Pharmaceutics

13 pages, 767 KB

Open AccessArticle

Do Cenobamate Pharmacokinetics Change with Co-Administered Antiseizure Medications? An Exploratory Analysis of Responder Patients with Focal Drug-Resistant Epilepsy

by Bruno Charlier, Viviana Izzo, Giovanni Assenza, Anna Chiara Balsamo, Flavia Cirillo, Albino Coglianese, Carlo Di Bonaventura, Mariana Fernandes, Antonio Gambardella, Emanuele Cerulli Irelli, Claudio Liguori, Sandra Rufolo, Ilaria Sammarra, Amelia Filippelli and Francesca Felicia Operto

Pharmaceutics 2026, 18(1), 92; https://doi.org/10.3390/pharmaceutics18010092 (registering DOI) - 10 Jan 2026

Abstract

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved for the treatment of drug-resistant focal epilepsy in adults. Notwithstanding significant proof of efficacy, real-world pharmacokinetics (PK) data are lacking, particularly regarding sex-based variations and the effect of concomitant ASMs. This exploratory study aimed [...] Read more.

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved for the treatment of drug-resistant focal epilepsy in adults. Notwithstanding significant proof of efficacy, real-world pharmacokinetics (PK) data are lacking, particularly regarding sex-based variations and the effect of concomitant ASMs. This exploratory study aimed to investigate the PK profile of CNB in responder adults with drug-resistant focal epilepsy and assess potential relationship with concomitant ASMs and clinical variables. Methods: We enrolled 17 patients receiving add-on CNB. The concentration-to-dose ratio (C/D), incremental slope (ΔC/ΔD), and dose-to-concentration AUC were calculated. Enrolled individuals were stratified into three exposure clusters (low, medium, and high). Univariate ANOVA was used to explore associations between PK parameters, clinical variables and concomitant ASMs. Results: Sex appeared to be associated with AUC cluster classification (p = 0.026), showing females predominating in the high-exposure group. A nonlinear dose-concentration relationship emerged from the ΔC/ΔD analysis, showing steeper slopes at low doses (12.5–50 mg), great variability at higher doses (100–200 mg), and a negative slope in some individuals. Higher CNB concentrations were observed in patients co-treated with lacosamide, while concomitant topiramate was associated with lower exposure. Carbamazepine and valproate showed non-significant trends consistent with their known enzyme-inducing and inhibiting properties. Conclusions: PK of CNB appears highly variable and seems to be influenced by sex and concomitant ASMs. These findings highlight the importance of therapeutic drug monitoring and individualized titration strategies to optimize efficacy and safety in clinical practice. These results should be regarded as exploratory and hypothesis-generating due to the small and monocentric sample size and need to be confirmed in larger, multicenter cohorts. Full article

(This article belongs to the Special Issue Personalized Drug Therapy: The Role of Pharmacokinetics and Therapeutic Drug Monitoring)

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21 pages, 697 KB

Open AccessArticle

Two Comprehensive Liquid Chromatography High-Resolution Mass Spectrometry (UPLC-MS/MS) Multi-Methods for Real-Time Therapeutic Drug Monitoring (TDM) of Five Novel Beta-Lactams and of Fosfomycin Administered by Continuous Infusion

by Ilaria Trozzi, Beatrice Giorgi, Riccardo De Paola, Milo Gatti and Federico Pea

Pharmaceutics 2026, 18(1), 91; https://doi.org/10.3390/pharmaceutics18010091 (registering DOI) - 10 Jan 2026

Abstract

Background/Objectives: Therapeutic drug monitoring (TDM) of β-lactams (BL), BL/β-lactamase inhibitor (BLI) combinations (BL/BLIc), and of fosfomycin may play a key role in optimizing antimicrobial therapy and in preventing resistance development, especially when used by continuous infusion in critically ill or immunocompromised patients. [...] Read more.

Background/Objectives: Therapeutic drug monitoring (TDM) of β-lactams (BL), BL/β-lactamase inhibitor (BLI) combinations (BL/BLIc), and of fosfomycin may play a key role in optimizing antimicrobial therapy and in preventing resistance development, especially when used by continuous infusion in critically ill or immunocompromised patients. Unfortunately, analytical methods for simultaneously quantifying multiple BL/BLIc in plasma are still lacking. Methods: The aim of this study was to develop and validate two rapid, sensitive, and accurate UPLC–qTOF–MS/MS methods for the simultaneous quantification of five novel β-lactam or β-lactam/β-lactamase inhibitor combinations (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, cefiderocol, and ceftobiprole) along with fosfomycin. Methods: Human plasma samples were prepared by protein precipitation using methanol containing isotopically labeled internal standards. Chromatographic separation was achieved within 10–12 min using two Agilent Poroshell columns (EC-C18 and PFP) under positive and negative electrospray ionization modes. The method was validated according to the EMA guidelines by assessing selectivity, linearity, precision, accuracy, matrix effects, extraction recovery, and stability. Results: The methods exhibited excellent linearity (R² ≥ 0.998) across the calibration ranges for all of the analytes (1.56–500 µg/mL), with limits of quantification ranging from 1.56 to 15.62 µg/mL. Intra- and inter-day precision and accuracy were always within ±15%. Extraction recovery always exceeded 92%, and the matrix effects were effectively corrected through isotopic internal standards. No carry-over or isobaric interferences were observed. All the analytes were stable for up to five days at 4 °C, but the BL and BL/BLIc stability was affected by multiple freeze–thaw cycles. Conclusions: These UPLC-qTOF-MS/MS multi-analyte methods enabled a simultaneous, reliable quantification in plasma of five novel beta-lactams and of fosfomycin. Robustness, high throughput, and sensitivity make these multi-methods feasible for real-time TDM, supporting personalized antimicrobial dosing and improved therapeutic outcomes in patients with severe or multidrug-resistant infections. Full article

