaluate the anti-neuroinflammatory potential of a standardized 60% [...] Read more.

Background/Objectives: Perilla frutescens var. acuta Kudo, a member of the Lamiaceae family, has been previously reported to reduce neuroinflammation and potentially decrease Aβ plaque accumulation in 5XFAD mice. In this study, we aimed to evaluate the anti-neuroinflammatory potential of a standardized 60% ethanol extract of Perilla leaves (PE), optimized for commercial application. Methods: The inflammatory response was assessed in LPS-stimulated BV2 microglial cells, and the cognitive improvement was evaluated in an AD animal model induced by intracerebroventricular injection of Aβ. Results: Using LPS-stimulated BV2 microglial cells and an Aβ-injected ICR mouse model of Alzheimer’s disease, we found that PE significantly suppressed the LPS-induced production of nitric oxide and pro-inflammatory mediators, including IL-6, TNF-α, NF-κB, iNOS, and COX-2, along with inhibition of JNK and p38 MAPK activation. Furthermore, PE upregulated CREB and BDNF expression. In vivo, PE administration alleviated Aβ-induced cognitive deficits, which were associated with reduced expression of JNK, NF-κB, iNOS, and COX and increased CREB/BDNF signaling in the hippocampus. Behavioral assessments—including passive avoidance, Morris water maze, novel object recognition, and Y-maze tests—confirmed the improvement in cognitive function. Conclusions: Collectively, these findings demonstrate that PE exerts significant anti-neuroinflammatory and neuroprotective effects, supporting its potential as a functional ingredient for cognitive enhancement. Full article

(This article belongs to the Section Biopharmaceutics)

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33 pages, 10768 KiB

Open AccessArticle

Pharmacodynamic-Driven Sequence-Dependent Synergy Effects in Pemetrexed-Osimertinib Combination Against Non-Small Cell Lung Cancer (NSCLC): Optimizing Synergy Through Sequential Interval

by Kuan Hu, Yu Xia, Tong Yuan, Yan Lin and Jin Yang

Pharmaceutics 2025, 17(8), 1044; https://doi.org/10.3390/pharmaceutics17081044 - 12 Aug 2025

Abstract

Background: Combining pemetrexed (PEM) with Osimertinib (OSI) improves outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), but optimal scheduling remains undefined. Sequential PEM → OSI strategies may outperform concurrent administration; however, the critical dosing interval determining synergy has not [...] Read more.

Background: Combining pemetrexed (PEM) with Osimertinib (OSI) improves outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), but optimal scheduling remains undefined. Sequential PEM → OSI strategies may outperform concurrent administration; however, the critical dosing interval determining synergy has not been explored. Methods: PEM pharmacodynamics were divided into an OSI-antagonized early phase (S-phase arrest and DNA damage accumulation) and OSI-synergized late phase (DNA damage peak, apoptosis initiation, and feedback EGFR activation). Time-course profiling of cell cycle, DNA damage, apoptosis, and EGFR pathways was evaluated under monotherapy or sequential combination regimens to elucidate the mechanisms underlying synergistic/antagonistic effects. Results: OSI antagonizes PEM’s early phase via G1 arrest but potently enhances late-phase apoptosis through Rad51/thymidylate synthase suppression, Bim upregulation, and inhibition of EGFR signaling. The 48 h interval PEM → OSI uniquely enabled complete early-phase execution and aligned OSI exposure with late-phase initiation, yielding robust synergy across OSI-sensitive cell lines. In contrast, the 24 h interval PEM → OSI sequence demonstrated synergy only in PEM-sensitive PC9 cells. Both concurrent PEM + OSI and OSI → PEM sequence induced attenuated DNA damage and apoptotic signaling. Conclusions: The 48 h interval PEM → OSI sequence maximizes efficacy by temporally segregating antagonistic and synergistic interactions. This pharmacodynamically optimized regimen represents a promising strategy for clinical translation. Full article

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

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50 pages, 2436 KiB

Open AccessReview

Harnessing Phytonanotechnology to Tackle Neglected Parasitic Diseases: Focus on Chagas Disease and Malaria

by Manuela García, María S. Magi and Mónica C. García

Pharmaceutics 2025, 17(8), 1043; https://doi.org/10.3390/pharmaceutics17081043 - 12 Aug 2025

Abstract

Neglected parasitic diseases such as Chagas disease and malaria continue to pose major public health challenges, particularly in low-resource settings. Current therapies are often limited by high toxicity, poor efficacy, drug resistance, and limited accessibility. Phytochemicals, naturally occurring compounds in plants, have played [...] Read more.

