Pharmaceutical Research[JOURNAL]
Sun
200 papers
Spatial Targeting of Sialic Acid Receptors for MRI/BNCT-Integrated Boron Drug-Based Antitumor Therapy.
Sun X, Qin Y, Ben Z … +8 more , Zhang Z, Bao X, Yang Y, Shui Y, Chen H, Wu D, Wei Q, Han M
Pharm Res · 2026 Mar · PMID 41760875 · Publisher ↗
OBJECTIVE: Boron neutron capture therapy (BNCT) is limited by inadequate boron delivery to tumor cells and the inability to visualize boron agents for personalized treatment. This study introduces DOTA-BPA-Gd, a dual-fun...
OBJECTIVE: Boron neutron capture therapy (BNCT) is limited by inadequate boron delivery to tumor cells and the inability to visualize boron agents for personalized treatment. This study introduces DOTA-BPA-Gd, a dual-function boron agent integrating BNCT efficacy with drug tracing. METHODS: DOTA-BPA-Gd was designed with four phenylboronic acid groups to target sialic acid residues on cancer cell surfaces. This strategy aims to enhance tumor boron accumulation while avoiding LAT1-mediated exocytosis and transporter saturation associated with BPA-F. With a molecular weight of ~ 1200 Da, DOTA-BPA-Gd allows efficient spatial binding to sialic acid, improving targeting specificity. Cellular uptake, cytotoxicity, and boron distribution were evaluated, followed by in vivo BNCT experiments with MRI monitoring. RESULTS: DOTA-BPA-Gd effectively delivered boron to cancer cells without detectable toxicity. Under neutron irradiation, the DOTA-BPA-Gd + N group showed significant tumor inhibition, with tumor volumes reduced to about one-third of those in the BPA-F + N group. Furthermore, gadolinium enabled real-time MRI-based tracking of boron biodistribution, confirming the agent's dual functionality. CONCLUSIONS: DOTA-BPA-Gd offers a promising strategy for BNCT by combining targeted boron delivery with non-invasive imaging. This integrated approach improves treatment precision, enhances therapeutic efficacy, and may help overcome key clinical challenges in BNCT.
A Top-Down Physiologically Based Pharmacokinetic Modeling Approach to Explore Unexpected Bio-inequivalence of Experimental Oral Formulations in Dogs.
Martinez MN, Lukacova V, Gao S … +1 more , Myers MJ
Pharm Res · 2026 Mar · PMID 41760874 · Publisher ↗
PURPOSE: A physiologically based pharmacokinetic (PBPK) modeling approach was used to explore potential reasons for the unexpected in vivo/in vitro inconsistencies previously observed in an investigation exploring the co...
PURPOSE: A physiologically based pharmacokinetic (PBPK) modeling approach was used to explore potential reasons for the unexpected in vivo/in vitro inconsistencies previously observed in an investigation exploring the comparative oral bioavailability and in vitro dissolution of three experimental treatments. All treatments contained two poorly soluble drugs: ivermectin (IVM) and praziquantel (PRZ). The purpose of that investigation was identification of alternative (non-terminal animal studies) pathways for assessing the bioequivalence (BE) of non-systemically available, locally acting oral formulations. METHODS: Treatment differences in gastrointestinal (GI) IVM and PRZ in vivo dissolution and absorption were examined using the GastroPlus PBPK software. Drug models included Michaelis Menten kinetics and canine-specific relative abundances of the primary metabolizing enzyme and efflux transporter. Individual dog predictions were generated using a top-down approach where a double or triple Weibull function was fitted to the previously generated in vivo data (27 dogs × 3 treatments = 81 profiles per drug). RESULTS: By examining the predicted treatment differences in in vivo performance, it was possible to exclude several previously proposed reasons for the unexpected poor performance of one of the treatments (e.g., IVM precipitation or intestinal efflux, unintended excipient effects, and rapid dissolution increasing PRZ exposure to enterocyte Cyp3a12) for the unexpected poor performance for one of the treatments. CONCLUSIONS: The top-down approach provided insights into the intestinal location of in vivo dissolution and absorption, eliminating previously proposed causes and raising alternative possibilities for the observed in vivo/in vitro disparities (indirectly related to the granule diameters of the three treatments). It also helped identify in vitro test procedures worthy of future consideration.
Development of Proniosomal Dry Powder for Dual Pulmonary Delivery of Salbutamol Sulfate and Carvacrol: A Design of Experiment Approach.
Neopane D, Kushwaha P, Badruddeen
Pharm Res · 2026 Feb · PMID 41741912 · Publisher ↗
BACKGROUND: Proniosomes are dry, free-flowing, carrier-based systems designed to enhance pulmonary drug delivery and improve the aerosolization of therapeutic agents. Such systems are gaining attention for optimizing the...