(This article belongs to the Section Clinical Pharmaceutics)

28 pages, 6726 KB

Open AccessArticle

Intestinal Permeation Characteristics via Non-Everted Gut Sac of Diterpene Lactones from Pure Andrographolide and Three Different Andrographis Extracts: An Investigation into Liqui-Mass with Different Solvents

by Peera Tabboon, Ekapol Limpongsa, Thitiphorn Rongthong, Thaned Pongjanyakul and Napaphak Jaipakdee

Pharmaceutics 2026, 18(1), 90; https://doi.org/10.3390/pharmaceutics18010090 (registering DOI) - 10 Jan 2026

Abstract

Objectives: This study aimed to assess the intestinal permeation behaviors of andrographolide (AG) and 14-deoxy-11,12-didehydroandrographolide (DDAG), diterpene lactones from Andrographis paniculata extract (APE), pure AG, and three distinct source APEs. The effects of different solvents were also investigated. Methods: Solubility investigation [...] Read more.

Objectives: This study aimed to assess the intestinal permeation behaviors of andrographolide (AG) and 14-deoxy-11,12-didehydroandrographolide (DDAG), diterpene lactones from Andrographis paniculata extract (APE), pure AG, and three distinct source APEs. The effects of different solvents were also investigated. Methods: Solubility investigation was performed using APE. APEs and pure AG were prepared as liqui-masses, cohesive mixtures of APE, solvents, and solid carriers. PXRD, in vitro release, and ex vivo intestinal permeation using the non-everted gut sac method were investigated. Results: Solubility of AG and DDAG in N-methyl-2-pyrrolidone (NMP) > NMP/diethylene glycol monoethyl ether (DG) mixtures > DG. PXRD indicated that crystallinity loss of liqui-mass was affected by solvent’s solvency capacity. The release behaviors of AG and DDAG in phosphate buffer from pure AG and APEs varied depending on their solid state. The release efficiencies of AG and DDAG from liqui-mass systems increased significantly. The apparent permeability (P_app) of AG from pure AG was 0.11 ± 0.05 ×10⁻⁵ cm·s⁻¹, which was 11–25 times less than that of APEs. The P_app of DDAG from various APEs was comparable, ranging between 5.95 and 7.37 × 10⁻⁵ cm·s⁻¹. The presence of a solvent, specifically NMP, in liqui-mass significantly enhanced the release rate and permeation flux. The P_app of AG and DDAG from liqui-mass increased by factors of 1.0–2.3 and 1.1–2.7, respectively. Conclusions: This study is the first to emphasize the differences in the release and intestinal permeation characteristics of AG and DDAG from APEs. These findings offer essential insights into the intestinal permeation behavior of diterpene lactones, along with a straightforward mechanistic strategy for enhancement. Full article

(This article belongs to the Section Biopharmaceutics)

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39 pages, 4559 KB

Open AccessArticle

Potentiation of the Pharmacological Effects of an Aristolochia clematitis L. Extract by Loading into Liposomes Facilitating Release to HaCaT Cells

by Laura Grațiela Vicaș, Nicole Alina Marian, Diana Haj Ali, Narcis Duteanu, Paula Svera, Cristina Dehelean, Ana-Maria Vlase, Olimpia-Daniela Frenț, Ioana-Lavinia Dejeu, Rodica Anamaria Negrean, Răzvan Mihai Oros, Luminița Fritea, Andreea Smeu and Mariana Eugenia Mureșan

Pharmaceutics 2026, 18(1), 89; https://doi.org/10.3390/pharmaceutics18010089 (registering DOI) - 10 Jan 2026

Abstract

Background: Aristolochia clematitis L. (AC), a plant with diverse traditional uses, has gained increasing scientific interest due to its rich content of bioactive compounds such as flavonoids and polyphenols. However, its systemic use is limited by the presence of aristolochic acids, which [...] Read more.

Background: Aristolochia clematitis L. (AC), a plant with diverse traditional uses, has gained increasing scientific interest due to its rich content of bioactive compounds such as flavonoids and polyphenols. However, its systemic use is limited by the presence of aristolochic acids, which are known for their nephrotoxic and carcinogenic potential. Method: In this context, the present study investigates the therapeutic potential of A. clematitis extract by encapsulating it in liposomes with the aim of enhancing its topical efficacy. Results: The extract was characterized in terms of its flavonoid content (67.23 ± 0.33 mg QE/g DW (quercetin/dry plant material)) and polyphenols expressed as gallic acid equivalents (64.38 ± 0.16 mg GAE/g DW), as well as its antioxidant capacity using the reagents 1,1-diphenyl-2-picrylhydrazyl (DPPH − IC₅₀ = 0.1619 mg/mL extract) and diammonium 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS − IC₅₀ = 205.57 μg/mL extract). Four types of liposomes were synthesized (two loaded with extract and two empty), and their characterization was performed using Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS), Zeta Potential, polydispersity index, and in vitro release studies. Conclusions: The results demonstrated a high entrapment efficiency (over 82%), good stability over 30 days, and controlled release of flavonoids. Microbiological studies revealed relevant antimicrobial activity against Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa strains. The evaluation on HaCaT skin-derived cells (at 10–100 µg/mL) proved that the samples displayed good overall tolerability, slightly decreasing cell viability (the most statistically significant being associated with AC treatment) and showing no structural, nuclear, or mitochondrial morphological changes. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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16 pages, 2571 KB

Open AccessArticle

A Nanoparticle-Based Strategy to Stabilize 5-Azacytidine and Preserve DNA Demethylation Activity in Human Cardiac Fibroblasts

by Kantaporn Kheawfu, Chuda Chittasupho, Sudarshan Singh, Siriporn Okonogi and Narainrit Karuna

Pharmaceutics 2026, 18(1), 88; https://doi.org/10.3390/pharmaceutics18010088 - 9 Jan 2026

Abstract

Background: 5-Azacytidine (5-Aza) is a clinically important DNMT inhibitor with the potential to modulate cardiac remodeling by epigenetically reprogramming human cardiac fibroblasts (HCFs). However, its clinical utility is limited by rapid hydrolytic degradation. Nanoparticle (NP) encapsulation offers a strategy to mitigate this instability. [...] Read more.

