Pharmaceutics最新文献

{"title":"Manganese Dioxide Nanoparticles Protect PC12 Cells Against H₂O₂-Induced Oxidative Stress Injury by Regulating PI3K/Akt-Mediated Autophagy.","authors":"Weijian Zeng, Duanyang Zhou, Tianlong Wang, Zhan-Lu Ma-Högemeier, Song Cai, Bingfeng Liu, Chao Song, Ling Guo, Rihong Zhai, Xun Song, Zhendan He, Yun Dong","doi":"10.3390/pharmaceutics18091156","DOIUrl":"10.3390/pharmaceutics18091156","url":null,"abstract":"<p><p><b>Background:</b> Oxidative stress-mediated neuronal injury is critically involved in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Manganese dioxide (MnO₂), owing to its intrinsic reactive oxygen species (ROS)-scavenging capacity, has emerged as a promising neuroprotective candidate; however, the underlying molecular mechanisms remain insufficiently defined. <b>Methods:</b> Bovine serum albumin-templated MnO₂ nanoparticles (BSA-MnO₂ NPs) were synthesized, and their protective effects were evaluated in H₂O₂-treated PC12 cells. <b>Results:</b> BSA-MnO₂ NPs significantly inhibited H₂O₂-induced reductions in cell viability, ROS overproduction, and mitochondrial membrane potential disruption. Mechanistically, H₂O₂ increased both LC3-II and p62 levels, indicating impaired autophagic flux. Activation of autophagy by serum starvation alleviated H₂O₂-induced injury, whereas chloroquine exacerbated cellular damage and abolished the protective effects of BSA-MnO₂ NPs, suggesting that the restoration of autophagy contributes to BSA-MnO₂ NPs-mediated neuroprotection. Further analysis showed that BSA-MnO₂ NPs enhanced Akt phosphorylation, while LY294002, a PI3K inhibitor, suppressed Akt activation, disrupted autophagy regulation, and eliminated their neuroprotective effects. In contrast, chloroquine did not affect Akt phosphorylation, indicating that PI3K/Akt signaling acts upstream of autophagy regulation. <b>Conclusions:</b> Collectively, these findings demonstrate that BSA-MnO₂ NPs protect PC12 cells against H₂O₂-induced oxidative injury by restoring autophagy through the PI3K/Akt signaling pathway, highlighting a potential role of BSA-MnO₂ NPs in the treatment of oxidative-stress-related neurodegenerative disorders.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13609983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Subcutaneous Infliximab: A Real-World Study of Naïve and Switch Patients.","authors":"Blanca Vicente, Hinojal Zazo, José Germán Sánchez-Hernández, Natalia Revilla, Paulo Teixeira-da-Silva","doi":"10.3390/pharmaceutics18091162","DOIUrl":"10.3390/pharmaceutics18091162","url":null,"abstract":"<p><p><b>Background</b>: Subcutaneous infliximab (SC-IFX) represents a significant advance for patients with inflammatory bowel disease (IBD) due to the possibility of home self-administration. However, at this time, there are no clear recommendations for implementing model-informed precision dosing (MIPD) in accordance with real-world clinical knowledge. <b>Objective</b>: The aim of the present study is to develop a population pharmacokinetic (PopPK) model for SC-IFX. <b>Methods</b>: A multicenter retrospective observational study was performed in adult patients (both naïve patients and those switched from intravenous administration) diagnosed with IBD. PopPK analysis was performed using NONMEM with a nonlinear mixed-effects model approach. A stepwise covariate modeling approach was implemented to identify anthropometric and clinical factors influencing SC-IFX disposition. The bootstrap method was used for internal model validation. <b>Results</b>: A total of 250 serum concentration samples of IFX, corresponding to 45 patients, were analyzed. A one-compartment model with first-order absorption adequately described the data. The final model included total body weight and suspected immunogenicity as covariates of clearance (CL). Suspected immunogenicity was associated with a 70.0% increase in clearance, while each kg deviation from the median weight (73 kg) modified clearance by 0.888%/kg. <b>Conclusions</b>: A PopPK model for SC-IFX was successfully developed and validated using European real-world data. This exploratory model establishes a foundation for future MIPD applications, offering a structured approach to initiate or transition patients to SC-IFX therapy.