Neglected parasitic diseases such as Chagas disease and malaria continue to pose major public health challenges, particularly in low-resource settings. Current therapies are often limited by high toxicity, poor efficacy, drug resistance, and limited accessibility. Phytochemicals, naturally occurring compounds in plants, have played a crucial role in medicine since ancient times and have gained renewed attention for their demonstrated antiparasitic activity. However, many products of natural origin (PNOs) face significant barriers to clinical use, including poor solubility, low bioavailability, and chemical instability. These limitations have driven researchers to explore alternative and innovative approaches based on the use of PNOs to tackle these parasitic infections more effectively. This review provides a comprehensive overview of key PNOs with proven activity against Trypanosoma cruzi and Plasmodium spp., the causative agents of Chagas disease and malaria, respectively. Recent advances in the design of phytonanoformulations are analyzed and discussed, emphasizing the potential of nanocarrier-based systems incorporating PNOs as a strategy to improve the pharmacokinetic and therapeutic properties of these natural products. By critically examining the integration of phytochemicals into nanotechnology-based drug delivery platforms, this review highlights the promise of phytonanotechnology to overcome current limitations in antiparasitic therapy and support the development of more effective and accessible treatments for neglected parasitic diseases. Full article

(This article belongs to the Special Issue Advances in Antiparasitic Agents)

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24 pages, 4513 KiB

Open AccessArticle

Anticancer Activity of Paclitaxel-Loaded Mesoporous Silica Nanoparticles in B16F10 Melanoma-Bearing Mice

by Jihoon Lee, Jung Mo Kim, Yeon-Ju Baek, Hyojeung Kang, Min-Koo Choi and Im-Sook Song

Pharmaceutics 2025, 17(8), 1042; https://doi.org/10.3390/pharmaceutics17081042 - 11 Aug 2025

Viewed by 197

Abstract

Background/Objectives: Paclitaxel (PTX) faces clinical limitations in melanoma treatment due to poor solubility, P-glycoprotein (P-gp)-mediated efflux, and systemic toxicity. This study aimed to develop PTX-loaded mesoporous silica nanoparticles (PS), which would be co-administered with curcumin (CUR) and D-α-tocopherol polyethylene glycol 1000 succinate [...] Read more.

Background/Objectives: Paclitaxel (PTX) faces clinical limitations in melanoma treatment due to poor solubility, P-glycoprotein (P-gp)-mediated efflux, and systemic toxicity. This study aimed to develop PTX-loaded mesoporous silica nanoparticles (PS), which would be co-administered with curcumin (CUR) and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) to enhance intracellular accumulation and improve anti-tumor activity. CUR and TPGS were integrated with PS to inhibit P-gp-mediated PTX-efflux, to enhance the intracellular accumulation of PTX, and to improve anti-tumor activity in B16F10 cells. Methods: The physicochemical properties of PS were analyzed using standard characterization methods. The antitumor activity of PS co-administered with CUR and TPGS was evaluated using two-dimensional (2D) culture and three-dimensional (3D) spheroid assays, and also assessed in B16F10 tumor-bearing mice. The therapeutic mechanism of the PS combination was compared using apoptosis and microtubule disruption through flow cytometry and confocal microscopy. The pharmacokinetics and biodistribution of the PS combination were compared in B16F10 tumor-bearing mice. Results: PS formulations exhibited amorphous transformation with an approximate particle size of 200 nm. PS co-administered with CUR and TPGS reduced the IC₅₀ to 178.7 nM compared with 283.3 nM for free PTX in B16F10 melanoma cells and achieved significant tumor growth inhibition in B16F10 melanoma spheroid culture. The intracellular accumulation of PTX correlated with its therapeutic efficacy. Flow cytometry revealed a significant induction of both early and late apoptosis in cells treated with the PS + CUR + TPGS combination, while confocal imaging confirmed enhanced microtubule disruption. In B16F10 tumor-bearing mice, PS co-administered with CUR and TPGS demonstrated higher and selective distribution of PTX into tumor tissue without affecting systemic exposure of PTX in B16F10-xenografted mice. Conclusions: PS + CUR + TPGS combination enhanced PTX delivery by improving solubility and enhancing distribution to tumor tissue through P-gp inhibition, thereby increasing its therapeutic potential. The combination of CUR and TPGS offers synergistic apoptosis induction and microtubule disruption. Thus, the PS + CUR + TPGS combination represents a promising approach for treating drug-resistant melanomas. Full article

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

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24 pages, 580 KiB

Open AccessReview

Overcoming the Blood–Brain Barrier: Advanced Strategies in Targeted Drug Delivery for Neurodegenerative Diseases

by Han-Mo Yang

Pharmaceutics 2025, 17(8), 1041; https://doi.org/10.3390/pharmaceutics17081041 - 11 Aug 2025

Viewed by 299

Abstract

The increasing global health crisis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood–brain barrier (BBB), which prevents more [...] Read more.

