Pharmaceutics

23 pages, 2196 KB

Open AccessArticle

Nanococrystals of Diclofenac Acid to Improve Biopharmaceutical Performance: Understanding the Key Drivers

by Katangur Vishruth Reddy, Soumalya Chakraborty, Sourav Chougule, Amit Pariskar, Rohit Y. Sathe, Ashish Dangi, Prasad V. Bharatam and Arvind K. Bansal

Pharmaceutics 2026, 18(9), 1119; https://doi.org/10.3390/pharmaceutics18091119 (registering DOI) - 6 Sep 2026

Abstract

Background: In this study, two cocrystals of diclofenac acid (DCA) with the coformers theophylline (THEO) and isonicotinamide (ISNT) were prepared. Subsequently, nanococrystals were generated from these cocrystals using a top-down wet media milling approach. Methods: Critical process parameters such as milling [...] Read more.

Background: In this study, two cocrystals of diclofenac acid (DCA) with the coformers theophylline (THEO) and isonicotinamide (ISNT) were prepared. Subsequently, nanococrystals were generated from these cocrystals using a top-down wet media milling approach. Methods: Critical process parameters such as milling time, milling volume, drug loading percentage, bead volume, and dispersion media were optimized to achieve the desired particle size distribution. The nanococrystals were characterized using dynamic light scattering (DLS), polarized light microscopy (PLM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results: In vitro dissolution studies revealed that nanococrystals of DCA-ISNT (DE_0–120 = 22.5% at pH 1.2 and DE_0–120 = 58.7% at pH 4.5) and DCA-THEO (DE_0–120 = 18.5% at pH 1.2 and DE_0–120 = 48.2% at pH 4.5) exhibited superior dissolution performance compared to DCA nanocrystals (DE_0–120 = 12.5% at pH 1.2 and DE_0–120 = 39.0% at pH 4.5), with the dissolution advantage decreasing as the pH of the medium increased. The improved dissolution behaviour was a complex interplay of factors including particle size distribution, surface wetting kinetics, exposure of hydrophilic/hydrophobic functional groups during dissolution, nanococrystal microenvironmental pH, DCA’s ionization behaviour, lattice energy, and intermolecular interaction strengths. Additionally, nanococrystals exhibited a significantly higher flux rate in simultaneous gastric transfer dissolution and flux studies compared with DCA, likely due to higher apparent solubility and superior diffusion through the unstirred water layer (UWL). Pharmacokinetic studies confirmed that nanococrystals DCA-ISNT NCC (AUC_0–∞ = 3062.65 ± 526.91 ng/mL·h) outperformed DCA nanocrystals (AUC_0–∞ = 2352.53 ± 537.78 ng/mL·h), DCA-THEO NCC (AUC_0–∞ = 2222.96 ± 151.19 ng/mL·h) and the cocrystals in terms of pharmacokinetic performance. Conclusions: The findings indicate that DCA-ISNT NCC exhibited superior pharmacokinetic performance and, together with the enhanced dissolution and flux properties of the nanococrystals, demonstrates their potential for enhanced therapeutic efficacy. Full article

(This article belongs to the Special Issue Advances in Solid and Semi-Solid Dosage Form Design for Enhanced Biopharmaceutical Performance)

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22 pages, 632 KB

Open AccessReview

Chitosan in Modern Pharmacotherapy: Chitosan Nanoparticles and Delivery Systems

by Lolita Kuršvietienė, Robertas Lažauskas and Inga Stanevičienė

Pharmaceutics 2026, 18(9), 1118; https://doi.org/10.3390/pharmaceutics18091118 (registering DOI) - 6 Sep 2026

Abstract

The development of effective delivery systems remains an important challenge in modern pharmaceutical and biomedical research, driving the development of biocompatible materials with versatile functional properties. This review provides an integrated overview of chitosan-based delivery systems, focusing on chitosan nanoparticles, chitosan derivatives, and [...] Read more.

The development of effective delivery systems remains an important challenge in modern pharmaceutical and biomedical research, driving the development of biocompatible materials with versatile functional properties. This review provides an integrated overview of chitosan-based delivery systems, focusing on chitosan nanoparticles, chitosan derivatives, and hybrid systems. Particular emphasis is placed on the relationship between the structural and functional characteristics of chitosan-based systems and their potential applications in pharmaceutical and biomedical fields. In addition to established applications, emerging approaches involving nucleic acid delivery, gene therapy, theranostics, and other biomedical applications are discussed. A further focus of this review is the consideration of critical quality attributes relevant to the development of GMP-oriented chitosan-based systems, providing a perspective that links material characteristics with quality and translational requirements. By integrating these aspects, this review highlights the versatility of chitosan as a platform for the development of innovative pharmaceutical and biomedical delivery technologies. Full article

(This article belongs to the Special Issue Chitosan in Modern Pharmacotherapy: From Drug Encapsulation to Targeted Delivery Systems)

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40 pages, 17501 KB

Open AccessReview

PK-Informed Microphysiological Systems: From Dynamic Dosing to Quantitative In Vitro–In Vivo Translation

by Su Jeong Kang, Sunghyun Bong, Min Jeong Jo, Jae Min Lee, Moon Sup Yoon, Seonmin Park, Yeseung Lee, Yuseon Shin, Hye Jin Lee, Chun-Woong Park and Dae Hwan Shin

Pharmaceutics 2026, 18(9), 1117; https://doi.org/10.3390/pharmaceutics18091117 - 4 Sep 2026

Abstract

Conventional in vitro drug evaluation relies largely on static concentration–response assays that fail to reproduce the dynamic pharmacokinetic (PK) profiles observed in vivo, contributing to the gap between preclinical findings and clinical outcomes. Recent advances in microphysiological systems (MPSs), particularly microfluidic organ-on-chip platforms, [...] Read more.