Background: 5-Azacytidine (5-Aza) is a clinically important DNMT inhibitor with the potential to modulate cardiac remodeling by epigenetically reprogramming human cardiac fibroblasts (HCFs). However, its clinical utility is limited by rapid hydrolytic degradation. Nanoparticle (NP) encapsulation offers a strategy to mitigate this instability. This study evaluated the physical and chemical stability of free 5-Aza and 5-Aza-loaded lipid nanoparticles (5-Aza-NP) under different storage temperatures and examined their effects on DNA methylation-related gene expression in HCFs. Methods: Hyaluronic acid-stabilized lipid NPs were prepared using a solvent displacement method. Particle size, polydispersity index (PDI), and zeta potential were monitored over four days at −20 °C, 4 °C, and 30 °C. Chemical stability was assessed using HPLC and first-order kinetic modeling. Functional activity was evaluated by treating HCFs with free 5-Aza or 5-Aza-NP stored for 96 h and measuring DNMT1, DNMT3A, and DNMT3B expression by RT-qPCR. Results: 5-Aza-NP remained physically stable at 4 °C, while −20 °C induced aggregation and 30 °C caused thermal variability. Free 5-Aza degraded rapidly at 30 °C (6.56% remaining at 72 h), whereas 5-Aza-NP preserved 11.54%. Kinetic modeling confirmed first-order degradation, with consistently longer half-lives for the NP formulation. Functionally, 5-Aza–NP preserved its ability to suppress DNMT1 expression following 96 h of storage at 4 °C, whereas free 5-Aza showed reduced activity. In contrast, DNMT3A and DNMT3B levels remained low and unchanged across all treatments. Conclusions: NP encapsulation enhances the physicochemical stability of 5-Aza and preserves its DNMT1-inhibitory activity, while DNMT3A/B remain unaffected. These findings support NP-based delivery as a promising strategy to stabilize labile epigenetic drugs such as 5-Aza. Full article

(This article belongs to the Special Issue Smart Materials for Advanced Drug Delivery Systems and Pharmaceutical Applications)

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17 pages, 3619 KB

Open AccessArticle

Nobiletin Attenuates Inflammation and Modulates Lipid Metabolism in an In Vitro Model of Intestinal Failure-Associated Liver Disease

by Marta Belka, Aleksandra Gostyńska-Stawna, Karina Sommerfeld-Klatta, Maciej Stawny and Violetta Krajka-Kuźniak

Pharmaceutics 2026, 18(1), 87; https://doi.org/10.3390/pharmaceutics18010087 - 9 Jan 2026

Abstract

Background: Intestinal failure-associated liver disease (IFALD) is a serious complication in patients receiving parenteral nutrition, often exacerbated by inflammation, lipid overload, and oxidative stress. Nobiletin (NOB), a polymethoxylated flavone, is known for its anti-inflammatory and lipid-regulating properties. Methods: We employed an [...] Read more.

Background: Intestinal failure-associated liver disease (IFALD) is a serious complication in patients receiving parenteral nutrition, often exacerbated by inflammation, lipid overload, and oxidative stress. Nobiletin (NOB), a polymethoxylated flavone, is known for its anti-inflammatory and lipid-regulating properties. Methods: We employed an in vitro model using THLE-2 human hepatocytes and primary human cholangiocytes exposed to Intralipid (INT) and lipopolysaccharide (LPS) to simulate IFALD conditions. NOB was tested at non-toxic concentrations (10 and 25 µM) to assess its protective effects. MTT viability assays, multiplex bead-based immunoassays (MAGPIX), RT-qPCR, and Western blotting were used to evaluate changes in inflammation markers, gene expression, and protein signaling. Moreover, ALT and AST activities were used to assess hepatocellular injury. Results: NOB maintained high cell viability in THLE-2 hepatocytes and cholangiocytes, confirming its low cytotoxicity. NOB normalized ALT and AST activities in both tested cell lines, but the effect reached statistical significance only for ALT in cholangiocytes. Under IFALD-like conditions (LPS+INT), NOB significantly preserved metabolic activity in both cell types. In THLE-2 and cholangiocytes, NOB markedly reduced the phosphorylation of pro-inflammatory proteins JNK, NF-κB, and STAT3, indicating a broad inhibition of inflammatory signaling. Moreover, in THLE-2 cells, NOB upregulated lipid metabolism-related genes (PRKAA2, CYP7A1, and ABCA1) and decreased oxidative stress, thereby enhancing the nuclear translocation of Nrf2 and increasing SOD1 level, which supports the activation of antioxidant defenses. Conclusions: NOB exhibits hepatoprotective properties under IFALD-like conditions in vitro, likely through modulation of inflammation-related signaling and lipid metabolism pathways. Full article

(This article belongs to the Special Issue Anti-Inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside, 3rd Edition)

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26 pages, 3313 KB

Open AccessSystematic Review

The Effect of GLP-1 Agonists on Patients with Metabolic-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis

by Denisia Adelina Tornea, Christian Goldis, Alexandru Isaic, Alexandru Catalin Motofelea, Alexandra Christa Sima, Tudor Ciocarlie, Andreea Crintea, Razvan Gheorghe Diaconescu, Nadica Motofelea and Adrian Goldis

Pharmaceutics 2026, 18(1), 86; https://doi.org/10.3390/pharmaceutics18010086 - 9 Jan 2026

Abstract

Background: Metabolically associated fatty liver disease (MASLD) constitutes a major burden. Glucagon-like peptide-1 agonists (GLP-1) could improve hepatic steatosis as well as weight loss. However, the effect of GLP-1 agonists on patients with and without diabetes and the effect of newer drugs [...] Read more.