The increasing global health crisis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood–brain barrier (BBB), which prevents more than 98% of small molecules and all biologics from entering the central nervous system. The therapeutic landscape for neurodegenerative diseases has recently undergone transformation through advances in targeted drug delivery that include ligand-decorated nanoparticles, bispecific antibody shuttles, focused ultrasound-mediated BBB modulation, intranasal exosomes, and mRNA lipid nanoparticles. This review provides an analysis of the molecular pathways that cause major neurodegenerative diseases, discusses the physiological and physicochemical barriers to drug delivery to the brain, and reviews the most recent drug targeting strategies including receptor-mediated transcytosis, cell-based “Trojan horse” approaches, gene-editing vectors, and spatiotemporally controlled physical methods. The review also critically evaluates the limitations such as immunogenicity, scalability, and clinical translation challenges, proposing potential solutions to enhance therapeutic efficacy. The recent clinical trials are assessed in detail, and current and future trends are discussed, including artificial intelligence (AI)-based carrier engineering, combination therapy, and precision neuro-nanomedicine. The successful translation of these innovations into effective treatments for patients with neurodegenerative diseases will require essential interdisciplinary collaboration between neuroscientists, pharmaceutics experts, clinicians, and regulators. Full article

(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)

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23 pages, 7940 KiB

Open AccessArticle

A Novel Iodine–Dextrin Complex Exhibits No Acute or Subacute Toxicity and Enhances Azithromycin Efficacy in an LPS-Induced Sepsis Model

by Nailya Ibragimova, Arailym Aitynova, Seitzhan Turganbay, Marina Lyu, Alexander Ilin, Karina Vassilyeva, Diana Issayeva, Tamari Gapurkhaeva, Arkadiy Krasnoshtanov, Galina Ponomareva and Amir Azembayev

Pharmaceutics 2025, 17(8), 1040; https://doi.org/10.3390/pharmaceutics17081040 - 11 Aug 2025

Viewed by 191

Abstract

Background/Objectives: Our work was designed to study the physicochemical properties, safety profile, pharmacokinetics, and prophylactic efficacy of an original iodine–dextrin-based pharmaceutical formulation (PA), both alone and in combination with azithromycin (AZ), in a murine model of LPS-induced sepsis. Methods/Results: UV–vis and ¹H-NMR [...] Read more.

Background/Objectives: Our work was designed to study the physicochemical properties, safety profile, pharmacokinetics, and prophylactic efficacy of an original iodine–dextrin-based pharmaceutical formulation (PA), both alone and in combination with azithromycin (AZ), in a murine model of LPS-induced sepsis. Methods/Results: UV–vis and ¹H-NMR spectroscopy confirmed the formation of a stable iodine–dextrin complex, with triiodide anions stabilized by hydrogen bonding and donor–acceptor interactions. No clinical signs of acute toxicity were observed at doses up to 5000 mg/kg, and subacute administration (62.5 and 125 mg/kg) showed no adverse effects on hematological or biochemical parameters. A mild, non-pathological enlargement of thyrocytes and parallel increases in TSH, T3, and T4 levels were observed at 125 mg/kg, consistent with physiological adaptation to iodine. Pharmacokinetic analysis revealed high oral bioavailability (~92%), prolonged half-life (~21 h), and wide tissue distribution with low clearance. In the sepsis model, pretreatment with AZ+PA alleviated clinical symptoms, maintained body weight, and significantly improved hematological parameters, reducing WBCs and CRP levels. The combination also decreased plasma IL-6 and TNF-α concentrations more effectively than either agent alone, indicating a synergistic anti-inflammatory effect. Histological analysis confirmed that PA, particularly in combination with AZ, mitigated LPS-induced tissue injury in the liver, kidney, and lungs. Conclusions: These findings suggest that PA is a safe, bioavailable compound with immunomodulatory properties that enhance azithromycin’s protective effects during systemic inflammation. This supports its potential use as a prophylactic agent in clinical settings, such as preoperative immune modulation to prevent sepsis-related complications. Full article

(This article belongs to the Section Biopharmaceutics)

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18 pages, 3002 KiB

Open AccessArticle

Smart-AMPs: Decorated Nanostructured Lipid Carriers for Improved Efficacy of Antimicrobial Peptides in Chronically Infected Burn Wounds

by Daniela Müller, Laura Nallbati and Cornelia M. Keck

Pharmaceutics 2025, 17(8), 1039; https://doi.org/10.3390/pharmaceutics17081039 - 10 Aug 2025

Viewed by 341

Abstract

Background/Objectives: Burn wound infections present significant clinical challenges due to multidrug-resistant pathogens and the limitations of traditional antimicrobials. While antimicrobial peptides (AMPs) have broad-spectrum effectiveness, their instability in wound environments limits their use. This study compares properties of AMP-decorated nanostructured lipid carriers [...] Read more.