BACKGROUND: Proniosomes are dry, free-flowing, carrier-based systems designed to enhance pulmonary drug delivery and improve the aerosolization of therapeutic agents. Such systems are gaining attention for optimizing the performance of dry powder inhalers (DPIs) in inhalation therapy. OBJECTIVE: This study aimed to develop and optimize a proniosomal powder system for dual pulmonary delivery of Salbutamol sulfate (SS) and Carvacrol (CAR) using the Box-Behnken design (BBD). METHODS: Proniosomes were prepared by the slurry method. A three-factor, three-level BBD was employed to assess the influence of Span 60, lactose monohydrate, and mannitol concentrations on particle size, entrapment efficiency (% EE), and drug loading capacity (% LC). The optimized formulation was characterized by FTIR, XRD, and SEM to confirm drug-excipient compatibility, amorphous dispersion, and surface morphology. RESULTS: The optimized proniosomal powder exhibited desirable particle size (827.4 ± 33.65 nm), high drug entrapment (SS: 84.37 ± 2.04%; CAR: 95.5 ± 1.52%), and efficient aerosolization performance. FTIR and XRD results confirmed chemical compatibility and amorphous nature of the entrapped drugs. In vitro release studies indicated sustained drug release pattern (SS: 67.34%; CAR: 68.89% over 24 h). Stability studies over 6 months demonstrated a good shelf-life and retention of vesicle-forming capability upon hydration. CONCLUSION: The developed dual-drug proniosomal powder offers a promising approach for pulmonary drug delivery. Its optimized physicochemical and aerosolization characteristics suggest potential utility in the effective management of respiratory disorders through sustained release and improved lung deposition.
Physicochemical and Biological Characterization of the TLR7 Agonist SZU-106.
Herbst M, Kipp J, Kessler SM … +1 more , Wischke C
Pharm Res · 2026 Apr · PMID 41741911 · Full text
OBJECTIVE: Toll-like receptor 7 (TLR7) recognizes single-stranded RNA and plays a crucial role in initiating immune responses against viral pathogens. This study characterizes SZU-106, a recently developed Toll-like rece...
OBJECTIVE: Toll-like receptor 7 (TLR7) recognizes single-stranded RNA and plays a crucial role in initiating immune responses against viral pathogens. This study characterizes SZU-106, a recently developed Toll-like receptor 7 (TLR7) agonist, focusing on its physicochemical and biological properties as key determinants for assessing its suitability for drug product development. METHODS: Distribution coefficients (LogD) of SZU-106 were determined in silico and confirmed experimentally by the shake-flask method. Stress stability tests were performed by incubation at different pH conditions using temperatures between room temperature and 60°C. HPLC ESI-MS/MS analysis was applied to determine the main degradation products. Cytotoxicity tests with different reporter cell lines allowed excluding TRL7-mediated as well as unspecific cytotoxicity in THP-1 monocytes and macrophages. RESULTS: The analysis of distribution coefficients conducted at pH 5.6 and 7.4 confirmed the predominantly hydrophilic nature of SZU-106. Stress stability testing revealed the stability of SZU-106 in neutral aqueous solutions, while rapid degradation was noted under acidic and basic conditions with rate constants of 2.21·10-3 d-1 to 0.39 h-1. HPLC ESI-MS/MS analysis showed that SZU-106 primarily degrades via hydrolytic cleavage of its amide bonds, with four major degradation products identified and structurally characterized. Cytotoxicity assays with THP-1 monocytes and differentiated macrophages at increasing drug concentrations (10 -1000 µM) illustrated no off-target cytotoxicity and only mild, time-dependent, receptor-mediated effects in TLR7-overexpressing THP-1 cells at high SZU-106 concentrations. CONCLUSIONS: This evaluation of SZU-106 supports its further development as a therapeutic TLR7 agonist, with formulation strategies representing the next stage for drug development.
Lapatinib-Loaded Glucose-Functionalized Silver Nanoparticles Enhance Efficacy in HER2-Positive Breast Cancer Cells and Modulate Survival-Associated Genes.
Dolatabadi B, Peymani M, Hashemi M … +3 more , Rouhi L, Salehzadeh A, Zarrabi A
Pharm Res · 2026 Feb · PMID 41741910 · Publisher ↗
BACKGROUND: Lapatinib is a dual EGFR/HER2 tyrosine kinase inhibitor used in HER2-positive breast cancer (BC). Here, we identified prognostic genes modulated by lapatinib and evaluated whether glucose-functionalized, lapa...
BACKGROUND: Lapatinib is a dual EGFR/HER2 tyrosine kinase inhibitor used in HER2-positive breast cancer (BC). Here, we identified prognostic genes modulated by lapatinib and evaluated whether glucose-functionalized, lapatinib-conjugated silver nanoparticles could enhance its anticancer efficacy. METHODS: Lapatinib-responsive genes were identified from the GSE38376 dataset and their prognostic associations were assessed using The Cancer Genome Atlas (TCGA). Silver nanoparticles were synthesized by Spirulina-mediated reduction of AgNO₃, functionalized with glucose, and conjugated to lapatinib (Ag@Glu-Lapatinib NP), then characterized by FTIR, XRD, zeta potential, SEM, and TEM. SKBR3 cells were treated with Ag@Glu-Lapatinib NP, Ag NP, or lapatinib and evaluated by MTT, Annexin V/PI apoptosis assay, and RT-qPCR for candidate genes. RESULTS: Transcriptomic analysis indicated that lapatinib suppresses proliferation-associated genes and enriches apoptosis-related pathways. In TCGA, ECE2 and CDCA5 were overexpressed and associated with poorer outcomes, whereas PDK4 and ALDH1A1 were reduced and linked to favorable prognosis. Ag@Glu-Lapatinib NP formation was confirmed, and the nanoformulation showed higher potency (IC₅₀ = 62 μg/mL at 24 h; 31 μg/mL at 48 h) than free lapatinib (250 μg/mL) or Ag NP (125 μg/mL), with markedly increased apoptosis. RT-qPCR verified significant modulation of ECE2, CDCA5, PDK4, and ALDH1A1 after Ag@Glu-Lapatinib NP treatment. CONCLUSION: Conjugating lapatinib to glucose-functionalized silver nanoparticles enhances its activity in HER2-positive BC cells and modulates survival-associated genes. This nano-therapeutic strategy may strengthen the therapeutic potential of lapatinib in breast cancer.