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the Complexities of Pharmacotherapy Parameters in Artificial Intelligence Models for Drug Selection, Precision Personalised Medicine and Optimal Therapeutic Outcomes.","authors":"Malamati Kourti, Lefteris Zacharioudakis, Annita Kolnagou, Iliada Evripidou, George J Kontoghiorghes","doi":"10.3390/pharmaceutics18091157","DOIUrl":"10.3390/pharmaceutics18091157","url":null,"abstract":"<p><p><b>Background</b>: Artificial intelligence (AI) is transforming pharmacology and pharmacotherapy by enabling the integration of large, heterogeneous datasets to support precision and personalised medicine. However, the reliability of AI-assisted therapeutic decision-making depends fundamentally on the selection, quality, and interpretation of pharmacological and clinical input features or parameters. Current AI models frequently overlook the multidimensional complexity of drug- and patient-specific factors, limiting their clinical applicability and generalisability. <b>Methods</b>: This narrative review was prepared based on 45 years of experimental work and relevant published research in drug design, development, and clinical experience in iron chelation therapy and personalised treatment approaches. Additional literature was identified through targeted searches of PubMed and Scopus using terms related to AI, machine learning, pharmacology, pharmacotherapy, and personalised medicine. Key pharmacological and clinical input features relevant to AI-assisted personalised drug selection include physicochemical drug properties, absorption, distribution, metabolism, excretion and toxicity characteristics, route of administration, drug interactions, pharmacokinetics, pharmacodynamics, multi-omics data, therapeutic efficacy, diagnostic biomarkers, statistical validation, governance, and explainable AI. A conceptual framework for AI-assisted personalised drug selection is also proposed as an example. <b>Results</b>: It is suggested that reliable AI-assisted pharmacotherapy requires the integration of diverse, interdependent datasets and parameters describing drug characteristics, patient variability, clinical outcomes, and real-world evidence. The incorporation of pharmacogenomics, electronic health records, diagnostic imaging and profiling, and validated computational descriptors can improve prediction of drug efficacy, toxicity, interactions, and therapeutic response. Furthermore, robust model validation, data governance, cybersecurity, and continuous monitoring are identified as essential prerequisites for safe clinical implementation. The proposed conceptual framework illustrates how clinical admissibility filtering, model-based ranking, local attribution, and clinically supervised decision support may enhance personalised drug selection while maintaining human oversight. <b>Conclusions</b>: Artificial intelligence has considerable potential to improve drug selection and personalised pharmacotherapy. However, its success depends on comprehensive integration of pharmacological knowledge with high-quality clinical data, rigorous validation, and responsible governance. The multidimensional framework presented here provides a foundation for the potential development of clinically interpretable, reliable, and patient-centred AI systems capable of supporting safer and more effective precision medicine.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Octreotide-Mediated Co-Solubilization of Paclitaxel and Docetaxel: A Novel Targeted Formulation for Synergistic Anticancer Chemotherapy.","authors":"Ahmed A H Abdellatif, Hesham M Tawfeek, Mahmoud Zaki El-Readi, Amani E Alharbi, Hamzah M Maswadeh, Mohammed A Amin, Safaa Y Eid, Abousree T Ellethy, Bassem Refaat, Akhmed Aslam, Waleed Mohammad Altowayan, Mahmoud A Younis","doi":"10.3390/pharmaceutics18091159","DOIUrl":"10.3390/pharmaceutics18091159","url":null,"abstract":"<p><p><b>Background</b>: Herein, we report on the development of a novel submicron-sized formulation that utilizes the somatostatin receptor agonist, octreotide (OCT), for the solubilization and targeted delivery of paclitaxel (PTX) and docetaxel (DTX) to the cancer cells. The formulation was prepared using a fast, single-step, and scalable method, and then, it was characterized in terms of physicochemical properties and pharmacological activities. <b>Methods</b>: Formulation analyses by Electrospray Ionization Mass Spectrometry (ESI-MS) and High-Performance Liquid Chromatography (HPLC) confirmed the successful formation of the formulation and the inclusion of all of its components. <b>Results:</b> Meanwhile, the developed formulation showed acceptable physicochemical properties with no incompatibilities among its components. In addition, the prepared formulation, OCT-PTX-DTX, demonstrated superior anticancer activities against colorectal carcinoma cell lines compared to the free drugs, with minimal effects on the normal cells. Furthermore, a synergistic anticancer activity of PTX and DTX was enabled by the novel formulation, leading to cell cycle arrest at low drug concentrations. <b>Conclusions</b>: Molecular-based mechanistic investigations verified that OCT-PTX-DTX is taken up by colorectal cancer cells via somatostatin receptors 1 and 2 (SSTR1 and SSTR2), followed by the upregulation of the tumor-suppressor p53/p21 cascade, and the induced cell cycle arrest via suppression of the cell cycle drivers CDK2 and Cyclin A. The formulation reported herein is promising for targeted and biotolerable anticancer chemotherapy compared to the commercially available taxane formulations based on surfactants or organic solvents.