Conventional in vitro drug evaluation relies largely on static concentration–response assays that fail to reproduce the dynamic pharmacokinetic (PK) profiles observed in vivo, contributing to the gap between preclinical findings and clinical outcomes. Recent advances in microphysiological systems (MPSs), particularly microfluidic organ-on-chip platforms, enable programmable concentration–time profiles that more closely mimic physiological drug exposure. These PK-informed platforms allow systematic investigation of schedule dependency, time-dependent pharmacodynamics (PD), and exposure-driven efficacy under controlled flow conditions. Spatially resolved analytical approaches further reveal heterogeneous drug penetration and metabolic responses within tissues, emphasizing the importance of spatiotemporal PK–PD coupling. Integration of multi-organ and vascularized chip systems with physiologically based pharmacokinetic (PBPK) modeling increasingly supports quantitative in vitro–in vivo translation. This review outlines how PK-informed MPSs can generate dynamic in vitro exposure and response data that inform PBPK modeling, thereby supporting quantitative in vitro–in vivo translation of drug disposition and response. Full article

(This article belongs to the Special Issue Novel Research on Physiologically-Based Pharmacokinetic Modeling)

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23 pages, 5286 KB

Open AccessArticle

CNP-miR146a Promotes NRF2-Related Ferroptosis-Protective Myeloid Programs and Immune–Vascular Regeneration in Diabetic Wounds

by Melisa Kafali, Emilia Mora Pinos, Katharina S. Berryman, Kellen Chen, Geoffrey C. Gurtner, Kenneth W. Liechty and Carlos Zgheib

Pharmaceutics 2026, 18(9), 1116; https://doi.org/10.3390/pharmaceutics18091116 - 4 Sep 2026

Abstract

Background: Diabetic wounds are characterized by chronic inflammation, oxidative stress, impaired angiogenesis, and delayed tissue repair. Ferroptosis has emerged as a potential contributor to diabetic wound pathology; however, its relationship with impaired tissue regeneration remains incompletely understood. Objectives: We investigated cellular and transcriptional [...] Read more.

Background: Diabetic wounds are characterized by chronic inflammation, oxidative stress, impaired angiogenesis, and delayed tissue repair. Ferroptosis has emerged as a potential contributor to diabetic wound pathology; however, its relationship with impaired tissue regeneration remains incompletely understood. Objectives: We investigated cellular and transcriptional responses associated with cerium oxide nanoparticle-conjugated microRNA-146a (CNP-miR146a) treatment and whether wound repair is associated with ferroptosis-protective programs and immune–vascular communication. Methods: Diabetic excisional wounds were treated with CNP-miR146a or phosphate-buffered saline controls. Single-cell RNA sequencing was performed on wound tissues, with primary analyses focused on postoperative Day 7. Cellular composition, ferroptosis-associated programs, pseudotime trajectories, and inferred ligand–receptor communication networks were analyzed. Results: CNP-miR146a treatment was associated with transcriptional remodeling of the diabetic wound microenvironment, with myeloid cells exhibiting a prominent response. Treatment was associated with higher NRF2-related antioxidant, ferroptosis-protective, and iron-homeostasis transcriptional programs and with a repair-associated myeloid state. Pseudotime analysis identified a trajectory from monocytes toward pro-regenerative macrophages accompanied by dynamic expression of antioxidant, iron-homeostasis, and repair-associated genes. CellChat predicted increased immune–vascular communication through angiogenic and extracellular matrix-associated pathways. Endothelial cells exhibited increased NRF2-associated transcriptional programs, angiogenesis-associated gene expression, and endothelial repair markers. Conclusions: CNP-miR146a-mediated wound repair is associated with coordinated ferroptosis-protective and NRF2-related transcriptional programs, pro-regenerative myeloid states, endothelial angiogenesis-associated programs, and predicted immune–vascular communication. These findings identify ferroptosis-associated and immune–vascular transcriptional networks as candidate mechanisms of CNP-miR146a-mediated diabetic wound repair requiring further functional validation. Full article

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

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33 pages, 4185 KB

Open AccessArticle

A Locally Injectable, pH/ROS-Responsive Hydrogel Platform for Combination Therapy of Cervical Cancer with Anti-Fibrotic and Chemotherapeutic Agents

by Qian Chen, Hui Yang, Meili Pei, Yanxia Sun, Yubei Li, Sen Yu and Xiaofeng Yang

Pharmaceutics 2026, 18(9), 1115; https://doi.org/10.3390/pharmaceutics18091115 - 4 Sep 2026

Abstract

Background: The fibrous tumor extracellular matrix (ECM), driven by cancer-associated fibroblasts (CAFs), forms a physical barrier against drugs and immune cells, yet direct CAF elimination risks promoting metastasis. Methods: In this study, we developed a locally injectable hydrogel based on synergistic dynamic covalent [...] Read more.

Background: The fibrous tumor extracellular matrix (ECM), driven by cancer-associated fibroblasts (CAFs), forms a physical barrier against drugs and immune cells, yet direct CAF elimination risks promoting metastasis. Methods: In this study, we developed a locally injectable hydrogel based on synergistic dynamic covalent crosslinking (imine and boronate ester bonds), enabling instant gelation, shear thinning, and dual-pH/ROS-responsive degradation. Two types of drug-loaded nanoparticles (NPs), coated with homotypic cell membranes, were incorporated into this hydrogel. In the acidic, reactive oxygen species (ROS)-rich tumor microenvironment (TME), the system responsively releases the antifibrotic drug SIS3 to reprogram CAFs while simultaneously delivering doxorubicin (DOX) specifically to tumor cells. Biological effects were evaluated in vitro using cell cultures and in vivo in mouse models. Results: This dynamic hydrogel-based co-delivery system effectively reprograms CAFs, reduces tumor mechanical stress, breaks the fibrotic barrier, and promotes the deep infiltration of chemotherapeutics and immune cells, thereby enhancing the efficacy of chemotherapy. Conclusions: This injectable pH/ROS-responsive dynamic covalent hydrogel, loaded with CAF- and cancer cell-targeting NPs, remodels the TME, enhances drug and immune cell penetration, and offers a promising biomaterial-based strategy for cervical cancer treatment. Full article