Estimating Human Jejunal Effective Permeability Using Numerical Deconvolution of Oral Solution Concentration Data.
Zhang W, Geng J, He X … +4 more , Yi H, Dong J, Mei L, Xie F
Pharm Res · 2026 Apr · PMID 41735694 · Publisher ↗
AIMS: Accurate determination of human intestinal effective permeability (P) typically relies on technically challenging human intestinal perfusion experiments. This study aimed to develop a numerical deconvolution method...
AIMS: Accurate determination of human intestinal effective permeability (P) typically relies on technically challenging human intestinal perfusion experiments. This study aimed to develop a numerical deconvolution method to estimate jejunal permeability using concentration data obtained from oral solution and intravenous administration. METHODS: Twenty-seven drugs (4 acidic, 11 basic, 7 amphophilic, and 5 neutral) were included using predefined criteria. Numerical deconvolution of intravenous and oral solution data across five time windows (0.25-0.75, 0.5-1, 0.75-1.25, 1-1.5, and 1.5-2 h) was applied to estimate regional jejunal permeability. Estimates were generated under two conditions: uncorrected (P) and corrected for first-pass metabolism (P). The resulting permeability values were compared with observed human perfusion data (P), as well as with the reported three-parameter average model and the site-specific data-based deconvolution method. RESULTS: Correlations of jejunal permeability were performed for 26 drugs (lisinopril excluded due to unreliable P). The 0.25-0.75 h window showed the best agreement with observed values. Within this window, correlations with P were moderate for P (R = 0.47) and strong for P (R = 0.83). The proposed method outperformed the three-parameter average model (R: 0.83 vs 0.57) and was comparable to the site-specific deconvolution method (R: 0.94 vs 0.96) using overlapping compounds. CONCLUSIONS: Our oral solution-based numerical deconvolution method, accounting for first-pass metabolism, enables accurate estimation of jejunal permeability.
Quantitative Analysis of the Effect of Gastrointestinal Water Dynamics on Oral Drug Absorption using a Physiologically Based Integrated Liquid and Intestinal Absorption Drug (ILIAD) Pharmacokinetic Model.
Suzuki S, Tamai I, Shirasaka Y
Pharm Res · 2026 Mar · PMID 41735693 · Publisher ↗
PURPOSE: This study aims to develop a physiologically based pharmacokinetic (PBPK) absorption model incorporating gastrointestinal (GI) fluid dynamics and to quantitatively evaluate the effects of GI fluid dynamics on th...
PURPOSE: This study aims to develop a physiologically based pharmacokinetic (PBPK) absorption model incorporating gastrointestinal (GI) fluid dynamics and to quantitatively evaluate the effects of GI fluid dynamics on the oral absorption of various drugs in humans. METHODS: By incorporating our previously developed physiologically based fluid kinetic (PBFK) model describing GI fluid dynamics into a PBPK absorption model, we constructed the Integrated Liquid and Intestinal Absorption Drug (ILIAD) model, which dynamically describes drug concentrations based on the GI disposition of both fluid and drugs. The scaling factors (SF) for membrane permeability, CYP3A-catalyzed metabolism, and P-gp-mediated efflux introduced into the ILIAD model were obtained as common parameters for all drugs through simultaneous optimization using the reported plasma concentration-time profiles of atenolol, midazolam, and talinolol. RESULTS: Simulation analysis using the ILIAD model accurately predicted the bioavailability and plasma concentration-time profile of various CYP3A and/or P-gp substrate drugs. Sensitivity analysis demonstrated that changes in GI fluid dynamics can lead to variations in GI fluid volume, resulting in altered drug absorption, particularly for low-permeability drugs. However, further analyses demonstrated that even high-permeability drugs may be affected by the GI fluid dynamics when they are substrates of CYP3A or P-gp. CONCLUSION: Our ILIAD model is expected to be a useful tool for predicting oral drug absorption properties, including the effects of changes in GI fluid dynamics.
The Advanced Integrated Respiratory (AIR) Model: Integration of Air-Liquid Interface Cell Cultures within a Human Airway Model for Inhalation Toxicology.