Background: Metabolically associated fatty liver disease (MASLD) constitutes a major burden. Glucagon-like peptide-1 agonists (GLP-1) could improve hepatic steatosis as well as weight loss. However, the effect of GLP-1 agonists on patients with and without diabetes and the effect of newer drugs (dual and triple agonists) are unclear. Objective: To investigate the effect of GLP-1 agonists, including dual and triple agonists, in patients with metabolic-associated liver steatosis and steatohepatitis, while exploring their effect on patients with and without type 2 diabetes. Methods: We searched PubMed, Scopus, and Web of Science in October 2025 for randomized parallel controlled trials that investigated the effect of GLP-1 agonists in patients with MASLD or metabolic-associated steatohepatitis (MASH). We assessed the quality of the included studies using Cochrane ROB2. We performed the analysis using RevMan 5.4. We performed subgroup analysis based on the status of diabetes, the control group, and the class of GLP-1 agonist (single, dual, or triple). Results: We included twenty studies. Compared to the control group, GLP-1 agonists were associated with a statistically significant increase in the resolution of MASH without worsening fibrosis (RR 3.03, p < 0.0001) and at least one stage of liver fibrosis without the worsening of MASH compared to the control group (RR: 1.45, p < 0.00001). GLP-1 agonists were associated with a statistically significant weight reduction (SMD −1.11, p < 0.0001), glycosylated hemoglobin (SMD −0.81, p < 0.00001), levels of aspartate aminotransferase (SMD −0.48, p = 0.008), and alanine aminotransferase (SMD −0.54, p = 0.008). However, in patients without type 2 diabetes, GLP-1 agonists had no significant effect on weight loss (SMD −0.97, p = 0.12) or improvement in fibrosis (RR 1.54, p = 0.24). There was a statistically significant increase in the overall adverse events (RR 1.10, p < 0.00001), while there was no significant difference in serious adverse events (p = 0.35). Conclusions: GLP-1 agonists improved liver fibrosis, steatohepatitis, weight loss, HbA1c, and liver enzymes in patients with MASLD or MASH. Overall, GLP-1 agonists were associated with a significantly higher risk of adverse events compared to the control, while serious adverse events were comparable between both groups. There was no significant effect on weight loss or improvement in fibrosis in patients without type 2 diabetes. However, there was a limited number of studies in this population. Thus, further research is needed before recommendations can be made for this subgroup. Full article

(This article belongs to the Special Issue GLP-1 Receptor Agonists: Current Understanding and Emerging Therapeutic Horizons)

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29 pages, 9445 KB

Open AccessArticle

Minimally Invasive Endovascular Administration for Targeted PLGA Nanoparticles Delivery to Brain, Salivary Glands, Kidney and Lower Limbs

by Olga A. Sindeeva, Lyubov I. Kazakova, Alexandra Sain, Olga I. Gusliakova, Oleg A. Kulikov, Daria A. Terentyeva, Irina A. Gololobova, Nikolay A. Pyataev and Gleb B. Sukhorukov

Pharmaceutics 2026, 18(1), 85; https://doi.org/10.3390/pharmaceutics18010085 - 9 Jan 2026

Abstract

Background: While intravenous administration of nanoparticles (NPs) is effective for targeting the lungs and liver, directing them to other organs and tissues remains challenging. Methods: Here, we report alternative administration routes that improve organ-specific accumulation of poly (lactic-co-glycolic acid) (PLGA) NPs (100 nm, [...] Read more.

Background: While intravenous administration of nanoparticles (NPs) is effective for targeting the lungs and liver, directing them to other organs and tissues remains challenging. Methods: Here, we report alternative administration routes that improve organ-specific accumulation of poly (lactic-co-glycolic acid) (PLGA) NPs (100 nm, negatively charged) loaded with the near-infrared dye Cyanine 7 (Cy7). NP cytotoxicity was evaluated in HEK293, mMSCs, C2C12, L929, and RAW264.7 cells. Hemocompatibility was assessed using WBCs and RBCs. NPs were administered via the tail vein, carotid, renal, and femoral arteries in BALB/c mice. Administration safety was evaluated by laser speckle contrast imaging and histological analysis. NP biodistribution and accumulation were assessed using in vivo and ex vivo fluorescence tomography and confocal microscopy of cryosections. Results: PLGA-Cy7 NPs demonstrate low cytotoxicity even at high doses and exhibit good hemocompatibility. Administration of NPs through the mouse carotid, renal, and femoral arteries significantly increases accumulation in the target ipsilateral brain hemisphere (31.7-fold) and salivary glands (28.3-fold), kidney (13.7-fold), and hind paw (3.6-fold), respectively, compared to intravenous administration. Injection of NPs through arteries supplying the target organs and tissues does not result in significant changes in blood flow, morphological alterations, or irreversible embolization of vessels, provided the procedure is performed correctly and the optimal dosage is used. Conclusions: These results highlight the potential of intra-arterial delivery of NPs for organ-specific drug targeting, underscoring the synergistic impact of advances in materials science, minimally invasive endovascular surgery, and nanomedicine. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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39 pages, 1558 KB