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

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24 pages, 8619 KB

Open AccessArticle

A Hyaluronic Acid-Coated Ethosomal Delivery System for Improving the Topical Delivery of Glycyrrhetinic Acid in Sensitive Skin

by Yuling Wang, Shujing Ren, Jun Deng, Dan Luo, Rui Liu, Yu Zhou, Siyuan Chen and Wei Liu

Pharmaceutics 2026, 18(9), 1114; https://doi.org/10.3390/pharmaceutics18091114 - 4 Sep 2026

Abstract

Background: Effective topical management of sensitive skin remains challenging because inadequate cutaneous delivery limits the therapeutic performance of many anti-inflammatory agents. Glycyrrhetinic acid (GA) possesses well-recognized anti-inflammatory and barrier-protective activities, yet its clinical potential is constrained by poor aqueous solubility and inefficient skin [...] Read more.

Background: Effective topical management of sensitive skin remains challenging because inadequate cutaneous delivery limits the therapeutic performance of many anti-inflammatory agents. Glycyrrhetinic acid (GA) possesses well-recognized anti-inflammatory and barrier-protective activities, yet its clinical potential is constrained by poor aqueous solubility and inefficient skin delivery. This study aimed to develop a hyaluronic acid (HA)-engineered ethosomal system to enhance the local delivery and therapeutic efficacy of GA for sensitive skin. Methods: HA-coated GA-loaded ethosomes (HAGA-ETs) were prepared by electrostatic adsorption of HA onto a cationic ethosomal template. The physicochemical properties, release behavior, storage stability, skin retention, cellular uptake, and biological activities of HAGA-ETs were systematically evaluated using TNF-α/IFN-γ-stimulated HaCaT cells and an SLS-induced 3D reconstructed skin model. Results: HAGA-ETs exhibited a mean particle size of 140.1 nm, encapsulation efficiency exceeding 95%, sustained drug release, and good storage stability. Compared with Free-GA and unmodified ethosomes, HAGA-ETs showed improved cytocompatibility, enhanced skin retention, greater keratinocyte uptake, and stronger anti-inflammatory activity. HA pre-saturation attenuated the enhanced cellular uptake of HAGA-ETs, supporting the involvement of HA receptor-mediated cellular interaction. HAGA-ETs also more effectively restored barrier-related markers, suppressed hyper-reactivity- and allergy-associated mediators, and inhibited the activation of MAPK/NF-κB, JAK1/STAT1, and TRPV1-related signaling pathways in both cellular and 3D skin models. Conclusions: HA surface engineering effectively improved the topical delivery and local therapeutic efficacy of GA by enhancing skin retention and keratinocyte interaction. HAGA-ETs represent a promising nanoplatform for the local management of sensitive skin. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Enhanced Transdermal and Dermal Delivery)

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18 pages, 3441 KB

Open AccessArticle

Pyridoxic Acid as a Novel Endogenous Biomarker for OAT-Mediated Clearance of Meropenem: A Population Pharmacokinetic Modeling and PK/PD-Response Analysis in Patients with Sepsis

by Zihan Lei, Hao Liang, Qin Cheng, Weijie Kong, Yipeng Du, Xueting Yao, Feifei Feng, Yuyan Jin, Wenting Wang, Haiyan Li, Ming Lu, Dongyang Liu and Ning Shen

Pharmaceutics 2026, 18(9), 1113; https://doi.org/10.3390/pharmaceutics18091113 - 4 Sep 2026

Abstract

Background/Objectives: Meropenem pharmacokinetic variability in sepsis often leads to suboptimal exposure and therapeutic failure. Existing covariates like creatinine clearance (CLcr) only partially explain this variability. This study evaluated pyridoxic acid (PDA), an endogenous biomarker of OAT1/3 transporters, as a novel covariate to quantify [...] Read more.

Background/Objectives: Meropenem pharmacokinetic variability in sepsis often leads to suboptimal exposure and therapeutic failure. Existing covariates like creatinine clearance (CLcr) only partially explain this variability. This study evaluated pyridoxic acid (PDA), an endogenous biomarker of OAT1/3 transporters, as a novel covariate to quantify active tubular secretion and explore pharmacokinetic/pharmacodynamic (PK/PD) linkages with clinical outcomes. Methods: A population PK (PopPK) model was constructed using data from a prospective septic cohort (n = 28). Subsequent exposure-response analysis was conducted in an expanded cohort (n = 49), and Monte Carlo simulations were utilized to evaluate various dosing regimens. Results: The PopPK analysis suggested that PDA may complement CLcr in characterizing meropenem clearance variability. While CLcr explained 10.7% of inter-individual variability (IIV) in clearance, the inclusion of PDA explained an additional 13.7%, reducing total IIV from 50.8% to 26.4%. Achieving a stringent target of 100%fT > 4MIC was significantly associated with a rapid decline in procalcitonin (p = 0.027), establishing a key PD endpoint. Simulations demonstrated that standard dosing (1 g q8h, 1 h infusion) is insufficient for patients with normal or augmented renal function. Target attainment was highly dependent on PDA levels. Conclusions: PDA is a valuable translational biomarker for OAT-mediated clearance. To achieve 100%fT > 4MIC, we recommend (i) 1 g q8h with 3 h infusion for patients with low CLcr and high PDA levels (MIC = 0.5 mg/L), and (ii) an intensified regimen of 2 g q8h with 3 h infusion for patients with normal CLcr and low PDA levels or high resistance risk (MIC ≥ 2 mg/L). Full article

(This article belongs to the Special Issue Pathophysiological Influences on Pharmacokinetics and Pharmacodynamics, 2nd Edition)

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23 pages, 1961 KB

Open AccessReview

Delivering the Gut to the Brain: Drug Delivery Strategies for Microbiota-Derived Therapeutics in Depression

by Yohan Seo and Chul Soon Park

Pharmaceutics 2026, 18(9), 1112; https://doi.org/10.3390/pharmaceutics18091112 - 3 Sep 2026

Abstract

Major depressive disorder remains a leading cause of disability worldwide, and the limited efficacy and delayed onset of conventional antidepressants have intensified interest in the microbiota–gut–brain axis as a source of therapeutic targets. Microbiota-associated candidates—short-chain fatty acids, bile acid and tryptophan metabolites, and [...] Read more.