He P, Gholizadeh H, Chong D … +7 more , Cheng S, Spicer P, Young PM, Ledo L, Wilson V, Traini D, Ong HX
Pharm Res · 2026 Mar · PMID 41735692 · Full text
PURPOSE: The Advanced Integrated Respiratory (AIR) model was developed as a physiologically relevant benchtop system designed to assess aerosol deposition and interactions within the respiratory tract. METHODS: This mode...
PURPOSE: The Advanced Integrated Respiratory (AIR) model was developed as a physiologically relevant benchtop system designed to assess aerosol deposition and interactions within the respiratory tract. METHODS: This model integrates a three-dimensional (3D) cast of the human airways with a vacuum driven aerosol inhalation flow and an air liquid interface (ALI) cell culture platform. In this study, the integrated AIR and ALI cell model was used to investigate the toxicity profile of aerosolized Ricinus communis agglutinin-1 (RCA I) toxin. RCA I was characterized in terms of particle size, surface charge, rheology, and aerosol performance. Additionally, real-time electrochemical detection using the Micro Analytical Device (MAD) provided high sensitivity quantification of aerosolized RCA I. The biological effects were assessed using human epithelial cells cultured under ALI conditions, which were exposed to RCA I aerosols. Cytotoxicity and barrier function assays were performed to evaluate its impact. RESULTS: Results show significant differences in toxic dose thresholds comparing 2D and AIR models. Transport study revealed that RCA I exhibited significantly increased mass transport across the epithelial cell layer at toxic concentrations compared to non-toxic concentrations. CONCLUSIONS: This integrated approach represents a significant advancement in the study of inhaled aerosol deposition, toxicity, and pharmacokinetics, offering a robust tool for predicting lung injury and enhancing the detection of a wide range of inhaled aerosols, including but not limited to toxins.
Role of ITIH4 in Modulating YAP/TAZ-Mediated Apoptosis of Type II Alveolar Epithelium during Acute Respiratory Distress Syndrome.
Shih YS, Chen XY, Lin YW … +6 more , Liao ZA, Liu YH, Laiman V, Peng SW, Ito K, Chuang HC
Pharm Res · 2026 Mar · PMID 41735691 · Publisher ↗
Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein with anti-inflammatory and anti-apoptotic properties. This study investigated the role of ITIH4 in regulating Hippo signaling and alveo...
Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein with anti-inflammatory and anti-apoptotic properties. This study investigated the role of ITIH4 in regulating Hippo signaling and alveolar epithelial type II cell (AECII) apoptosis during acute respiratory distress syndrome (ARDS) METHODS: A549 cells were used for ITIH4 knockdown, ITIH4 overexpression, and lipopolysaccharide (LPS) exposure following recombinant ITIH4 (rITIH4) treatment. The expressions of Hippo signaling components (YAP/TAZ), apoptotic markers (ATM, p53, caspase-3), and the senescence marker SIRT1 were examined. Next, C57BL/6JNarl and B6.Sftpc-CreERT2;Ai14(RCLtdT)-D mice were administered intratracheal LPS and daily intranasal rITIH4. Lung injury severity was assessed through H&E staining with K-means clustering and immunofluorescence quantified ITIH4, caspase-3, and YAP expression in SPC⁺ cells from different lung regions RESULTS: The expression of YAP and TAZ decreased with ITIH4 knockdown in A549, whereas p-YAP and SIRT1 increased, and p-TAZ/TAZ decreased with ITIH4 overexpression. We also observed the expression of p-TAZ/TAZ and SIRT1 increased, while ATM and caspase-3 decreased in LPS-injured A549 following rITIH4 treatment. Furthermore, rITIH4 administration restored ITIH4 in SPC⁺ cells and reduced caspase-3 expression in LPS-induced ARDS mice. rITIH4 elevated YAP in SPC⁺ cells within damaged and severely injured lung regions on day 3; this upregulation was attenuated by day 7, suggesting spatiotemporal regulation of Hippo signaling activity during lung repair CONCLUSION: rITIH4 mitigated LPS-induced lung injury by regulating YAP/TAZ activity and suppression of caspase-3 and ATM expression. The observed modulation of Hippo signaling and reduction of AECII apoptosis highlight ITIH4 as a therapeutic potential for ARDS.
An Overview of Endometriosis and Potential Pharmacogenetic Targets.
Pérez-Gómez N, Martínez-Zamora MÁ, Carmona F … +4 more , Novalbos J, Abad-Santos F, Koller D, Saiz-Rodríguez M
Pharm Res · 2026 Mar · PMID 41735690 · Full text
BACKGROUND: Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity. It affects approximately 10-15% of women of reproductive age globally and i...
BACKGROUND: Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity. It affects approximately 10-15% of women of reproductive age globally and is characterized by heterogeneous symptoms with chronic pelvic pain, dysmenorrhea, and infertility being the most common. Although pharmacological treatments are available to manage its symptoms, many women either do not respond to these therapies or experience adverse drug reactions (ADRs) that outweigh the original symptoms of endometriosis. RATIONALE/OBJECTIVES: The aim of this review is to provide a comprehensive overview of endometriosis and to identify pharmacogenetic markers that might influence drug response in its treatment and management. OUTCOMES: Current research highlights a critical gap in pharmacogenetic biomarkers for endometriosis treatment, limiting the potential for personalized therapeutic strategies. WIDER IMPLICATIONS: Integrative multi-omics approaches combining genetic, inflammatory, and hormonal profiles may enhance patient stratification and optimize individualized care.