Open AccessReview

Rewriting Tumor Entry Rules: Microfluidic Polyplexes and Tumor-Penetrating Strategies—A Literature Review

by Simona Ruxandra Volovat, Iolanda Georgiana Augustin, Constantin Volovat, Ingrid Vasilache, Madalina Ostafe, Diana Ioana Panaite, Alin Burlacu and Cristian Constantin Volovat

Pharmaceutics 2026, 18(1), 84; https://doi.org/10.3390/pharmaceutics18010084 - 9 Jan 2026

Abstract

Cancer immunotherapy increasingly relies on nucleic acid-based vaccines, yet achieving efficient and safe delivery remains a critical limitation. Polyplexes—electrostatic complexes of cationic polymers and nucleic acids—have emerged as versatile carriers offering greater chemical tunability and multivalent targeting capacity compared to lipid nanoparticles, with [...] Read more.

Cancer immunotherapy increasingly relies on nucleic acid-based vaccines, yet achieving efficient and safe delivery remains a critical limitation. Polyplexes—electrostatic complexes of cationic polymers and nucleic acids—have emerged as versatile carriers offering greater chemical tunability and multivalent targeting capacity compared to lipid nanoparticles, with lower immunogenicity than viral vectors. This review summarizes key design principles governing polyplex performance, including polymer chemistry, architecture, and assembly route—emphasizing microfluidic fabrication for improved size control and reproducibility. Mechanistically, effective systems support stepwise delivery: tumor targeting, cellular uptake, endosomal escape (via proton-sponge, membrane fusion, or photochemical disruption), and compartment-specific cargo release. We discuss therapeutic applications spanning plasmid DNA, siRNA, miRNA, mRNA, and CRISPR-based editing, highlighting preclinical data across multiple tumor types and early clinical evidence of on-target knockdown in human cancers. Particular attention is given to physiological barriers and engineering strategies—including size-switching systems, charge-reversal polymers, and tumor-penetrating peptides—that improve intratumoral distribution. However, significant challenges persist, including cationic toxicity, protein corona formation, manufacturing variability, and limited clinical responses to date. Current evidence supports polyplexes as a modular platform complementary to lipid nanoparticles in selected oncology indications, though realizing this potential requires continued optimization alongside rigorous translational development. Full article

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

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34 pages, 6962 KB

Open AccessArticle

Novel Repurposing of Empagliflozin-Loaded Buccal Composite (Chitosan/Silk Fibroin/Poly(lactic acid)) Nanofibers for Alzheimer’s Disease Management via Modulation of Aβ–AGER–p-tau Pathway

by Walaa A. El-Dakroury, Samar A. Salim, Abdelrahman R. Said, Gihan F. Asaad, Mohamed F. Abdelhameed, Marwa E. Shabana, Mohamed M. Ibrahim, Sara G. Abualmajd, Haidy H. Mosaad, Aliaa A. Salama, Shrouk E. Asran, Mayar L. Amer, Ahmed S. Doghish and Fatma Sa’eed El-Tokhy

Pharmaceutics 2026, 18(1), 83; https://doi.org/10.3390/pharmaceutics18010083 - 8 Jan 2026

Abstract

Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer’s disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. [...] Read more.

Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer’s disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 ± 173 to 668 ± 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle < 90°), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs/Fb/PLA NFs in an AlCl₃-induced AD rat model significantly reduced brain-amyloid-β, phosphorylated tau, IL-1β, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-β (1.78-fold), p-tau (1.42-fold), IL-1β (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs/Fb/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the Aβ–AGER–p-tau axis. Full article

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

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40 pages, 1110 KB

Open AccessReview

From Waste to Treasure: Therapeutic Horizons of Polyhydroxyalkanoates in Modern Medicine

by Farid Hajareh Haghighi, Roya Binaymotlagh, Paula Stefana Pintilei, Laura Chronopoulou and Cleofe Palocci

Pharmaceutics 2026, 18(1), 82; https://doi.org/10.3390/pharmaceutics18010082 - 8 Jan 2026

Abstract

Polyhydroxyalkanoates (PHAs), a family of biodegradable polyesters produced through microbial fermentation of carbon-rich residues, are emerging as attractive alternatives to petroleum-based plastics. Their appeal lies in their exceptional biocompatibility, inherent biodegradability, and tunable physicochemical properties across diverse applications. These materials are environmentally friendly [...] Read more.

Polyhydroxyalkanoates (PHAs), a family of biodegradable polyesters produced through microbial fermentation of carbon-rich residues, are emerging as attractive alternatives to petroleum-based plastics. Their appeal lies in their exceptional biocompatibility, inherent biodegradability, and tunable physicochemical properties across diverse applications. These materials are environmentally friendly not just at the end of their life, but throughout their entire production–use–disposal cycle. This mini-review presents an update on the expanding biomedical relevance of PHAs, with emphasis on their utility in tissue engineering and drug delivery platforms. In addition, current clinical evaluations and regulatory frameworks are briefly discussed, underscoring the translational potential of PHAs in meeting unmet medical needs. As the healthcare sector advances toward environmentally responsible and patient-focused innovations, PHAs exemplify the convergence of waste valorization and biomedical progress, transforming discarded resources into functional materials for repair, regeneration, and healing. Full article

(This article belongs to the Special Issue Biodegradable Polymer Platforms for Long-Acting Drug Delivery)

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29 pages, 980 KB

Open AccessReview

Ketamine in Diabetes Care: Metabolic Insights and Clinical Applications

by Shiryn D. Sukhram, Majandra Sanchez, Ayotunde Anidugbe, Bora Kupa, Vincent P. Edwards, Muhammad Zia and Grozdena Yilmaz

Pharmaceutics 2026, 18(1), 81; https://doi.org/10.3390/pharmaceutics18010081 - 8 Jan 2026

Abstract

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a [...] Read more.

