Pharmaceutical Research最新文献

{"title":"Matricaria chamomilla L. Essential Oil: The Preparation and Characterization of the Self-microemulsion Drug Delivery System, and Repair Effect in Ulcerative Colitis.","authors":"Wanjing Rong, Michael Adu-Frimpong, Hong Chen, Suqi Zhu, Zhe Wang, Jollibekov Berdiyar, Qilong Wang, Jiangnan Yu, Ximing Xu","doi":"10.1007/s11095-026-04140-1","DOIUrl":"https://doi.org/10.1007/s11095-026-04140-1","url":null,"abstract":"<p><strong>Purpose: </strong>Ulcerative colitis (UC) treatment has emerged as a worldwide healthcare challenge. Despite its anti-inflammatory properties, there are few reports on the Matricaria chamomilla L. essential oil (MEO) for the repair of UC. This study aims to extract natural MEO, prepare the self-microemulsion drug delivery system (SMEDDS) to improve the solubility and stability of MEO, and investigate its repair effects on UC.</p><p><strong>Methods: </strong>The MEO was extracted using steam distillation. The MEO (oil phase) loaded SMEDDS (MEO-SM) was prepared with Octylphenol ethoxylate (OP-10, emulsifier) and PEG400 (co-emulsifier), while MEO-SM-SA was modified with sodium alginate (SA). Their characteristics were determined by droplet size (DS), encapsulation efficiency (EE), stability, in vitro release. The safety was evaluated using zebrafish. Additionally, the repair effects of SMEDDS on UC mice were assessed through disease activity index and histopathological analysis. The tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and myeloperoxidase (MPO) levels in the colon of UC mice were tested by ELISA method.</p><p><strong>Results: </strong>The oil-in-water (O/W)-type of MEO-SM and MEO-SM-SA had small DS (28.16 ± 0.11 nm, 34.83 ± 0.27 nm), uniform dispersion, and high EE (91.09 ± 0.05%, 92.63 ± 0.17%). MEO-SM-SA was more stably stored at 25℃ for 30 days, and enhanced the release of MEO in the intestine. The SMEDDS demonstrated greatly repair effects compared to MEO alone. Specifically, MEO-SM-SA (150 mg/mL) exhibited inhibition of TNF-α, IL-6, and IL-1β and MPO activity.</p><p><strong>Conclusion: </strong>MEO-SM and MEO-SM-SA represent new approaches to enhance solubility, stability, intestinal release, and improve repair UC efficacy of MEO.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Design to Bedside: Brain-Targeted Engineered Nanoparticles and Predictive Modeling for Neurodegenerative Diseases Therapeutics.","authors":"Nguyen Nguyen, Muzhaozi Yuan, Ya Wang","doi":"10.1007/s11095-026-04201-5","DOIUrl":"https://doi.org/10.1007/s11095-026-04201-5","url":null,"abstract":"<p><p>Nanoparticle (NP)-based drug delivery systems offer promising solutions for neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, which have no cure due to the brain's structural complexity and the restrictive nature of the blood-brain barrier (BBB). Conventional therapeutics, despite strong in vitro efficacy, often fail clinically due to poor brain penetration. Recent advances in NP engineering, including optimization of size (10-100 nm), surface charge (-10 to -20 mV), and targeted ligand decoration, have improved BBB crossing and reduced premature clearance. In parallel, predictive in silico approaches, such as physiologically based pharmacokinetic (PBPK) modeling, computational fluid dynamics, and machine learning models, enable quantitative prediction of NP biodistribution, residence times, and region-specific uptake. By simulating key determinants, including blood flow dynamics, vasculature heterogeneity, permeability, and retention, these computational tools accelerate lead selection, reduce experimental burden, and inform design before in vivo testing. This review integrates recent progress in NP design with advanced computational modeling, highlighting how their convergence provides a rational framework for developing next-generation brain-targeted therapeutics. We further discuss regulatory and translational challenges, including safety, biocompatibility, and the need for humanized preclinical benchmarks. Together, these innovations offer a roadmap for advancing NP-based strategies toward clinical impact in neurodegenerative disease.