Silencing CD24 Inhibits Proliferation, Migration, and Chemoresistance in Triple-Negative Breast Cancer Cells.
Liu Y, Guo Y, Lin CY … +3 more , Zhang Y, Li G, Cheng K
Pharm Res · 2026 Apr · PMID 41735689 · Publisher ↗
PURPOSE: The expression of CD24 is significantly higher in triple-negative breast cancer (TNBC) compared to estrogen receptor and progesterone receptor-positive (ER PR) breast cancer and normal breast tissue. CD24 overex...
PURPOSE: The expression of CD24 is significantly higher in triple-negative breast cancer (TNBC) compared to estrogen receptor and progesterone receptor-positive (ER PR) breast cancer and normal breast tissue. CD24 overexpression is associated with tumorigenesis, metastasis, and drug resistance in TNBC. Moreover, CD24 functions as a "don't eat me" signal and disrupts macrophages-mediated phagocytosis of cancer cells. We, therefore, aim to investigate the therapeutic potential of downregulating CD24 in TNBC cells. METHODS: We designed four CD24 siRNAs and evaluated their silencing efficiency and biological activity in TNBC cells using different methods. We also examined the impact of CD24 silencing on doxorubicin resistance and macrophage-mediated phagocytosis of TNBC cells. RESULTS: We have identified a CD24 siRNA that exhibits potent silencing activity in TNBC cells, effectively inhibiting their proliferation, migration, and invasion. CD24 silencing also induces apoptosis of TNBC cells and arrests the cell cycle in the S phase. Moreover, silencing CD24 enhances the sensitivity of TNBC cells to doxorubicin and increases macrophage-mediated phagocytosis of TNBC cells. CONCLUSIONS: Targeting CD24 with siRNAs is a promising therapeutic strategy for TNBC and other cancers characterized by CD24 overexpression.
Cholesterol-Based Lipid Nanoparticles as an Intracellular Drug Reservoir for Enhanced Tumor Therapy.
Jiang Q, Qiu Y, Li P … +5 more , Yu C, Meng T, Hu F, Wang C, Yuan H
Pharm Res · 2026 Mar · PMID 41721070 · Publisher ↗
OBJECTIVE: Cancer remains a critical public health challenge. Conventional anti-tumor drugs are often limited by their short half-life and the requirement for frequent and/or high-dose administration, highlighting the ur...
OBJECTIVE: Cancer remains a critical public health challenge. Conventional anti-tumor drugs are often limited by their short half-life and the requirement for frequent and/or high-dose administration, highlighting the urgent need for drug delivery systems that can enhance intracellular drug accumulation. METHODS: Given that current research on drug delivery systems primarily focuses on developing active or passive targeting strategies to improve therapeutic efficacy, biocompatible cholesterol-based lipid nanoparticles (Cls-LNPs) were developed in this study. The Cls-LNPs were designed to function as an "intracellular drug reservoir" by enhancing cellular uptake and retention, thereby meeting the core requirement of enhanced intracellular drug accumulation. RESULTS: The reservoir capacity is likely attributed to the ability of Cls-LNPs to evade lysosomal degradation and target the endoplasmic reticulum (ER). When combined with the emerging anti-tumor technology of photodynamic therapy (PDT) and utilizing Ce6 as a model photosensitizer, the prepared Ce6@Cls-LNPs exhibited enhanced anti-tumor efficacy both in vitro and in vivo compared to free drugs. The therapeutic effect was achieved through the induction of ER stress, lipid peroxidation, and apoptosis, and it also exhibited a "bystander effect". CONCLUSION: This study offers valuable insights into the application of cholesterol in drug delivery systems and proposes innovative strategies for the development of retention-enhancing formulations.
Targeted Gene Therapy for Mutated H-ras and C-raf.1 Genes Exhibited Variable Efficacy in Inhibiting Hepatocellular Carcinoma in Rats: A Mechanistic Approach.
Mukherjee A, Chakraborty S, Sen R … +4 more , Chandra R, Gope S, Giri TK, Mukherjee B
Pharm Res · 2026 Mar · PMID 41721069 · Publisher ↗
OBJECTIVE: Mutated H-ras or c-raf.1 gene expressions are often associated with HCC development and progression. Using intravenous administration of respective backbone modified antisense oligomer (ASO) in chemically indu...