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a scoping review following PRISMA-ScR. MEDLINE/PubMed, CINAHL, and APA PsycInfo were searched (January 2020–31 May 2025). Eligible human and animal studies evaluated ketamine, esketamine, or norketamine in the context of diabetes (type 1 [T1DM], type 2 [T2DM], gestational [GDM]), or DN, and reported psychiatric, analgesic, metabolic, or mechanistic outcomes. Two reviewers independently screened and charted data; no formal risk-of-bias assessment was performed. Results: Eleven studies met inclusion criteria: four human case reports/series (three T1DM, one T2DM), one randomized trial in GDM, two narrative reviews of topical ketamine for DN, and four preclinical rodent studies using streptozotocin- or diet-induced diabetes models. Short-term improvements were reported for treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative analgesia in GDM. Glycemic effects varied across settings, with both hyperglycemia and hypoglycemia reported. Mechanistic and clinical drug–drug and drug-disease interactions (particularly involving metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and CYP3A4/CYP2B6 modulators) remain insufficiently studied. We outline a forward-looking population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK-PD) research agenda, including priority covariates (eGFR, hepatic function, inflammatory status, HbA1c, genotype, co-medications) and sparse-sampling windows for future model-informed precision dosing. Conclusions: Current evidence supports cautious, selective use of ketamine for refractory depression and DN within multidisciplinary diabetes care. Purpose-built popPK/PK-PD studies in both human and preclinical diabetic models cohorts are needed to quantify variability, define drug–disease–drug interactions and glycemic risk, and inform individualized dosing strategies. Full article

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

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32 pages, 1770 KB

Open AccessReview

New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders

by Henri Benech, Victoria Flament, Clara Lhotellier, Camille Roucairol and Thomas Joudinaud

Pharmaceutics 2026, 18(1), 80; https://doi.org/10.3390/pharmaceutics18010080 - 7 Jan 2026

Abstract

Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique [...] Read more.

Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood–brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations—critical for successful clinical implementation and commercial development—remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical–clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway—or, more precisely, the “Nose-to-Neurons” pathway—offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment. Full article

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

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30 pages, 65850 KB

Open AccessArticle

Antitumor Activity of the Ethanolic Extract from Syzygium aromaticum in Colorectal Cancer Xenograft Mice

by Thunyatorn Yimsoo, Weerakit Taychaworaditsakul, Hathaichanok Chuntakaruk, Worapapar Treesuppharat, Sumet Kongkiatpaiboon, Apipu Ariyachayut, Sunee Chansakaow, Teera Chewonarin, Parirat Khonsung and Seewaboon Sireeratawong

Pharmaceutics 2026, 18(1), 79; https://doi.org/10.3390/pharmaceutics18010079 - 7 Jan 2026

Abstract

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and the development of effective therapies with improved safety profiles is urgently needed. The hydrodistillation residue extract of Syzygium aromaticum (SA) is rich in phenolic compounds, including ellagic acid and [...] Read more.

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and the development of effective therapies with improved safety profiles is urgently needed. The hydrodistillation residue extract of Syzygium aromaticum (SA) is rich in phenolic compounds, including ellagic acid and gallic acid, which are known for their antioxidant and anticancer properties. This study aimed to evaluate the anticancer efficacy, safety, and metabolic effects of SA extract in CRC models. Methods: The anticancer activity of SA was investigated using in vitro and in vivo approaches. Human colorectal cancer HCT116-Red-FLuc cells were used to assess cytotoxicity, selectivity, and dose- and time-dependent effects. In vivo efficacy was evaluated in a CRC xenograft mouse model using tumor volume measurement, micro-ultrasound imaging, and bioluminescence analysis. Hematological and blood biochemical parameters were analyzed to assess systemic safety. Untargeted metabolomic profiling was performed to explore metabolic alterations associated with SA treatment. Results: SA inhibited HCT116-Red-FLuc cell proliferation in a dose- and time-dependent manner and demonstrated selective cytotoxicity toward cancer cells, with a selectivity index of 4.41 at 24 h, although selectivity declined with prolonged exposure. In xenograft mice, SA significantly suppressed tumor growth and reduced metastatic incidence. The 500 mg/kg dose (SA500) showed the greatest antitumor efficacy while maintaining normal hematological and biochemical profiles, indicating a favorable safety margin compared with 5-fluorouracil (5FU). The 1000 mg/kg dose (SA1000) induced marked suppression of Ki-67, Bcl-2, and CD31 expression and enhanced apoptosis. Metabolomic analysis identified 44 differential metabolites related to fatty acid, amino acid, and nucleotide metabolism. Conclusions: These findings suggest that SA extract exerts significant antitumor activity against CRC with improved tolerability compared with conventional chemotherapy, supporting its potential as a complementary natural therapeutic candidate. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals from Medicinal Plants: Formulation and Therapeutic Potential)

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20 pages, 4835 KB

Open AccessArticle

Cell-Penetrating Peptide-Mediated siRNA Targeting of LDHC Suppresses Tumor Growth in a Triple-Negative Breast Cancer Zebrafish Xenograft Model

by Hanan Qasem, Adviti Naik, Tricia Gomez, Janarthanan Ponraj, Umar Jafar, Martin Sikhondze, Remy Thomas, Khaled A. Mahmoud and Julie Decock

Pharmaceutics 2026, 18(1), 78; https://doi.org/10.3390/pharmaceutics18010078 - 7 Jan 2026

Abstract

Background: Lactate Dehydrogenase C (LDHC) is a promising therapeutic target due to its highly tumor-specific expression, immunogenicity, and oncogenic functions. We previously showed that LDHC silencing in triple-negative breast cancer (TNBC) cells enhances treatment response to DNA-damage response-related drugs, supporting its therapeutic [...] Read more.