Major depressive disorder remains a leading cause of disability worldwide, and the limited efficacy and delayed onset of conventional antidepressants have intensified interest in the microbiota–gut–brain axis as a source of therapeutic targets. Microbiota-associated candidates—short-chain fatty acids, bile acid and tryptophan metabolites, and neuroactive amines—show mood-relevant activity, yet almost none has reached the clinic. This review reframes that gap as a delivery problem. Rather than treating entry into the central nervous system as a universal requirement, we distinguish strategies intended for local intestinal, peripheral systemic, and direct central action, and we argue that delivery is a major but not exclusive translational bottleneck. We outline the barriers these agents face—upper gastrointestinal loss, poor colonic targeting, rapid metabolite turnover, first-pass exposure, and the blood–brain barrier—and synthesize delivery strategies across two fronts. Colon-targeted systems are technically established but have been validated for non-depression indications, whereas brain-directed approaches—bacterial extracellular vesicles, detoxified membrane-coated carriers, receptor-mediated transcytosis, and intranasal routes—reach the brain mainly in selected preclinical models. We foreground a paradox: microbial extracellular vesicles are at once one of the better-documented bio-derived routes for brain exposure in preclinical studies and prominent drivers of neuroinflammation, which defines a risk–opportunity continuum. We close with a route-specific validation roadmap encompassing quantitative exposure, target engagement, chronic efficacy, and safety. Full article

(This article belongs to the Special Issue Bridging the Gut–Brain Axis: Advanced Drug Delivery, Microbiome Modulation, and Translational Therapeutics)

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40 pages, 1026 KB

Open AccessReview

From Antimicrobial Activity to Topical Translation: An Integrated Framework for Testing, Cytotoxicity Assessment and Formulation of Plant Extracts, Essential Oils and Honey

by Diana Constanța Pelea, Laura Maria Endres, Laura Maghiar, Teodor-Andrei Maghiar, Mădălin Florin Ganea, Csaba Nagy, Corina Moisa, Gabriela Ciavoi, Georgiana Ioana Potra Cicalau, Olimpia-Daniela Frenț and Mariana Ganea

Pharmaceutics 2026, 18(9), 1111; https://doi.org/10.3390/pharmaceutics18091111 - 3 Sep 2026

Abstract

Background/Objectives: Antimicrobial resistance has renewed interest in plant extracts, essential oils and honey as topical adjuvants, yet antimicrobial potency, host-tissue safety and formulation performance are usually reported in separate bodies of literature, and the material tested is often characterized only superficially. This structured [...] Read more.

Background/Objectives: Antimicrobial resistance has renewed interest in plant extracts, essential oils and honey as topical adjuvants, yet antimicrobial potency, host-tissue safety and formulation performance are usually reported in separate bodies of literature, and the material tested is often characterized only superficially. This structured narrative review aimed to integrate these dimensions into a single decision-oriented pathway. Methods: The Web of Science Core Collection was searched using seventeen predefined strings across fourteen thematic domains, restricted to English-language articles and reviews from 2021 to 2026, with supplementary PubMed/MEDLINE searches, hand-searching, and normative documents from the issuing organizations. Results: The framework comprises seven decision domains: pre-analytical standardization of each matrix class; antibacterial and antifungal testing with matrix-specific controls; biofilm endpoints named according to what they measure; strain selection tiered from reference to clinical and resistant isolates; host safety from monolayer cytotoxicity to reconstructed human epidermis; selectivity, expressed per microorganism and extended to the resident cutaneous microbiota; and formulation performance, with permeation interpreted against a retention rather than a maximization target. Resistance under sub-inhibitory exposure forms an advanced stage. Conclusions: Progression is governed by proposed Go, Conditional Go and No-Go criteria, supported by a matrix-specific control table and a minimum reporting checklist. The framework has not been prospectively validated, and no universal selectivity threshold is proposed. Full article

(This article belongs to the Special Issue Innovative Approaches in Skin Formulation Development and Characterization: Scientific Foundations for Regulatory Transformation)

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27 pages, 13311 KB

Open AccessArticle

Scalable Production of a De Novo SARS-CoV-2 Antiviral Miniprotein in Escherichia coli

by Jinhwan Shin, Eu-min Kim, Jun-hong Jang, Seok-won Jee, Sang-hoon Kim, Seonggwan Yu, Minguen Yoon, Daniel Craig, Ryan Swoyer, Sandip Patel, Praveen Alamuri, Albert Price, Rashmi Ravichandran, Lauren Carter and Sammaiah Pallerla

Pharmaceutics 2026, 18(9), 1110; https://doi.org/10.3390/pharmaceutics18091110 - 3 Sep 2026

Abstract

Background/Objectives: The rapid emergence of SARS-CoV-2 variants that evade neutralizing antibodies underscores the need for new antiviral biologics that integrate precise molecular design with scalable, cost-effective manufacturing. Computationally designed miniproteins targeting the spike protein’s receptor-binding domain (RBD) offer a promising alternative to monoclonal [...] Read more.