OBJECTIVE: Mutated H-ras or c-raf.1 gene expressions are often associated with HCC development and progression. Using intravenous administration of respective backbone modified antisense oligomer (ASO) in chemically induced HCC rats, we tried to understand the efficacy and mechanistic intervention of the treatments. METHODS: ASO-mediated in vitro cell cytotoxicity, cellular apoptosis, and alteration of mitochondrial membrane potential (MMP), and their hepatic accumulation in HCC rats, H-ras and c-raf.1 gene and protein expression, immunohistochemical evaluation of various proteins, caspase 3/9 activities, hepatic cytosolic alanine aminotransferase and microsomal aspartate aminotransferase assays were carried out. RESULTS: Nanosize and well-dissociated ASOs treated against mutated H-ras and c-raf.1 showed variable IC50 values in human HCC cells and had no significant toxicity at the experimental dose range in normal human liver cells. Labeled ASOs were distributed well in normal rat liver. ASO treatments showed increased apoptosis and loss of MMP in HepG2 and Huh7 cells. ASOs remarkably altered hepatic focal lesion counts and inhibited tumor incidences. ASO treatments inhibited respective gene expression, increased p53 protein expression, and reduced Hep Par I and HSP70 protein expressions in HCC rat liver. ASO treatments variably induced caspase-3 and -9 protein levels in HCC rats. Hepatic marker enzymes did not alter upon ASO administration in normal rats and improved towards normal levels in carcinogen-treated rats. CONCLUSIONS: ASO treatment against mutated H-ras showed better therapeutic efficacy than ASO treatment against c-raf.1. Thus, blocking mutated H-ras than c-raf.1 might appreciably influence HCC inhibition in rats.
Application of a Stochastic Simulation-estimation Approach to Optimize Pharmacokinetic Study Design in the Context of Paediatric Extrapolation: A Tool to Support Decision-making by Drug Sponsors and Regulators.
Djokoto HP, Ernst L, Dogné JM … +1 more , Musuamba FT
Pharm Res · 2026 Mar · PMID 41721068 · Publisher ↗
BACKGROUND: Extrapolation-based approaches are widely used in paediatric drug development. These often rely on pharmacokinetic (PK) matching to support inference on the benefit-risk balance (BRB). PK-based extrapolation...
BACKGROUND: Extrapolation-based approaches are widely used in paediatric drug development. These often rely on pharmacokinetic (PK) matching to support inference on the benefit-risk balance (BRB). PK-based extrapolation requires generation of PK data in children. Given ethical and practical challenges in paediatric trials, collected data must be relevant and informative. METHODS: This work proposes a stochastic simulation-estimation (SSE) approach to optimise key study design factors (number of patients, samples per patient, and sampling times) for paediatric PK studies in extrapolation contexts. Using three illustrative case studies a subcutaneous monoclonal antibody (mosunetuzumab) and two small molecules with intravenous (meropenem) and oral (olanzapine) administration we demonstrate how SSE can be used in paediatric drug development and how it meets regulatory requirements. RESULTS: SSE enabled prospective optimisation of paediatric study designs using adult drug development data. For each case drug, designs were identified where key model parameter imprecision (normalised root mean squared error, NRMSE) remained below 30% and bias (relative bias, RBias) below 20%. CONCLUSIONS: These case studies illustrate how SSE can be used to evaluate paediatric PK study design options in extrapolation settings and provides drug sponsors and regulators with a practical tool to decision-making related to study design optimization.
Regional Extrathoracic Deposition of Inhaled Epinephrine in an Idealized Child Airway: Influence of Pressurized Metered Dose Inhaler Actuator Orifice Diameter.
Pillay K, Tavernini S, Ruzycki CA … +4 more , Luciuk GH, Stapleton KW, Finlay WH, Martin AR
Pharm Res · 2026 Apr · PMID 41714548 · Publisher ↗
OBJECTIVE: The actuator orifice diameter (OD) of pressurized metered dose inhalers (pMDIs) is known to influence the plume geometry and spray pattern exiting the orifice. Actuator OD has previously been found to influenc...
OBJECTIVE: The actuator orifice diameter (OD) of pressurized metered dose inhalers (pMDIs) is known to influence the plume geometry and spray pattern exiting the orifice. Actuator OD has previously been found to influence in vitro regional deposition in an adult extrathoracic airway model for a suspension epinephrine formulation, with smaller OD reducing oral cavity deposition. Whether this effect persists in the smaller extrathoracic airways of school-aged children is unknown. METHODS: Regional extrathoracic deposition of epinephrine from pMDIs was investigated using an idealized child mouth-throat geometry. A sectioned version of the Alberta Idealized Child Throat (AICT), divided into analogues of the oral cavity, the pharynx/larynx, and the upper trachea, was used to test pMDIs with small and large ODs (0.22 and 0.44 mm) across a range of inhalation flowrates (10, 30, 60, and 100 L/min), with two inhaler insertion angles (transverse and coaxial). In addition, the effect of increasing ambient humidity on regional extrathoracic deposition was explored with both actuator ODs. RESULTS: Actuator OD strongly influenced in vitro regional extrathoracic deposition in the child model, with the smaller OD decreasing oral cavity deposition, and increasing delivery to the laryngeal region and lungs. While increased ambient humidity influenced in vitro regional extrathoracic deposition, the influence of environmental changes was minor when compared with changes associated with actuator OD. CONCLUSION: Overall, for the suspension epinephrine formulation tested, the reduction in oral cavity deposition observed for the smaller OD actuator was maintained despite varying extrathoracic airway size (child vs. adult) and varying ambient humidity.