Background: Lactate Dehydrogenase C (LDHC) is a promising therapeutic target due to its highly tumor-specific expression, immunogenicity, and oncogenic functions. We previously showed that LDHC silencing in triple-negative breast cancer (TNBC) cells enhances treatment response to DNA-damage response-related drugs, supporting its therapeutic potential. However, no selective LDHC inhibitors exist, highlighting the need for innovative targeting strategies. Methods: We assessed the physicochemical properties and evaluated the delivery efficiency, anti-tumor activity, and safety of four cell-penetrating peptides (CPPs)—R10, 10R-RGD, cRGD-10R, and iRGD-10R—for siRNA-mediated LDHC silencing in TNBC. Clonogenic assays were used to evaluate effects on olaparib sensitivity, and TNBC zebrafish xenografts were utilized to study in vivo anti-tumor activity. Results: All CPP:siRNA complexes formed uniform nanocomplexes (129–168 nm) with low polydispersity indices (<0.25) and positive zeta potentials (+6.47 to +29.6 mV). Complexes remained stable in human serum for 24 h and showed no significant cytotoxicity in TNBC and non-cancerous cell lines. The 10R-RGD and cRGD-10R:siLDHC complexes achieved 40% LDHC protein knockdown, reduced TNBC clonogenicity by 30–36%, and enhanced olaparib sensitivity. Treatment of TNBC zebrafish xenografts with 10R-RGD or cRGD-10R:siLDHC complexes significantly reduced tumor growth by approximately 50% without major toxicity. Conclusions: These results demonstrate that CPP-mediated siRNA delivery enables selective LDHC silencing with tumor growth inhibition in triple-negative breast cancer models. This approach represents a novel, effective, and safe proof-of-concept therapeutic strategy to target LDHC, with potential translational relevance as a standalone therapy or in combination with common anti-cancer drugs. Full article

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

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19 pages, 912 KB

Open AccessReview

Old Drug, New Science: Metformin and the Future of Pharmaceutics

by Alfredo Caturano, Davide Nilo, Roberto Nilo, Marta Chiara Sircana, Enes Erul, Katarzyna Zielińska, Vincenzo Russo, Erica Santonastaso and Ferdinando Carlo Sasso

Pharmaceutics 2026, 18(1), 77; https://doi.org/10.3390/pharmaceutics18010077 - 7 Jan 2026

Abstract

Metformin, a 60-year-old biguanide and cornerstone of type 2 diabetes therapy, continues to challenge and inspire modern pharmaceutical science. Despite its chemical simplicity, metformin displays highly complex pharmacokinetic and pharmacodynamic behavior driven by transporter dependence, luminal activity, and formulation-sensitive exposure. Originally regarded as [...] Read more.

Metformin, a 60-year-old biguanide and cornerstone of type 2 diabetes therapy, continues to challenge and inspire modern pharmaceutical science. Despite its chemical simplicity, metformin displays highly complex pharmacokinetic and pharmacodynamic behavior driven by transporter dependence, luminal activity, and formulation-sensitive exposure. Originally regarded as limited by low permeability and incomplete absorption, metformin has emerged as a paradigm for gut-targeted therapy, controlled- and delayed-release systems, and personalized pharmaceutics. Growing evidence has repositioned the intestine, rather than systemic plasma exposure, as a major site of action, highlighting the central role of organic cation transporters and multidrug efflux systems in determining efficacy, variability, and gastrointestinal tolerability. Beyond metabolic control, insights into transporter regulation, pharmacogenetics, microbiome interactions, and manufacturing quality have expanded metformin’s relevance as a model compound for contemporary drug development. Advances in formulation design, quality-by-design manufacturing, and regulatory control have further reinforced its clinical robustness, while repurposing efforts in oncology, immunometabolism, and regenerative medicine underscore its translational potential. This review integrates mechanistic pharmacology, formulation science, and clinical translation to position metformin not merely as an antidiabetic agent, but as a didactic model illustrating the evolution of pharmaceutics from molecule-centered design to system-oriented, precision-driven therapy. Full article

(This article belongs to the Section Biopharmaceutics)

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17 pages, 3097 KB

Open AccessArticle

Charge Effects: Influence of Surface Charge on Protein Corona Adsorption Behavior on Liposomal Formulations

by Qian Chen, Yeqi Huang, Chuanbin Wu, Xin Pan, Changjiang Yu, Jiu Wang, Wenhao Wang and Zhengwei Huang

Pharmaceutics 2026, 18(1), 76; https://doi.org/10.3390/pharmaceutics18010076 - 7 Jan 2026

Abstract

Background: Liposomes have been successfully used in clinics as an excellent drug delivery system. However, once they enter the body, they adsorb surrounding proteins and form a protein corona, which affects how liposomes behave in vivo. Therefore, controlling the formation of the [...] Read more.