Background/Objectives: Burn wound infections present significant clinical challenges due to multidrug-resistant pathogens and the limitations of traditional antimicrobials. While antimicrobial peptides (AMPs) have broad-spectrum effectiveness, their instability in wound environments limits their use. This study compares properties of AMP-decorated nanostructured lipid carriers (NLCs) to free AMPs, focusing on their dermal penetration, retention, and antimicrobial efficacy in simulated ex vivo burn wound models. Methods: AMP-decorated NLCs (smart-AMPs) were produced by electrostatic and hydrophobic surface adsorption and characterized regarding their size, zeta potential, and physical short-term stability. The distribution of AMPs within the wounds was evaluated using an ex vivo porcine ear model with various wound types. The antimicrobial efficacy was assessed by monitoring the bioluminescence of Aliivibrio fischeri as a live bacterial marker for 24 h. Results: The size and zeta potential measurements confirmed the successful formation of smart-AMPs. The dermal penetration of AMPs was influenced by the type of wound and the type of AMP formulation (free AMPs vs. smart-AMPs). In the chronically infected burn wounds, which were characterized by the formation of a biofilm in a protein-rich wound fluid, the smart-AMPs resulted in a 1.5-fold higher and deeper penetration of the AMPs, and the antimicrobial activity was 6-fold higher compared to the free AMPs. Conclusions: smart-AMPs present an innovative approach for treating chronic, biofilm-associated wounds more efficiently than the current treatment options. Full article

(This article belongs to the Special Issue Advances in Delivery of Peptides and Proteins)

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5 pages, 163 KiB

Open AccessEditorial

Editorial on Special Issue: “Advances in Nanotechnology-Based Drug Delivery Systems”

by Carla Serri

Pharmaceutics 2025, 17(8), 1038; https://doi.org/10.3390/pharmaceutics17081038 - 10 Aug 2025

Viewed by 236

Abstract

Nanotechnology enables the design and application of nanostructures to improve drug delivery by modulating release, enhancing solubility, and increasing bioavailability of poorly soluble APIs, while reducing side effects. This Special Issue includes original research articles and reviews on innovative nanocarriers, such as liposomes, [...] Read more.

Nanotechnology enables the design and application of nanostructures to improve drug delivery by modulating release, enhancing solubility, and increasing bioavailability of poorly soluble APIs, while reducing side effects. This Special Issue includes original research articles and reviews on innovative nanocarriers, such as liposomes, metal and carbon nanoparticles, nanocrystals, and polymeric systems, utilizing sustainable and environmentally friendly synthesis methods. Special emphasis is placed on formulation strategies for encapsulating biological macromolecules, advancing the development of efficient, eco-friendly delivery platforms. Full article

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

30 pages, 4173 KiB

Open AccessReview

Recent Advances in Nanomedicine: Cutting-Edge Research on Nano-PROTAC Delivery Systems for Cancer Therapy

by Xiaoqing Wu, Yueli Shu, Yao Zheng, Peichuan Zhang, Hanwen Cong, Yingpei Zou, Hao Cai and Zhengyu Zha

Pharmaceutics 2025, 17(8), 1037; https://doi.org/10.3390/pharmaceutics17081037 - 10 Aug 2025

Viewed by 359

Abstract

Proteolysis-targeting chimeras (PROTACs) selectively degrade target proteins by recruiting intracellular E3 ubiquitin ligases, overcoming the limitations of traditional small-molecule inhibitors that merely block protein function. This approach has garnered significant interest in precision cancer therapy. However, the clinical translation of PROTACs is hindered [...] Read more.

Proteolysis-targeting chimeras (PROTACs) selectively degrade target proteins by recruiting intracellular E3 ubiquitin ligases, overcoming the limitations of traditional small-molecule inhibitors that merely block protein function. This approach has garnered significant interest in precision cancer therapy. However, the clinical translation of PROTACs is hindered by their typically high molecular weight, poor membrane permeability, and suboptimal pharmacokinetic properties. Nanodrug delivery technologies represent a promising approach to overcome the limitations of PROTACs. By encapsulating, conjugating, or integrating PROTACs into functionalized nanocarriers, these systems can substantially enhance solubility and biostability, enable tumor-targeted and stimuli-responsive delivery, and thereby effectively alleviate the “hook effect” and minimize off-target toxicity. This review systematically outlines the primary design strategies for current nano-PROTAC delivery systems, including physical encapsulation, chemical conjugation, carrier-free self-assembly systems, and intelligent “split-and-mix” delivery platforms. We provide an overview and evaluation of recent advances in diverse nanomaterial carriers—such as lipid-based nanoparticles, polymeric nanoparticles, inorganic nanoparticles, biological carriers, and hybrid nanoparticles—highlighting their synergistic therapeutic potential for PROTACs delivery. The clinical translation prospects of these innovative systems are also discussed. This comprehensive analysis aims to deepen the understanding of this rapidly evolving field, address current challenges and opportunities, promote the advancement of nano-PROTACs, and offer insights into their future development. Full article

(This article belongs to the Special Issue Prodrug Strategies for Enhancing Drug Stability and Pharmacokinetics)

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27 pages, 942 KiB

Open AccessReview

Emerging Frontiers in GLP-1 Therapeutics: A Comprehensive Evidence Base (2025)

by Shikha Patel and Sarfaraz K. Niazi

Pharmaceutics 2025, 17(8), 1036; https://doi.org/10.3390/pharmaceutics17081036 - 9 Aug 2025