Population Pharmacokinetic/Pharmacodynamic Modeling of Volagidemab, a Glucagon Receptor Antagonist, in Healthy Chinese and US Subjects Following Single Subcutaneous Administration.
Hu Z, Zhu M, Tang L … +6 more , Zhu J, Yu F, Huang H, Yan H, Xu R, He H
Pharm Res · 2026 Apr · PMID 41714547 · Publisher ↗
AIMS: Volagidemab, a fully human IgG2 monoclonal antibody, is a competitive glucagon receptor (GCGR) inhibitor that blocks endogenous glucagon (GCG) activity. This study developed a population pharmacokinetics/pharmacody...
AIMS: Volagidemab, a fully human IgG2 monoclonal antibody, is a competitive glucagon receptor (GCGR) inhibitor that blocks endogenous glucagon (GCG) activity. This study developed a population pharmacokinetics/pharmacodynamics (PopPK/PD) model and established the exposure-response (E-R) relationship for Volagidemab. METHODS: Data from healthy Chinese and US subjects administered a single subcutaneous (SC) dose of Volagidemab were analyzed. A PopPK/PD model characterized drug disposition and effect. E-R analyses evaluated the relationship between plasma GCG concentrations and fasting plasma glucose (FPG). RESULTS: Volagidemab exhibited dose-dependent PK, characterized by a nonlinear distribution and linear elimination model incorporating a single transit absorption compartment. The PD response, defined as the log-transformed fold change in GCG, was well described by an E model. Body mass index (BMI) was identified as a significant covariate for apparent central volume of distribution (V). Empirical Bayes (EBE) estimates indicated no clinically meaningful differences in PopPK/PD parameters between Chinese and US subjects. E-R analysis demonstrated a linear relationship between GCG fold change and FPG. Baseline FPG was identified as a significant covariate influencing the slope, suggesting greater glucose reduction in individuals with higher baseline FPG. Simulations showed a distinct plateau in the E-R relationship, with minimal additional therapeutic effect observed between 35 and 42 mg. CONCLUSIONS: This analysis confirms minimal ethnic differences in the PK/PD of Volagidemab between healthy Chinese and US subjects. The limited impact of covariates supports dose bridging, facilitating clinical development in China.
Freezing-Induced Stress in mRNA-Lipid Nanoparticles During Lyophilization: Mechanistic Insights From Process and Formulation Studies.
Ruppl A, Hutanu A, Köll-Weber M … +1 more , Allmendinger A
Pharm Res · 2026 Mar · PMID 41714546 · Full text
INTRODUCTION: Lyophilization is a promising strategy to enhance the long-term stability of messenger RNA lipid nanoparticles (mRNA-LNPs). However, lyophilization-induced stresses can impact product quality and the underl...
INTRODUCTION: Lyophilization is a promising strategy to enhance the long-term stability of messenger RNA lipid nanoparticles (mRNA-LNPs). However, lyophilization-induced stresses can impact product quality and the underlying mechanisms remain poorly understood. In this study, we systematically investigated stresses that arise during the freezing step, during the initial stage of the lyophilization process. METHODS: We examined the impact of different freezing protocols (freezing at 0.1, 0.5, and 1.5 K/min, plus controlled nucleation at -10°C) on mRNA-LNP stability. We also explored formulation strategies to mitigate freezing stress: (A) increasing mRNA-LNP concentration or adding empty LNPs to induce colloidal crowding, (B) adding Poloxamer 188 to reduce interfacial stress, (C) incorporating sucrose within LNPs to protect mRNA and reduce osmotic stress, and (D) adding NaCl or L-Methionine to modulate mRNA-lipid interactions. We evaluated particle size, polydispersity index, encapsulation efficiency (EE), mRNA integrity, and eGFP expression in HeLa cells. RESULTS: Faster freezing minimized LNPS particle size increase by trend but reduced EE. Controlled nucleation improved EE but increased LNP particle size. However, eGFP expression was more influenced by particle size than EE. CONCLUSION: These findings provide a mechanistic understanding of how freezing-induced stresses affect mRNA-LNP quality. We hypothesize that cryo-concentration caused by slow freezing leads to increasing size of LNP particles, while higher ice-liquid interfacial stress caused by fast freezing reduces EE. As these effects follow opposing trends, optimizing freezing conditions is crucial. Understanding these mechanisms will guide rational formulation and lyophilization process design for mRNA-LNPs.
Biopharmaceutic Assessment of Post-Approval Changes for Azithromycin Immediate Release Tablets Using Predictive In Vitro Dissolution and a Model-Informed Approach.
García MA, González PM
Pharm Res · 2026 Mar · PMID 41714545 · Publisher ↗
BACKGROUND: Post-approval changes (PACs) in formulations requires a risk assessment of safety and efficacy for extending the product lifecycle. While BCS class I and III are candidates for biowaivers, standard bioequival...