Background: Liposomes have been successfully used in clinics as an excellent drug delivery system. However, once they enter the body, they adsorb surrounding proteins and form a protein corona, which affects how liposomes behave in vivo. Therefore, controlling the formation of the protein corona is crucial for achieving effective treatment outcomes. Among the many variables affecting liposome protein corona formation, the composition of the liposomes themselves and the surrounding ionic environment are two particularly critical factors. Methods: In this context, this study selected bovine serum albumin as a model protein to investigate the influence and mechanism of physiologically relevant inorganic ions (magnesium chloride) and varying proportions of cationic lipid components (1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)) on protein adsorption behavior of liposomes. We evaluated characterization parameters, including particle size and zeta potential, and employed various spectroscopic techniques to elucidate the changes during the interaction between bovine serum albumin and liposomes. Results: The zeta potential results showed that liposomes without DOTAP exhibited a significantly negative potential (−45.20 ± 0.24 mV), while the zeta potential became increasingly positive with higher DOTAP proportions (+19.64 ± 0.39 mV and +51.03 ± 1.74 mV). Correspondingly, the amount of protein adsorption also increased with the rising DOTAP content. Furthermore, fluorescence spectroscopy indicated that the addition of either DOTAP or magnesium ions led to a decrease in both the K_sv and K_a parameters. Conclusions: Specific hypothetical models were advanced subsequently; per the varying proportion of DOTAP, we proposed an insertion or surface adsorption model, and further examined the influence of magnesium chloride on the interactions between the liposomes and proteins. We believe this study will provide a new research paradigm for the design and application of liposomes, laying a foundation for further in vivo investigations. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation, 2nd Edition)

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30 pages, 1916 KB

Open AccessReview

Ambivalent Copper: Mechanistically Distinct Immune Effects Driving Innovation in Cancer Nanomedicine

by Devon Heroux, Xu Xin Sun, Zeynab Nosrati and Marcel B. Bally

Pharmaceutics 2026, 18(1), 75; https://doi.org/10.3390/pharmaceutics18010075 - 7 Jan 2026

Abstract

Copper (Cu) is an essential element required by all living cells, where it supports critical enzymatic and signaling functions. In cancer, this balance is often disrupted, creating vulnerabilities that can be therapeutically exploited. Changes in Cu availability have been shown to influence key [...] Read more.

Copper (Cu) is an essential element required by all living cells, where it supports critical enzymatic and signaling functions. In cancer, this balance is often disrupted, creating vulnerabilities that can be therapeutically exploited. Changes in Cu availability have been shown to influence key immunoregulatory pathways, including those involved in inflammation, cell death, and immune evasion. Notably, Cu can drive expression of programmed death ligand 1 (PD-L1), contributing to immunosuppression, while also promoting immunogenic cell death, which stimulates adaptive immune responses. These dual effects highlight the complexity and therapeutic potential of Cu-based interventions, particularly in the context of immune modulation and toxicity. This review argues that Cu-based nanomedicines can selectively deliver high concentrations of bioactive Cu to tumor cells, inducing cell death and triggering adaptive immune responses. We summarize current knowledge on Cu’s roles in cancer and immunity, emphasizing recent insights into how these intersect through Cu-mediated modulation of anticancer immune pathways. Finally, we explore the clinical potential of Cu-based nanomedicines to convert immunologically “cold” tumors into “hot” ones, thereby improving responses to immunotherapy. Realizing this potential will depend on the thoughtful integration of Cu delivery approaches with existing immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Targeted Immune Modulation Strategies for Cancer, Infectious and Autoimmune Diseases)

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44 pages, 2030 KB

Open AccessReview

Recent Developments in Protein-Based Hydrogels for Advanced Drug Delivery Applications

by Giuseppe Scopelliti, Claudia Ferraro, Ortensia Ilaria Parisi and Marco Dattilo

Pharmaceutics 2026, 18(1), 74; https://doi.org/10.3390/pharmaceutics18010074 - 6 Jan 2026

Abstract

Protein-based hydrogels are increasingly recognized as promising biomaterials for advanced drug delivery, owing to their biocompatibility, biodegradability, and ability to recreate extracellular matrix-like environments. By tailoring the protein source, crosslinking strategy, molecular architecture, and functionalization, these hydrogels can be engineered to mimic the [...] Read more.

Protein-based hydrogels are increasingly recognized as promising biomaterials for advanced drug delivery, owing to their biocompatibility, biodegradability, and ability to recreate extracellular matrix-like environments. By tailoring the protein source, crosslinking strategy, molecular architecture, and functionalization, these hydrogels can be engineered to mimic the mechanical and biological features of native tissues. Protein-derived hydrogels are currently explored across biomedical and pharmaceutical fields, including drug delivery systems, wound healing, tissue engineering, and, notably, cancer therapy. In recent years, growing attention has been directed toward natural protein hydrogels because of their inherent bioactivity and versatile physicochemical properties. This review provides an updated overview of protein-based hydrogel classification, properties, and fabrication methods. It highlights several widely studied natural proteins, such as gelatin, collagen, silk fibroin, soy protein, casein, and whey protein, that can form hydrogels through physical, chemical, or enzymatic crosslinking. These materials offer tunable mechanical behavior, controllable degradation rates, and abundant functional groups that support efficient drug loading and the development of stimuli-responsive platforms. Furthermore, we examine current advances in their application as drug delivery systems, with particular emphasis on cancer treatment. Protein-based hydrogels have demonstrated the ability to protect therapeutic molecules, provide sustained or targeted release, and enhance therapeutic effectiveness. Although critical challenges, such as batch-to-batch variability, sterilization-induced denaturation, and the requirement for comprehensive long-term immunogenicity assessment, must still be addressed to enable successful translation from preclinical studies to clinical application, ongoing advances in the design and functionalization of natural protein hydrogels highlight their promise as next-generation platforms for precision drug delivery. Full article

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

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