Viewed by 405

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved from glucose-lowering agents to transformative therapies across multiple organ systems. This comprehensive review synthesizes current evidence on the mechanisms, established applications, and emerging therapeutic frontiers of GLP-1 RAs. Methods: We conducted a systematic literature search [...] Read more.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved from glucose-lowering agents to transformative therapies across multiple organ systems. This comprehensive review synthesizes current evidence on the mechanisms, established applications, and emerging therapeutic frontiers of GLP-1 RAs. Methods: We conducted a systematic literature search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception through May 2025, using controlled vocabulary and free-text terms related to GLP-1 RAs, their mechanisms, and clinical applications. Results: GLP-1 RAs demonstrate pleiotropic effects through fundamental cellular mechanisms, including enhanced mitochondrial function, anti-inflammatory actions, improved cellular quality control, and comprehensive metabolic regulation. Established applications demonstrate robust efficacy in diabetes management (HbA1c reductions of 1.5–2.0%), obesity treatment (weight loss of 7–24%), and cardiovascular protection (14–20% reduction in major adverse cardiovascular events, or MACE). Emerging applications span neurological disorders, dermatological conditions, respiratory diseases, and novel applications in addiction medicine and autoimmune disorders. Conclusions: GLP-1 RAs represent a paradigmatic shift toward multi-system therapeutic intervention, with expanding evidence supporting their role as comprehensive metabolic modulators. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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17 pages, 2810 KiB

Open AccessArticle

Two-Step Nucleation and Amorphization of Carbamazepine Using a Micro-Droplet Precipitation System

by Xiaoling Zhu, Cheongcheon Lee, Ju Hyun Park, Eun Min Go, Suha Cho, Jonghwi Lee, Sang Kyu Kwak, Jaehyeong Bae and Tae Seok Seo

Pharmaceutics 2025, 17(8), 1035; https://doi.org/10.3390/pharmaceutics17081035 - 9 Aug 2025

Viewed by 316

Abstract

Objectives: Transforming poorly soluble crystalline drugs into their amorphous form is a well-established strategy in pharmaceutical science to enhance their solubility and improve their clinical efficacy. However, developing amorphous forms of organic drugs for pharmaceutical applications presents significant technical hurdles due to [...] Read more.

Objectives: Transforming poorly soluble crystalline drugs into their amorphous form is a well-established strategy in pharmaceutical science to enhance their solubility and improve their clinical efficacy. However, developing amorphous forms of organic drugs for pharmaceutical applications presents significant technical hurdles due to the lack of suitable analytical tools for the amorphization process. Carbamazepine is a crystalline BCS class II drug commonly used for epilepsy and trigeminal neuralgia, whose clinical efficacy is compromised by its low solubility and slow dissolution. Therefore, this study focuses on investigating the amorphization of carbamazepine to enhance its solubility by using a micro-droplet precipitation system. Methods: These micro-droplets serve as individual reactors, enabling homogeneous nucleation for precipitation of carbamazepine. During crystallization, carbamazepine undergoes an intermediate liquid–liquid phase transition characteristic of two-step nucleation. By varying the solvent’s composition (methanol/water), we characterized the kinetics and stability of the intermediate liquid phase under various conditions. Results: Our results indicate that carbamazepine can undergo either a one-step liquid-to-amorphous-solid phase transition or a two-step liquid-to-crystalline-solid phase transition. Notably, both transitions pass through a liquid-to-dense-liquid phase separation process starting from the supersaturated solution, where the generated intermediate phases exhibit different sizes and numbers that are influenced by the solvent and its concentration. Conclusions: Our findings not only elucidate the mechanism underlying the carbamazepine phase transition but also propose a novel method for studying the amorphous process, which could be broadly applicable to other poorly soluble pharmaceutical compounds and may be helpful to amorphous formulations production, potentially offering significant improvements in drug efficacy and patient compliance. Full article

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

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17 pages, 10690 KiB

Open AccessArticle

Tumor Microenvironment Specifically Regulated Nano Chemoamplifier for Chemosensitization and Activation of Anti-Tumor Immune Response by Coordinating Intracellular Magnesium Overload

by Chao Liu, Gaofei Huang, Lu Zhu, Shasha Li, Kun Yang, Nuernisha Alifu and Yingni Duan

Pharmaceutics 2025, 17(8), 1034; https://doi.org/10.3390/pharmaceutics17081034 - 9 Aug 2025

Viewed by 268

Abstract

Background and objectives: Chemotherapy is an established treatment modality for breast cancer; however, it is impaired by issues such as highly refractory chemoresistance and significant side effects. Magnesium ions (Mg²⁺), inorganic metal ions with anti-tumor bioactivity, sensitize cancer cells to chemotherapy [...] Read more.