BACKGROUND: Post-approval changes (PACs) in formulations requires a risk assessment of safety and efficacy for extending the product lifecycle. While BCS class I and III are candidates for biowaivers, standard bioequivalence trials are recommended for compounds with controversial classification (i.e., azithromycin). Surrogate techniques, including predictive in vitro dissolution and modeling, have shown their potential in biopharmaceutic assessment of formulations. In this paper, we aimed to assess the risk associated with PACs in azithromycin immediate-release (IR) tablets using a model-informed approach. METHODS: Two bioequivalent bio-batches (test and reference) were compared to a new test formulation. Dissolution was studied in the gastric and predictive in vitro surrogate media. This latter was tailored to azithromycin IR formulations using the reversible non-equilibrium and Mooney's models to calculate surface pH and equivalent phosphate molarities, respectively. A virtual population that matched the bioequivalence study was created using dissolution input and individual pharmacokinetic data. With these, contributions of dissolution and permeation were estimated using a series resistance model, and virtual bioequivalence was tested. RESULTS: The new formulation dissolved noticeable faster in gastric media, although dissolution was comparable in surrogate media across formulations. Nonetheless, the series resistance model revealed that dissolution was much faster than transepithelial absorption, indicating absorption is rate-limited by permeability. Bioequivalence simulations supported this result. CONCLUSIONS: The potential of integrating predictive dissolution in a model-informed PACs (MIPACs) approach was demonstrated. However, a waiver of bioequivalence studies for azithromycin may not be justified before evaluating the potential effect of excipient on azithromycin permeability.
Nanotherapeutics to Overcome Chemotherapy Resistance in Ovarian Cancer.
Mahira S, Sathe P, Krishnan S … +2 more , Shaik R, Pamula V
Pharm Res · 2026 Feb · PMID 41714544 · Publisher ↗
BACKGROUND: Ovarian cancer remains a challenging oncology concern owing to its late diagnosis, high risk of recurrence, and predisposition for developing chemoresistance. Despite their initial effectiveness, traditional...
BACKGROUND: Ovarian cancer remains a challenging oncology concern owing to its late diagnosis, high risk of recurrence, and predisposition for developing chemoresistance. Despite their initial effectiveness, traditional chemotherapy regimens frequently trigger multidrug resistance through multiple mechanisms. By improving drug solubility, stability, tumor-specific accumulation, and overcoming resistance pathways, nanotechnology offers revolutionary potential in addressing these limitations. OBJECTIVE: With an emphasis on nanotechnology-based drug delivery methods as a potential means to combat chemoresistance in ovarian cancer, this review aims to address the urgent need for innovative approaches that can overcome these treatment barriers. METHODS: In view of their ability to alter cancerous pathways as well as enhance chemosensitivity, novel approaches such as siRNA, miRNA, exosomebased treatments, ligand-functionalized nanoparticles, and antibody-drug conjugates are mentioned. Notably, exosomes and liganddecorated carriers enhance biocompatibility and selective cellular uptake, whereas siRNA and miRNA delivery systems are designed to silence genes associated with drug resistance. A comprehensive evaluation of preclinical and clinical studies was mentioned, focused on nanotechnology-enabled approaches. RESULTS: Clinically, several nanoformulations have gone through trials or been approved, showing potential for translation. Preclinical results are encouraging, but there are still challenges with immune responses, tumor heterogeneity, and scalable production. Optimizing therapy outcomes requires combining patient-specific targeting, novel carrier designs, and molecular diagnostics. CONCLUSION: This review emphasizes the significance of ongoing interdisciplinary efforts to close the gap between clinical adoption and experimental success, as well as the paradigm change toward precision nanomedicine in ovarian cancer. Nanotechnology-driven therapeutics represent a promising frontier in overcoming chemoresistance in ovarian cancer.
Mechanistic Modelling of Transdermal Delivery Dependence on Drug Properties.
Benbrook N, Zhan W
Pharm Res · 2026 Mar · PMID 41714543 · Full text
PURPOSE AND OBJECTIVE: Microneedles have emerged as a promising platform for transdermal drug delivery, offering high patient compliance, ease of use, and minimal invasiveness. Despite extensive research on microneedle d...
PURPOSE AND OBJECTIVE: Microneedles have emerged as a promising platform for transdermal drug delivery, offering high patient compliance, ease of use, and minimal invasiveness. Despite extensive research on microneedle design and fabrication, the influence of intrinsic drug properties on delivery performance remains insufficiently understood. This study is aimed to determine the individual effects of key transport properties of the loaded drug on delivery outcomes across different skin layers and the systemic circulation. METHODS: A multiphysics model is employed to characterise transdermal drug delivery via microneedles, based on a multilayer skin model that incorporates realistic anatomical structures and dimensions. Nine key drug-related parameters are investigated, including drug diffusivity in the microneedle and skin tissues, partition coefficients between the tissue and microneedle, between the cell membrane and interstitial space, and between the cell interior and interstitial space, as well as the protein binding coefficient, transvascular permeability, elimination rate in the skin tissue, and plasma clearance. RESULTS: The simulations reveal distinct responses of drug delivery performance in each skin layer and in the blood circulation to variations in each property, with optimal values existing depending on the location of the therapeutic target within the skin. CONCLUSIONS: The findings provide mechanistic insights into the interplay between drug physicochemical characteristics and transdermal transport dynamics, offering valuable guidance for rational drug selection, formulation design, and the development of microneedle-based therapeutics.
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