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Relevance of In Vitro Skin Models: Absorption, Cutaneous Distribution, Metabolism, and Clearance-like Removal in Dermal and Transdermal Drug Testing.","authors":"Filip Dugonik, Urška Jeršič, Lejla Kač, Uroš Maver, Tina Maver","doi":"10.3390/pharmaceutics18091152","DOIUrl":"10.3390/pharmaceutics18091152","url":null,"abstract":"<p><p><b>Background</b>: In vitro skin models are widely used in dermal and transdermal drug development, yet their pharmacokinetic interpretation often remains endpoint-dependent and does not fully capture cutaneous disposition, including partitioning, local metabolism, or clearance-like removal. This review evaluates the utility of these models through a comprehensive pharmacokinetic process framework. <b>Methods</b>: Using a structured literature search, we critically compared data from studies utilizing a range of in vitro skin models, including synthetic membranes, ex vivo human skin, reconstructed human epidermis, full-thickness equivalents, and advanced bioprinted or microfluidic platforms. The assessment focused on model performance across the key processes of absorption, distribution, metabolism, and elimination. <b>Results</b>: Our analysis reveals that alternative barriers exhibit no uniform direction of bias relative to human skin; model rank order varies with compound, formulation, and dose, so that the available evidence does not currently support a single universal scaling relationship, although calibration within a defined applicability domain may remain possible. Synthetic membranes provide reproducible platforms for formulation ranking but lack biological retention and metabolism. Ex vivo human skin remains the closest reference for permeation and mass balance, though donor variability and storage sensitivity limit standardization. Reconstructed epidermis supports standardized permeation and epidermal targeting, while full-thickness equivalents permit dermal retention analysis. Advanced perfused constructs extend experimental capabilities, but their predictive performance remains largely uncharacterized. <b>Conclusions</b>: No single model universally replicates human pharmacokinetics. Model selection must therefore be carefully aligned with the specific pharmacokinetic process of interest, the model's biological capacity, and the intended context of use to ensure clinically relevant data interpretation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biologically Mediated Nanoparticle Synthesis as a Potential Green Strategy: Principles, Methods, and Pharmaceutical Applications.","authors":"Mahmoud M Mokhtar, Rahma Wael Soliman, Jassy Salim, Shrouk Khaled Mohamed, Lobna Abdelsalam, Rehab Abdelmonem","doi":"10.3390/pharmaceutics18091151","DOIUrl":"10.3390/pharmaceutics18091151","url":null,"abstract":"<p><p>Nanoparticles have gained considerable attention as important platforms in pharmaceutical and biomedical research due to their size, morphology, surface chemistry, and colloidal behavior, which can affect drug delivery, antimicrobial activity, diagnostics, imaging, and therapeutic performance. However, conventional chemical and physical synthesis routes may require hazardous reagents, high energy demands, and procedures that raise environmental, safety, and scalability concerns. In this context, biologically mediated synthesis has emerged as an approach in which plants, microorganisms, including fungi and algae, and isolated biomolecules contribute to nanoparticle formation by acting as reducing, capping, and stabilizing agents. This narrative review evaluates these routes as potential green strategies, covering formation principles, biological sources, nanoparticle classes, characterization challenges, pharmaceutical applications, comparison with conventional synthesis, and limitations. The reviewed evidence indicates that the composition of biological sources and reaction conditions can shape nanoparticle size, morphology, surface chemistry, stability, and biological activity, highlighting green synthesis as a design-dependent process rather than a simple substitute for chemical reducing agents. Integrated characterization using optical, spectroscopic, diffraction, microscopic, and colloidal techniques is essential for interpreting nanoparticle identity and reproducibility. Biologically mediated nanoparticles show experimental and preclinical potential in drug delivery, antimicrobial therapy, anticancer research, biosensing, imaging, and diagnostics; however, most evidence remains preclinical and model-dependent. Translation remains limited by source variability, batch inconsistency, scale-up and purification challenges, stability, incomplete safety evidence, and