Background/Objectives: The rapid emergence of SARS-CoV-2 variants that evade neutralizing antibodies underscores the need for new antiviral biologics that integrate precise molecular design with scalable, cost-effective manufacturing. Computationally designed miniproteins targeting the spike protein’s receptor-binding domain (RBD) offer a promising alternative to monoclonal antibodies because of their small size, high thermal stability, and compatibility with microbial expression systems. Here, we detail the full development and cGMP manufacturing of IPD-52520, a novel antiviral miniprotein produced using an optimized E. coli platform. Methods: Two candidate miniproteins, a homotrimeric construct (Trimer, IPD-52520, 17 kDa) and a tandem fusion construct (Daisy, IPD-52521, 25 kDa), were evaluated in parallel through systematic optimization of strain selection, media formulation, fed-batch fermentation, inclusion-body solubilization, refolding, and chromatographic purification. The leading candidate was scaled from 5 L to 50 L under cGMP conditions, and biophysical and stability analyses were conducted to support nonclinical and Phase 1 clinical development. Results: The Trimer was selected as the lead molecule based on superior preclinical efficacy, favorable pharmacokinetics, and higher volumetric yields. The optimized process yields about 2 g/L of purified protein at over 90% purity. Scale-up from 5 L to 50 L demonstrated excellent batch consistency across six independent runs. Biophysical studies confirmed a well-folded, predominantly alpha-helical trimer (Tm = 73.4 °C; polydispersity = 1.005) with an intact primary structure and strong target binding (KD < 1 pM). Stability studies show the drug remains stable at 2–8 °C for at least 12 months, with ongoing long-term studies. Conclusions: These findings demonstrate that computationally designed antiviral miniproteins can be translated into scalable biologics and establish a platform for rapid therapeutic development against current and future pandemics. Full article

(This article belongs to the Section Biopharmaceutics)

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18 pages, 1254 KB

Open AccessArticle

Nasal Nanoparticle Vaccine Induces a Cross-Strain T-Cell Immunity Against Toxoplasma gondii

by Aurane Lecouffe, Thomas Bouillet, Bryan Thiroux, Amélie Degraeve, Anaïs-Camille Vreulx, Romain Magnez, Angelo Scuotto, Christophe Barnier-Quer and Didier Betbeder

Pharmaceutics 2026, 18(9), 1109; https://doi.org/10.3390/pharmaceutics18091109 - 3 Sep 2026

Abstract

Background/Objectives: Toxoplasma gondii is a globally distributed parasite responsible for significant morbidity in both humans and animals. VXN-Toxo, is an intranasal vaccine based on maltodextrin nanoparticles formulated with inactivated T. gondii parasites. A vaccination campaign conducted worldwide in zoological parks demonstrated high [...] Read more.

Background/Objectives: Toxoplasma gondii is a globally distributed parasite responsible for significant morbidity in both humans and animals. VXN-Toxo, is an intranasal vaccine based on maltodextrin nanoparticles formulated with inactivated T. gondii parasites. A vaccination campaign conducted worldwide in zoological parks demonstrated high efficacy across multiple species and geographical regions. These findings suggest that VXN-Toxo may induce broad cross-reactive immunity against T. gondii strains circulating in various regions. Methods: To further characterize the immune mechanisms, we evaluated the cellular immune response induced by VXN-Toxo in C57BL/6 mice. Following vaccination, splenocytes were stimulated with antigens derived from multiple T. gondii strains, representing the major haplogroups (types I, II, III, and atypical strains). Results: ELISPOT analysis demonstrated that VXN-Toxo induced strong antigen-specific T cell responses, characterized by robust IFN-γ and IL-17 production upon stimulation with both homologous and heterologous antigens. Flow cytometry analysis further revealed the activation of both CD4⁺ and CD8⁺ T cells, with the notable presence of IFN-γ–producing CD8⁺ central and effector memory cells and CD4⁺ effector memory T cells. Conclusions: Altogether, these results indicate that VXN-Toxo induces a broad, T cell–mediated immune response with cross-reactive properties and highlight its potential as a promising vaccine candidate for both human and veterinary applications. Full article

(This article belongs to the Special Issue Cutting-Edge Approaches to Smart Pharmaceutics and Vaccine Development)

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24 pages, 4534 KB

Open AccessReview

Extracellular Vesicle–Lipid Hybrid Systems for RNA Delivery in Cancer: Structural Classification, Functional Delivery, and Translational Challenges

by Lu Lu, Yige Qiu, Jiayu Wu, Wei Dou, Jing Yang and Bo Zhang

Pharmaceutics 2026, 18(9), 1108; https://doi.org/10.3390/pharmaceutics18091108 - 2 Sep 2026

Abstract

RNA therapeutics offer considerable potential for cancer treatment. Their therapeutic application, however, remains limited by rapid degradation, inefficient cellular uptake, and restricted intracellular release. Extracellular vesicles (EVs) are cell-derived membrane vesicles that have been exploited as promising vehicles for drug delivery due to [...] Read more.

RNA therapeutics offer considerable potential for cancer treatment. Their therapeutic application, however, remains limited by rapid degradation, inefficient cellular uptake, and restricted intracellular release. Extracellular vesicles (EVs) are cell-derived membrane vesicles that have been exploited as promising vehicles for drug delivery due to their high biocompatibility and low immunogenicity, whereas liposomes and lipid nanoparticles provide tunable lipid composition and efficient loading of exogenous nucleic acids. Combining these carriers has led to EV–lipid hybrid systems designed to integrate their complementary properties. This review summarizes recent advances in EV–lipid hybrids for cancer therapy and organizes the reported systems according to their structural architecture and preparation. EV–liposome fusion hybrids, EV–lipid nanoparticle hybrids, and EV membrane-integrated lipid nanocarriers are discussed in relation to their RNA-loading strategies and representative therapeutic designs. The review also examines the key processes involved in functional RNA delivery and summarizes representative applications across different cancer types. Challenges associated with safety evaluation are also discussed, together with future directions for clinical translation. Overall, EV–lipid hybrids represent a promising strategy for RNA-based cancer therapy. Full article

(This article belongs to the Special Issue Unlocking Cancer Treatment: Harnessing Lipid Nanocarriers for Precision Drug Delivery)

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32 pages, 1505 KB

Open AccessArticle

Development of an Oral Delivery System for Live Adenovirus Based on Bionic Chrysanthemum Sporopollenin Exine Armor

by Jun Liu, Shuang Liu, Jianxiong Wei, Zifang Ding, Xiaodan Yan, Jin Sun, Shujun Wang, Shanhu Li and Yuanqing Li

Pharmaceutics 2026, 18(9), 1107; https://doi.org/10.3390/pharmaceutics18091107 - 2 Sep 2026

Abstract

Background: The oral application of adenovirus is hindered by its poor in vitro storage stability and rapid degradation by gastric acid. To address this, a biomimetic oral adenovirus delivery system (CSP-AdV@LYO) was constructed based on three key properties of natural chrysanthemum sporopollenin [...] Read more.