Background and objectives: Chemotherapy is an established treatment modality for breast cancer; however, it is impaired by issues such as highly refractory chemoresistance and significant side effects. Magnesium ions (Mg²⁺), inorganic metal ions with anti-tumor bioactivity, sensitize cancer cells to chemotherapy by depressing P-glycoprotein (P-gp) expression. Moreover, Mg²⁺ functions as an immunoadjuvant to potentiate anti-tumor immune responses, while excessive Mg²⁺ can induce marked tumor cell apoptosis. Methods: To enable Mg²⁺ to serve as a chemotherapeutic adjuvant for enhanced treatment efficacy, a Trojan horse-like chemoamplifier, denoted as MMSN@Dox, endowed with tumor microenvironment (TME) responsiveness and capable of achieving chemotherapy sensitization and anti-tumor immune activation, was constructed to enhance the efficacy of breast cancer treatment. Leveraging Mg²⁺-enabled TME-responsive degradability of the chemoamplifier, density functional theory (DFT) simulations were conducted to elucidate carrier structural dynamics. Results: Under stimulation of TME, the chemoamplifier decomposes, accompanied by a substantial release of chemotherapeutic agents and metal ions. Excessive Mg²⁺ induces significant tumor cell apoptosis by triggering mitochondrial dysfunction and generating reactive oxygen species (ROS), and reinforces chemotherapy sensitivity by depressing P-gp expression. Furthermore, MMSN@Dox weakens the stemness of tumor cells, further enhancing chemotherapy. The remarkable tumor-killing capability of chemoamplifier MMSN@Dox led to a remarkable immunogenic cell death (ICD) effect. Combined with the regulatory function of Mg²⁺ on T cells, it ultimately activates anti-tumor immune responses and achieves exceptional anti-tumor performance in both in vitro and in vivo models. Conclusions: This approach, leveraging Mg²⁺ to enhance chemotherapy efficacy, establishes a new paradigm for overcoming chemotherapy resistance and offers a novel strategic avenue for advancing nanomedicine in breast cancer treatment. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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26 pages, 3841 KiB

Open AccessArticle

Palladium Complex-Loaded Magnetite Nanoparticles as Drug Delivery Systems for Targeted Liver Cancer Therapy

by Sara A. M. El-Sayed, Ghadha Ibrahim Fouad, Hanan H. Beherei, Mohamed R. Shehata and Mostafa Mabrouk

Pharmaceutics 2025, 17(8), 1033; https://doi.org/10.3390/pharmaceutics17081033 - 8 Aug 2025

Viewed by 344

Abstract

Background/Objectives: Liver cancer is considered one of the most dangerous types of cancer due to both the patients’ and the physician’s delay in diagnosis. Metal/ligand complexes represent antitumor drugs; however, they have several limitations such as a lack of specificity that results [...] Read more.

Background/Objectives: Liver cancer is considered one of the most dangerous types of cancer due to both the patients’ and the physician’s delay in diagnosis. Metal/ligand complexes represent antitumor drugs; however, they have several limitations such as a lack of specificity that results in damage to healthy organs. Therefore, there is a need for a material that improves specificity and decreases side effects. Magnetite nanoparticles (MNPs) show outstanding findings in the targeting and treatment of cancer-diseased organs. Methods: Herein, a metal/ligand palladium complex with antitumor activity was prepared and loaded onto magnetite nanoparticles for the treatment of liver cancer. The proposed structures with the lowest energy geometries were identified by density functional theory (DFT) utilizing the Gaussian09 program. Molecular docking simulation was conducted on an HP Pavilion dv6 Notebook PC equipped with an AMD Phenom™ N930 Quad processor. Afterward, the prepared nano-systems were investigated using FTIR and TEM. In vitro drug release measurement was evaluated in PBS at different time intervals. Eventually, the selectivity of these nano-systems was investigated using an animal rat model. Results: The results showed that MNPs with a crystalline structure and superparamagnetic characteristics (Ms = 71.273 emu/g) were created with a large surface area (63.75 m²/g), and they were validated to be acceptable for drug delivery applications. The palladium complex [Pd(DMEN)Cl₂] loaded onto magnetite released highly in acidic circumstances (pH 4.5), implying that it could be employed for targeted therapy of liver cancer. Conclusions: In vivo investigations in a rat model of liver cancer induced by diethylnitrosamine and thioacetamide (DEN/TAA) showed that the combination of the palladium complex and magnetite demonstrated a potent anticancer therapeutic activity on liver cancer in rats, improving liver function and structure while mitigating inflammation. Full article

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

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26 pages, 4076 KiB

Open AccessArticle

Yeast-Derived Glucan Particles: Biocompatibility, Efficacy, and Immunomodulatory Potential as Adjuvants and Delivery Systems

by João Panão-Costa, Mariana Colaço, Sandra Jesus, Filipa Lebre, Maria T. Cruz, Ernesto Alfaro-Moreno and Olga Borges

Pharmaceutics 2025, 17(8), 1032; https://doi.org/10.3390/pharmaceutics17081032 - 8 Aug 2025

Viewed by 237

Abstract

Background/Objectives: Glucan particles (GPs), derived from Saccharomyces cerevisiae yeast, possess unique biomedical properties. Nevertheless, it is imperative that a comprehensive risk assessment is conducted during pre-clinical development. GPs are primarily constituted of a naturally occurring polymer known as β-glucan. This study characterized [...] Read more.