regulatory uncertainty. Progress will require standardized process control, comparative life cycle and techno-economic assessment, scalable manufacturing, and rigorous pharmacokinetic, biodistribution, toxicological, and regulatory validation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PSMA-Targeted Liposomes for Therapeutic Delivery into a Prostate Cancer Cell Model.","authors":"Miguel Ferreira, Neelum Aziz Yousafzai, Lital Ben Naim, Bahar Ataeinia, Umar Mahmood, Pedram Heidari","doi":"10.3390/pharmaceutics18091150","DOIUrl":"10.3390/pharmaceutics18091150","url":null,"abstract":"<p><p><b>Background:</b> Prostate cancer (PCa) remains a significant health challenge, requiring innovative treatments. Here, we evaluated the efficacy of Talazoparib-loaded liposomes incorporating a targeting moiety, in combination with BI 2536, in PCa. This study develops lipid nanoparticles (LIPOs) targeting prostate-specific membrane antigen (PSMA) for better drug delivery. <b>Methods:</b> Two new PSMA-targeting agents, DUPA-DSPE and DUPA-PEG-DSPE, were created and incorporated into LIPOs via thin-film hydration. LIPOs' size and morphology were characterized using Dynamic light scattering, and structural analysis was done via TEM imaging. In vitro cytotoxicity and cell viability were assessed using an MTT assay, while in vivo radioactivity was evaluated by PET imaging, and radioactive activity was quantified using a γ-counter. <b>Results:</b> These LIPOs demonstrated excellent stability and specific binding to PSMA-expressing prostate cancer cells in vitro. In vivo, mouse model studies showed that PSMA-targeted LIPOs accumulated preferentially at tumor sites. Talazoparib, a PARP inhibitor with low solubility and cytotoxicity, has limited use in PCa. <b>Conclusions:</b> These findings provide proof-of-concept evidence that PSMA-targeted DUPA-PEG LIPOs can facilitate Talazoparib delivery and, particularly in combination with BI 2536, may enhance antitumor activity in PCa models. Further studies with expanded control groups and larger cohorts are warranted to validate the therapeutic efficacy of this combination strategy and support its further development for PCa treatment.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leachable-Derived Impurities in Oral Solid Dosage Forms Generated by Solid-State Packaging-Excipient Interactions: A Case Study of a Polyvinyl Chloride Heat Stabilizer Reacting with Povidone.","authors":"Ewoud Vaneeckhaute, Julie Van Hooste, Pasquinel Weckx, Andrew Teasdale, Ruud Cuyvers, Jonathan Hammond, Daniel Wood, Ward D'Autry, Laura Martin, Eric Breynaert","doi":"10.3390/pharmaceutics18091153","DOIUrl":"10.3390/pharmaceutics18091153","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Oral solid dosage (OSD) forms are historically categorized as low-risk vectors for leachables under the assumption that solid-state matrices impose severe kinetic barriers against migrant migration and reactivity. This study investigates an unexpected unknown impurity, detected as part of a routine ICH Q3B testing program to control drug product impurities in a blister-packed tablet. Since the impurity exceeded the ICH Q3B identification threshold applicable for this drug product (1.0% <i>w</i>/<i>w</i> relative to API or 5 µg total daily intake (TDI), whichever is lower), a forensic investigation into the origins and identity of the impurity was performed. <b>Methods:</b> Placebo and packaging line studies were performed to isolate the origin of the impurity. Systematic structure elucidation was carried out using high-resolution mass spectrometry (HRMS), isotopic fine structure analysis, and de novo chemical synthesis. To enable definitive characterization, preparative HPLC was utilized to isolate the compound for high-field 2D-NMR spectroscopy (801 MHz). <b>Results:</b> The impurity was proven to be independent of active pharmaceutical ingredient degradation, forming only when tablet excipients were stored in sealed PVC blister packaging. Co-incubation of the PVC heat stabilizer derivative dimethyltin bis(2-ethylhexyl mercaptoacetate) (DMTE) with pyrrolidin-2-one (a povidone excipient degradation product) generated an identical chromatographic and MS/MS spectral profile. NMR spectroscopy unambiguously identified the structure as 2-ethylhexyl 2-((5-oxopyrrolidin-2-yl)thio)acetate. <b>Conclusions:</b> This study provides the first direct evidence of an organotin-catalyzed solid-state reaction between a packaging leachable and a tablet excipient under 25 °C/60% RH storage conditions. While this implies that the impurity should not be evaluated under the ICH Q3B guidelines, the findings directly challenge the assumed \"low-risk\" status of OSD packaging regarding leachables and highlight the necessity for interaction-focused, chemistry-based risk assessments, as outlined in emerging ICH Q3E guidelines.