Background: The oral application of adenovirus is hindered by its poor in vitro storage stability and rapid degradation by gastric acid. To address this, a biomimetic oral adenovirus delivery system (CSP-AdV@LYO) was constructed based on three key properties of natural chrysanthemum sporopollenin (CSP): chemical inertness, intelligent “acid-shrinking/alkali-swelling” responsiveness, and mucosal adhesion via its spike structures, aiming to enhance oral stability and delivery efficiency. Methods: First, low-allergenic chrysanthemum pollen was screened using proteomics and a zebrafish allergy model. High-purity sporopollenin (SPO) was then extracted via an acidolysis method, followed by systematic characterization of its morphology, particle size, zeta potential, contact angle, and reversible acid-shrinking/alkali-swelling behavior. Subsequently, a CSP-AdV@LYO formulation was prepared by optimizing a cryoprotectant formulation (sucrose:gelatin = 1:1) and a vacuum loading process. Its protective and release properties were evaluated in vitro using simulated gastric and intestinal fluids, and its long-term stability was assessed. Further in vivo studies in mice assessed its intestinal colonization efficiency. The adhesion mechanism of the sporopollenin spike structures was investigated through mucosal retention experiments. Results: Mucosal retention experiments confirmed that the spike structures on the sporopollenin surface enhanced retention by approximately 3-fold through mechanical interlocking compared to smooth particles. In long-term stability tests, the viral genome copy number retention rate was improved more than 10-fold compared to the virus stock solution. The system enabled a steady and controlled release of the virus in simulated intestinal fluid, with the released virus maintaining its infectivity. In vivo studies demonstrated that CSP-AdV@LYO promoted efficient intestinal colonization and reduced acute mortality from 75% (AdV@LYO group) to 25%. Conclusion: By leveraging the unique physicochemical properties of chrysanthemum sporopollenin, this study successfully developed a biomimetic oral delivery system for live adenovirus that provides gastric acid protection, intelligent pH-responsive release, and mucosal adhesion. This system significantly enhances the oral stability and intestinal delivery efficiency of adenovirus while reducing systemic exposure risks. It offers a novel biomimetic strategy for the oral delivery of adenovirus and other biological macromolecules. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems: From Precision Targeting to Intelligent Release)

16 pages, 276 KB

Open AccessArticle

Pre-Analytical Stability of Mycophenolic Acid and Its Glucuronide in Saliva Samples Stored in Cotton Salivette^® Devices Before Centrifugation

by Grzegorz Szynkaruk, Julia Kerner, Ahata Nelipovich, Kacper Osuch, Maria Miotk, Agata Bartkowiak and Joanna Sobiak

Pharmaceutics 2026, 18(9), 1106; https://doi.org/10.3390/pharmaceutics18091106 - 2 Sep 2026

Abstract

Background/Objectives: Saliva may provide a non-invasive alternative to blood sampling for therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) in children. This study assessed MPA and, secondarily, mycophenolic acid glucuronide (MPAG) in non-centrifuged Salivette^® devices to determine an acceptable interval between [...] Read more.

Background/Objectives: Saliva may provide a non-invasive alternative to blood sampling for therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) in children. This study assessed MPA and, secondarily, mycophenolic acid glucuronide (MPAG) in non-centrifuged Salivette^® devices to determine an acceptable interval between saliva collection and laboratory processing. Methods: Phosphate-buffered saline (PBS), artificial saliva, and saliva from five healthy adult volunteers were externally spiked with MPA and MPAG at 5 and 500 ng/mL and applied to Salivette^® cotton swabs. Samples were stored for 12, 24, and 48 h at 22 °C and 6 °C and analyzed by liquid chromatography-tandem mass spectrometry. Percentage deviations from nominal concentration within ±15% were considered acceptable. Results: In PBS, both analytes met the acceptance criterion for up to 24 h under both conditions. In artificial saliva, both met the criterion for at least 24 h and, under some conditions, for 48 h. In human saliva, all volunteer-level MPA results met the criterion after 12 h at both temperatures, whereas MPAG did not consistently meet it. Mean MPA deviations across volunteers ranged from −10.8 to 1.9% at 22 °C and from −12.3 to 2.4% at 6 °C. Conclusions: MPA met the acceptance criterion after 12-h in non-centrifuged Salivette^® devices, supporting the feasibility of a 12-h pre-centrifugation interval under comparable conditions. Prompt centrifugation and processing are advisable when MPAG determination is required. Confirmation using incurred post-dose saliva from pediatric patients receiving mycophenolate mofetil is required. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring as a Useful Tool in Therapy Improvement, 3rd Edition)

22 pages, 30628 KB

Open AccessArticle

Colquhounia Root Tablet Modulates Psoriatic Immune Responses Involving NF-κB-Driven Dendritic-Cell Maturation and Th17/Treg Imbalance: An Integrative Network Pharmacology and Transcriptomic Study

by Qingqing Xu, Lisong Sheng, Hui Zhao, Lingyun Du, Jingjing Wei, Huijie Zhang, Tianyu Zhang, Huanhuan Zhang, Chunhong Zhang and Rong Sun

Pharmaceutics 2026, 18(9), 1105; https://doi.org/10.3390/pharmaceutics18091105 - 2 Sep 2026

Abstract

Background/Objectives: Psoriasis is a chronic inflammatory skin disease driven by Th17/Treg imbalance. Colquhounia Root Tablet (CRT), derived from Tripterygium hypoglaucum, has shown clinical potential for psoriasis, but its mechanisms remain unclear. This study aimed to evaluate the anti-psoriatic effects of CRT [...] Read more.