Background/Objectives: Glucan particles (GPs), derived from Saccharomyces cerevisiae yeast, possess unique biomedical properties. Nevertheless, it is imperative that a comprehensive risk assessment is conducted during pre-clinical development. GPs are primarily constituted of a naturally occurring polymer known as β-glucan. This study characterized GPs, focusing on physicochemical attributes, biocompatibility, and immunomodulatory potential. Methods: GPs were characterized for size, morphology, surface charge, and protein encapsulation efficiency using dynamic light scattering (DLS), electron microscopy, and encapsulation assays. Biocompatibility was assessed through cytotoxicity assays (MTT), hemolysis tests, and measurement of reactive oxygen (ROS) and nitric oxide (NO) production in immune cells. Immunomodulatory potential was evaluated by cytokine and chemokine secretion analysis in peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (moDCs) and through in vivo immunization studies in a murine model, focusing on cellular immune responses. Results: GPs demonstrated stable physicochemical properties and efficient protein encapsulation, highlighting their suitability as vaccine delivery systems. They exhibited biocompatibility by not inducing cytotoxicity, hemolysis, or excessive ROS and NO production. In PBMCs, GPs stimulated cytokine secretion, suggesting their adjuvant potential. GPs were efficiently internalized by monocytes and led to specific chemokine secretion in stimulated moDCs. In a murine model, GPs induced distinctive cellular immune responses, including TNF-α and IFN-γ production and effector memory T cell activation. Conclusions: These findings emphasize GPs’ biocompatibility and immunomodulatory effects, highlighting their potential in immunotherapy and vaccine development, particularly for targeting infectious agents like hepatitis B virus. Full article

(This article belongs to the Special Issue Applications of Nanomaterials in Immunotherapies)

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23 pages, 6102 KiB

Open AccessArticle

The Anti-Glioblastoma Effects of Novel Liposomal Formulations Loaded with Cannabidiol, Celecoxib, and 2,5-Dimethylcelecoxib

by Anna Rybarczyk, Aleksandra Majchrzak-Celińska, Ludwika Piwowarczyk and Violetta Krajka-Kuźniak

Pharmaceutics 2025, 17(8), 1031; https://doi.org/10.3390/pharmaceutics17081031 - 8 Aug 2025

Viewed by 268

Abstract

Background/Objectives: Glioblastoma multiforme (GBM) therapy efficacy remains limited due to the poor blood-brain barrier-penetrating power of drugs as well as dysregulated cellular signaling pathways of tumor cells leading to drug resistance. Novel drug delivery systems such as liposome-based nanoformulations improve the bioavailability [...] Read more.

Background/Objectives: Glioblastoma multiforme (GBM) therapy efficacy remains limited due to the poor blood-brain barrier-penetrating power of drugs as well as dysregulated cellular signaling pathways of tumor cells leading to drug resistance. Novel drug delivery systems such as liposome-based nanoformulations improve the bioavailability and stability of water-insoluble drugs, while co-delivery of two anti-cancer compounds can further increase their anti-tumor effectiveness due to synergistic effects. Thus, the aim of this study was to obtain liposomal nanoformulations encapsulating cannabidiol (CBD), celecoxib (CELE), and 2,5-dimethylcelecoxib (DMC) and their combinations and to verify their anti-GBM properties. Methods: Five liposomal nanoformulations were obtained using a modified thin-film hydration technique. Two GBM cell lines and non-cancerous astrocytes were used for the biological evaluation of the tested nanoformulations. The cytotoxicity experiments were performed using the MTT assay, whereas flow cytometry-based analysis assessed the effect of the liposomes on apoptosis, cell cycle distribution, and oxidative stress. To determine the impact of the tested nanoformulations on Nrf2, Wnt/β-catenin, and NF-κB signaling pathways, qPCR, Western blot and ELISA techniques were used. Results: The findings of this study demonstrate that liposomal nanoformulations containing CBD, CELE, and DMC exhibit significant anti-GBM activity, particularly through the induction of apoptosis and oxidative stress and modulation of the key signaling pathways. Although no clear synergistic/additive effects were observed between CBD and CELE or DMC when co-loaded in nanoformulations, the combination of CBD and CELE effectively suppressed Wnt/β-catenin and NF-κB signaling and activated the Nrf2 pathway. These results support the therapeutic potential of liposome-based co-delivery of CBD and CELE in GBM therapy. However, further in vivo studies are warranted to determine these nanoformulations’ translational relevance and clinical applicability. Full article

(This article belongs to the Special Issue Advances in Bioactive Compounds and Nanotechnology: Sustainable Approaches for Pharmaceutical Applications)

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13 pages, 1069 KiB

Open AccessArticle

Cyclosporine Dissolution Test from a Lipid Dosage Form: Next Step Towards the Establishment of Release Method for Solid Lipid Microparticles

by Eliza Wolska, Patrycja Dudek and Małgorzata Sznitowska

Pharmaceutics 2025, 17(8), 1030; https://doi.org/10.3390/pharmaceutics17081030 - 8 Aug 2025

Viewed by 205

Abstract

Background: The release study is a standard tool for the development, evaluation, and control of dosage forms. In the case of traditional drug delivery systems, it is conducted in accordance with the established principles available in the European and American Pharmacopoeias or guidelines [...] Read more.