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytochrome P450-Catalyzed Hydroxylation of Δ8-Tetrahydrocannabinol and Implications for Pharmacogenetics.","authors":"Mengqi Zhao, Philip Lazarus","doi":"10.3390/pharmaceutics18091149","DOIUrl":"10.3390/pharmaceutics18091149","url":null,"abstract":"<p><p><b>Introduction:</b> The use of Δ8-tetrahydrocannabinol (Δ8-THC) has become increasingly prevalent in the United States, but its metabolic pathways remain poorly characterized. This study aimed to identify the key enzymes responsible for the 11'-hydroxylation of Δ8-THC, its primary metabolic pathway, and assess the effect of metabolizing enzyme genotype on this activity. <b>Results:</b> The intrinsic clearance of recombinant (r) CYP2C9 was >6200-fold higher than that observed for rCYP2C19, the only other tested CYP450 with detectable activity against Δ8-THC. The Km,u of rCYP2C9 (0.013 ± 0.0032 µM) was comparable to that observed in human intestinal microsomes (0.0076 ± 0.00067 µM), but it was substantially lower than that observed for human liver microsomes (0.73 ± 0.065 µM). Inhibition of 11-OH-Δ8-THC formation in rCYP-overexpressing microsomes was observed when using CYP probe inhibitors (sulfaphenazole for CYP2C9 and tranylcypromine for CYP2C19). The intrinsic clearance was markedly reduced in CYP2C9 variant microsomes, with 20- to 60-fold decreases observed for CYP2C9*2 (59 ± 7.9 µL·min^-1·mg^-1 protein), CYP2C9*3 (34 ± 3.6 µL·min^-1·mg^-1 protein), CYP2C9*8 (96 ± 13 µL·min^-1·mg^-1 protein), and CYP2C9*9 (34 ± 11 µL·min^-1·mg^-1 protein) as compared to wild-type CYP2C9*1 (6028 ± 266 µL·min^-1·mg^-1 protein). <b>Conclusions:</b> Given that the expression of CYP2C9 is much higher than that of CYP2C19 in both human intestine and liver, these data suggest that CYP2C9 is the primary enzyme responsible for intestinal 11'-hydroxylation of Δ8-THC and that other untested CYPs may be important in hepatic Δ8-THC hydroxylation. In addition, the reduced 11-OH-Δ8-THC formation activity observed with CYP2C9 variants (*2, *3, *8, *9) suggests interindividual variability in Δ8-THC disposition.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Degradable Silylated Castor Oil-Based Microparticles for the Sustained Release of a Lipophilic Anti-Cancer Drug.","authors":"Lucas M Favre, Ezechiel Romone, Pierre Cuq, Nicolas Masurier, Anne Aubert-Pouëssel","doi":"10.3390/pharmaceutics18091145","DOIUrl":"10.3390/pharmaceutics18091145","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Hybrid microparticles (HMP) based on silylated vegetable oils have recently emerged as promising carriers for the sustained delivery of poorly water-soluble drugs, offering a controlled release without a burst effect and excellent biocompatibility. However, their limited degradability and the acidic conditions required for the sol-gel encapsulation process restrict their biomedical applicability, particularly for acid-sensitive active compounds. The aim of the present study was to develop new degradable vegetable oil-based HMP with improved drug-solubilization capacity while preserving compatibility with acid-sensitive molecules through an adapted mild sol-gel process, buffered with sodium citrate. <b>Methods</b>: Two new modified oils were synthesized from castor oil derivatives, including a monoglyceride (glyceryl monoricinoleate) and a polylactic acid (PLA) conjugate, to enhance both solubilization capacity and degradability. The acid-sensitive, lipophilic antitumor compound JMV5038 was used as a model drug. Modified oils were evaluated for drug-solubilization capacity, and the resulting HMPs were characterized for particle size, encapsulation efficiency, in vitro release kinetics, cytocompatibility, antiproliferative activity against melanoma cells, and in vitro enzymatic degradability. The sol-gel protocol was optimized to minimize drug degradation during encapsulation. <b>Results</b>: Microparticles (20-111 µm) exhibited a hybrid composition with efficient cross-linking. Encapsulation efficiencies of 85-100% were achieved, aided by up to 10-fold higher drug solubility in the new oils compared to original ICOe. Release kinetics were sustained and linear (11-53 days), fastest for IGRe- and slowest for ICOLAe-based HMP. Enzymatic degradation reached up to 46% after 30 days in the presence of fungal lipases, twofold higher than previously published ICOe microparticles, with ICOLAe degrading fastest due to PLA incorporation. Encapsulated JMV5038 retained its cytotoxic efficacy against A375 melanoma cells. <b>Conclusions</b>: These results highlight the promising use of such microparticles as versatile carriers for the prolonged release of lipophilic and acid-sensitive drugs.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 9","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13610840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}