Background/Objectives: Psoriasis is a chronic inflammatory skin disease driven by Th17/Treg imbalance. Colquhounia Root Tablet (CRT), derived from Tripterygium hypoglaucum, has shown clinical potential for psoriasis, but its mechanisms remain unclear. This study aimed to evaluate the anti-psoriatic effects of CRT and elucidate its underlying mechanisms. Methods: Anti-psoriatic activity was evaluated in an IMQ-induced psoriasis-like mouse model. Mice received oral CRT at 0.085, 0.17, or 0.35 g/kg daily from days 2 to 8. Immune-cell populations were analyzed by flow cytometry. Bone marrow-derived dendritic cells (BMDCs) were used for in vitro studies. Network pharmacology, transcriptomics, molecular docking, and experimental validation were integrated to explore the mechanisms. Results: CRT dose-dependently ameliorated psoriasiform dermatitis and reduced Th17/Treg ratio while inhibiting CD11c⁺MHC II⁺ DC activation in vivo. In vitro, CRT suppressed R848-induced BMDC maturation and inhibited p65/IκBα phosphorylation. Transcriptomic analysis revealed modulation of TNF, NF-κB, IL-17, and JAK-STAT pathways. Molecular docking predicted the strong binding of multiple CRT compounds to RELA. Conclusions: CRT exerts anti-psoriatic effects in a murine model with concurrent modulation of NF-κB-related DC maturation and Th17/Treg correction, suggesting a potential immunomodulatory mechanism requiring further causal validation. Full article

(This article belongs to the Special Issue New Therapeutic Approaches for the Application of Natural Products in Skin Diseases)

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22 pages, 2115 KB

Open AccessReview

Algal Bioactive Metabolites with Important Roles in Wound Healing

by Tünay Karan, Çağrı Çağlar Sinmez, Sevgi Durna Daştan, Murat Çakir, Mücahit Seçme and René van den Hoven

Pharmaceutics 2026, 18(9), 1104; https://doi.org/10.3390/pharmaceutics18091104 - 2 Sep 2026

Abstract

A wound is defined as disruption or destruction of tissue integrity. In order to support healing in wound management, a good wound bed free of necrotic tissue and infection is desired, but intensive chemical antiseptics will cause cell destruction and delay healing. In [...] Read more.

A wound is defined as disruption or destruction of tissue integrity. In order to support healing in wound management, a good wound bed free of necrotic tissue and infection is desired, but intensive chemical antiseptics will cause cell destruction and delay healing. In order for wound healing to be rapid, the nature and contamination of the wound should be taken into consideration and appropriate methods should be utilized. Today, many types of algae are frequently preferred as an alternative to medicine and are the subject of research. Since the metabolites contained in algae display several notable biological activities such as antimicrobial, anti-inflammatory, and antioxidant, they are a good option in wound treatment. Algae contain pigments, peptides, fatty acids, and polysaccharides that are crucial for wound healing. These compounds play vital roles at all stages of the healing process by accelerating cell proliferation, promoting collagen deposition, scavenging reactive oxygen species (ROS), and regulating key inflammatory cytokines. Furthermore, their unique physical and functional properties enable the development of novel bio-inspired wound dressings, hydrogels, and drug-delivery scaffolds. This review discusses the bioactive metabolites found in algae that are effective in wound healing. Full article

(This article belongs to the Section Biopharmaceutics)

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41 pages, 5852 KB

Open AccessArticle

Pharmacokinetic Variability of Direct Oral Anticoagulants and Calcium Channel Blockers: A Comparative Analysis of Exposure Data from Clinical Studies

by Lara Marques and Nuno Vale

Pharmaceutics 2026, 18(9), 1103; https://doi.org/10.3390/pharmaceutics18091103 - 2 Sep 2026

Abstract

Background/Objectives: Interindividual pharmacokinetic (PK) variability remains a daunting challenge for effective and safe drug therapy. Despite the widespread use of direct oral anticoagulants (DOACs) and calcium channel blockers (CCBs), a substantial number of adverse drug reactions have been reported for both classes. Herein, [...] Read more.

Background/Objectives: Interindividual pharmacokinetic (PK) variability remains a daunting challenge for effective and safe drug therapy. Despite the widespread use of direct oral anticoagulants (DOACs) and calcium channel blockers (CCBs), a substantial number of adverse drug reactions have been reported for both classes. Herein, this study aimed to assess and analyze the PK variability of DOACs and CCBs across diverse clinical and demographic profiles under both single- and multiple-dose conditions. Methods: A PubMed search identified clinical PK studies reporting maximum plasma concentration (C_max) and/or area under the concentration-time curve (AUC). The coefficient of variation (CV%) was calculated and used as a measure of PK variability. A CV% < 40% indicated low-to-moderate variability, and a CV% > 40% was defined as high variability. Results: A total of 264 studies were included following systematic screening, and the dataset was further characterized according to population features and clinical context. Among DOACs, edoxaban exhibited the lowest PK variability, whereas dabigatran showed the highest. CCBs demonstrated a broad variability spectrum, ranging from predictable agents (amlodipine and felodipine) to highly variable compounds (nisoldipine, isradipine, nimodipine, diltiazem, and verapamil). Studies evaluating drug–drug interactions, ethnicity, and specific drug-related factors were associated with increased PK variability. Conclusions: These findings suggest that fixed-dose strategies may not be universally appropriate for DOACs and CCBs, particularly in high-risk subgroups where altered exposure may lead to sub- or supratherapeutic concentrations and compromise clinical outcomes. Therefore, clinicians should avoid evaluating individual risk factors in isolation and instead consider the patient’s complete profile when selecting and adjusting pharmacotherapy. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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20 pages, 12036 KB

Open AccessArticle

Therapeutic Efficacy and Safety of Intraperitoneally Administered ²¹¹At-Labeled Gold Nanoparticles for Peritoneally Disseminated Malignancies

by Hiroki Kato, Xuhao Huang, Erina Hilmayanti, Yuichiro Kadonaga, Kazuhiro Ooe, Masashi Murakami, Kazuya Kabayama, Kazuko Kaneda-Nakashima, Atsushi Toyoshima, Xiaojie Yin, Hiromitsu Haba and Koichi Fukase

Pharmaceutics 2026, 18(9), 1102; https://doi.org/10.3390/pharmaceutics18091102 (registering DOI) - 2 Sep 2026

Abstract

Background/Objectives: Peritoneal dissemination of malignancies leads to poor prognoses, and no effective treatment currently exists. The difficulty of treating such malignancies is likely because systemically administered drugs cannot easily target malignant cells in the abdominal cavity. High intraperitoneal drug retention, non-toxicity towards [...] Read more.