Background: The release study is a standard tool for the development, evaluation, and control of dosage forms. In the case of traditional drug delivery systems, it is conducted in accordance with the established principles available in the European and American Pharmacopoeias or guidelines proposed by registration agencies. The problem is the study of modern carriers, not yet described in compendia, which require adjustments to traditionally used methods. Objectives: The present study focuses on developing an optimal method for testing the release of cyclosporine (Cs, 0.5–4%) incorporated in solid lipid microparticles (SLM) dispersions (10%) intended for administration in the form of eye drops. This is a multicompartment lipid carrier that provides prolonged release of the active substance. Methods: Three methods of testing the release were compared: the dialysis bag method, the horizontal cells technique, and a method without a membrane. Results: During the analyses, the proper membrane was selected and the effect of the lysozyme enzyme on the release profile was analyzed. The effect of the composition of the acceptor fluid on the obtained results was also assessed. In the model without a membrane, up to 60% of the Cs was released within 30 min due to the burst effect. In horizontal chambers, no formulation released more than 14% of the Cs over 96 h, while at the same time, 60–70% of the Cs was released from the dialysis bag. Conclusions: Based on the obtained results, the dialysis bag method was selected to study the release of Cs from SLM without the need to use multicomponent artificial tear fluid as an acceptor medium. Full article

(This article belongs to the Special Issue Solid Dispersions for Drug Delivery: Development, Preparation and In Vitro/In Vivo Characterization)

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20 pages, 4142 KiB

Open AccessArticle

Repeated Administration of Guar Gum Hydrogel Containing Sesamol-Loaded Nanocapsules Reduced Skin Inflammation in Mice in an Irritant Contact Dermatitis Model

by Vinicius Costa Prado, Bruna Rafaela Fretag de Carvalho, Kauani Moenke, Amanda Maccangnan Zamberlan, Samuel Felipe Atuati, Ana Clara Perazzio Assis, Evelyne da Silva Brum, Raul Edison Luna Lazo, Andréa Inês Horn Adams, Luana Mota Ferreira, Sara Marchesan Oliveira and Letícia Cruz

Pharmaceutics 2025, 17(8), 1029; https://doi.org/10.3390/pharmaceutics17081029 - 7 Aug 2025

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Abstract

Background/Objectives: Dermatitis is frequently treated with dexamethasone cutaneous application, which causes adverse effects mainly when it is chronically administered. Sesamol is a phytochemical compound known for its anti-inflammatory activity and low toxicity. Therefore, this study reports the optimization of a guar gum [...] Read more.

Background/Objectives: Dermatitis is frequently treated with dexamethasone cutaneous application, which causes adverse effects mainly when it is chronically administered. Sesamol is a phytochemical compound known for its anti-inflammatory activity and low toxicity. Therefore, this study reports the optimization of a guar gum hydrogel with enhanced physicochemical and microbiological stability, providing an effective dosage form for topical application of sesamol nanocapsules to treat irritant contact dermatitis. Methods: Nano-based hydrogel containing 1 mg/g sesamol was prepared by adding the nanocapsule suspension to form a 2.5% (w/v) guar gum dispersion. Dynamic rheological analysis indicates that the formulations exhibit a non-Newtonian flow with pseudoplastic behavior. Hydrogels were evaluated by Fourier-transformed infrared (FTIR) spectroscopy, and, following spectrum acquisition, an unsupervised chemometrics model was developed to identify crucial variables. Additionally, the physicochemical and microbiological stability of the hydrogel was evaluated over a 60-day period. Results: ATR-FTIR spectra of all hydrogels evaluated are very similar after preparation and 60 days of storage. However, it showed a slight increase in average diameter and PDI and decreased pH values after 60 days. Microbiological assessment demonstrated that the hydrogel met the requirements for the microbial count over 60 days. The dermatitis model was induced by repeated applications of croton oil in the right ears of mice. The effectiveness of the hydrogels was evaluated by assessing ear edema and migration of polymorphonuclear cells. The nano-based hydrogel exhibited anti-inflammatory properties similar to those of dexamethasone. Conclusions: Therefore, the nano-based hydrogel containing sesamol exhibits therapeutic potential for treating cutaneous inflammatory diseases. Full article

(This article belongs to the Special Issue Bio-Based Hydrogels: Sustainable and Efficient Drug Delivery Solutions)

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Pharmaceutics, Volume 17, Issue 8 (August 2025) – 112 articles

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