Background/Objectives: Peritoneal dissemination of malignancies leads to poor prognoses, and no effective treatment currently exists. The difficulty of treating such malignancies is likely because systemically administered drugs cannot easily target malignant cells in the abdominal cavity. High intraperitoneal drug retention, non-toxicity towards normal tissues, and successful targeting of malignant cells are important for an effective therapy. The aim of this study was to evaluate an intraperitoneally administered astatine-labeled, integrin-targeted nanodrug, mPEG(Mn:350)-S-AuNP[²¹¹At]-c[RGDfK(C)] ([²¹¹At]AuNP@PEG/RGD), with respect to its kinetics, therapeutic efficacy, and safety. Methods: C6 rat glioma cells (10⁷), and BxPC3 (10⁷) and PANC-1 (10⁷) human pancreatic cancer cells were seeded intraperitoneally into nude mice, and [²¹¹At]AuNP@PEG/RGD (0.979 ± 0.194 MBq for C6 models (n = 3), 1.139 ± 0.035 MBq for BxPC3 models (n = 10), and 1.308 ± 0.039 MBq for PANC-1 models (n = 10) per mouse) or saline were intraperitoneally administered 4–7 days later. Cytotoxicity against malignant cells, pharmacokinetics after administration, therapeutic efficacy, and safety in abdominal organs were evaluated. Results: Intraperitoneally administered [²¹¹At]AuNP@PEG/RGD accumulated exclusively in the peritoneal cavity for a long period of time and showed minimal systemic diffusion through the blood. In the C6 model, the intraperitoneal tumor mass was significantly lower in the treated group compared with that of the controls (p = 0.05). For the BxPC3 (median survival time: control/treated = 41/65 days, p < 0.001) and PANC-1 (median survival time: control/treated = 19/35 days, p < 0.001) peritoneal dissemination models, survival analysis revealed that [²¹¹At]AuNP@PEG/RGD significantly prolonged overall survival. Although transient weight loss, leukopenia, and thrombocytopenia were observed at one week post-administration, a short recovery trend was evident thereafter. One month after administration, no abnormalities were found in hematological tests or histological analyses of intra-abdominal organs. Conclusions: The intraperitoneal administration of astatine-labeled integrin-targeted [²¹¹At]AuNP@PEG/RGD nanoparticles showed promising findings in terms of safety and efficacy for treating peritoneally disseminated malignant tumors. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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53 pages, 2332 KB

Open AccessReview

Natural Product-Based Nanomedicine in the Treatment of Breast Cancer

by Kaiyan Su, Yan Li, Dongmei Zhang, Yuxuan Zhou, Jianping Zhang, Hongyan Zhu, Yun Zhao, Cheng Guo and Quanjun Yang

Pharmaceutics 2026, 18(9), 1101; https://doi.org/10.3390/pharmaceutics18091101 - 1 Sep 2026

Abstract

Background: Breast cancer remains the most common malignant tumor among women worldwide. Although conventional treatments including surgery, chemotherapy, and radiotherapy are effective, they are confronted with challenges such as tumor heterogeneity, systemic toxicity, and recurrence driven by drug resistance. To overcome these limitations, [...] Read more.

Background: Breast cancer remains the most common malignant tumor among women worldwide. Although conventional treatments including surgery, chemotherapy, and radiotherapy are effective, they are confronted with challenges such as tumor heterogeneity, systemic toxicity, and recurrence driven by drug resistance. To overcome these limitations, natural products have emerged as promising therapeutic alternatives owing to their multi-target efficacy and favorable biocompatibility. However, their clinical translation is still hindered by poor chemical stability, low aqueous solubility, and inadequate bioavailability. Nanodelivery systems offer a transformative solution by enhancing bioavailability and enabling precision targeting through the enhanced permeation and retention effect, thereby widening the therapeutic window and minimizing off-target toxicity. Purpose: This review evaluates diverse nanoparticle-based delivery systems and their targeting mechanisms in natural product-based breast cancer therapy. By examining inherent advantages and translational challenges, this analysis provides critical insights into the clinical development and application of these nanoformulations. Methods: A systematic literature search was performed in PubMed, ScienceDirect, Springer, Taylor & Francis, and Web of Science to identify relevant studies on natural product-based nanoformulations for breast cancer therapy. Results: Natural products exert anti-breast cancer effects through mechanisms such as inducing apoptosis, arresting the cell cycle, inhibiting invasion and metastasis, suppressing angiogenesis, and regulating autophagy. To overcome clinical hurdles, three complementary targeting strategies have been developed: passive, active, and stimuli-responsive targeting. These advances are shifting nanomedicines toward active precision therapy, markedly improving the therapeutic index. With multiple formulations already approved or in clinical pipelines, this field is rapidly progressing from laboratory research to clinical implementation. Conclusions: Natural products possess potent anti-breast cancer effects, and the application of nanodelivery technology effectively overcomes their inherent limitations of poor stability and low bioavailability. Although preliminary findings are promising, large-scale, randomized controlled clinical trials are urgently needed to systematically evaluate their safety, efficacy, and practical potential for clinical translation in breast cancer management. Full article

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

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