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fab-Level LC-MS Assessment of Chain Pairing in Asymmetric Bispecific Antibodies Enabled by IdeS Digestion and Selective Hinge Reduction.","authors":"Biao Shen, Tri Nguyen, Hui Xiao, Yang Shen, Ning Li","doi":"10.1007/s11095-026-04213-1","DOIUrl":"https://doi.org/10.1007/s11095-026-04213-1","url":null,"abstract":"<p><strong>Purpose: </strong>Accurate assessment of heavy/light chain pairing is essential for asymmetric bispecific antibodies (BsAbs), because low-level mispairing (including light-chain swapping) can be difficult to resolve at the intact IgG level. We sought to enable robust Fab-level pairing assessment with a workflow broadly applicable across human IgG subclasses.</p><p><strong>Methods: </strong>IgG-like BsAbs were digested with FabRICATOR (IdeS) to generate uniform F(ab)₂ and Fc fragments, followed by selective hinge reduction using 2-mercaptoethylamine (2-MEA) to produce discrete Fab fragments. Reduction conditions were optimized to minimize over-reduction and suppress 2-MEA-derived Fab adducts. Fab-level species were evaluated by LC-MS, and an RP-LC method was developed to separate Fc from Fab to reduce spectral interference.</p><p><strong>Results: </strong>Compared with DTT and TCEP, 2-MEA preferentially reduced hinge-region disulfides to efficiently convert F(ab)₂ to Fab under practical conditions (e.g., 10 mM, 37 °C, 30-60 min). A key analytical artifact was formation of 2-MEA-related Fab adducts (Δmass ~ 76 Da) that can suppress or overlap Fab signals. Adduct formation was reduced in PBS relative to Tris buffer (pH 8) and was further suppressed to near-background levels by inclusion of EDTA (5 mM). Under optimized conditions, Fab-level mispairing was detected across multiple BsAb case studies, including low-concentration early-stage samples analyzed without pre-treatment, and the workflow was demonstrated for IgG1/IgG4-based BsAbs and bispecific modalities (altibodies), as well as IgG2/IgG3 antibodies.</p><p><strong>Conclusions: </strong>IdeS digestion combined with selective hinge reduction and controlled solution chemistry (PBS + EDTA) provides a practical, scalable LC-MS framework for routine Fab-level chain pairing assessment to support BsAb development and characterization.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platinum(IV) Complexes Suppress Tumor Growth in MDA-MB-231 Cells and a DMBA- Induced Mammary Carcinoma Model.","authors":"Amjad Slika, Saba Al Alam, Joelle Bou Chacra, Christina Haydar, Chris Abou Jaoude, Joe Bou Gharios, Joya Maria Mrad, Stephanie Mehanna, Maria George Elias, Krishant M Deo, Robin I Taleb, Janice R Aldrich-Wright, Costantine F Daher","doi":"10.1007/s11095-026-04215-z","DOIUrl":"https://doi.org/10.1007/s11095-026-04215-z","url":null,"abstract":"<p><strong>Purpose: </strong>The anticancer activity of two platinum(IV) complexes, P-PENT and P-HEX, was evaluated against MDA-MB-231 triple negative breast cancer cells and DMBA-induced mammary carcinoma in rats.</p><p><strong>Method: </strong>MDA-MB-231 and MCF-7 cell viability was evaluated using WST-1 kit. Biological characterization was carried out on MDA-MB-231 cells. Subcellular localization of platinum complexes were assessed with a subcellular fractionation kit and ICP-MS. Apoptosis and ROS production were assessed by flow cytometry and cell-permeant fluorogenic probe 2',7'-dichlorofluorescein diacetate, respectively. Dose escalation study was conducted on rats. Chemotherapeutic activity of P-PENT and P-HEX was evaluated for 4 weeks using a DMBA-induced breast carcinogenesis rat model.</p><p><strong>Results: </strong>P-PENT and P-HEX were ~ tenfold more cytotoxic than cisplatin against MDA-MB-231 cells and 8.6- and 5.8-fold more cytotoxic against MCF-7 cells, respectively, while showing ~ tenfold lower toxicity to rat bone marrow MSCs (Selectivity Index: 8.9, 9.5 vs. 0.3). Both complexes showed peak intracellular accumulation at 24 h with higher and faster uptake than cisplatin. P-PENT is mostly localized in the nuclear/cytoskeletal fraction (42%) and P-HEX in the cytoplasmic fraction (62%). A significant increase in ROS production and apoptotic type of cell death were observed post treatment with P-PENT and P-HEX. Maximum tolerated doses were 45 and 40 mg/kg for P-PENT and P-HEX, respectively; both significantly inhibited mammary tumor growth (15 mg/kg; IP; weekly) without detectable toxicity.</p><p><strong>Conclusion: </strong>P-PENT and P-HEX exhibited potent antitumor activity against breast cancer both in vitro and in vivo and may be considered as promising candidates for further preclinical investigation.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Oral Nanoparticles: Navigating Biological Barriers in the Gastrointestinal Tract.","authors":"Asly Chua An Wen, Xiancheng Chen, Wenli Zhang","doi":"10.1007/s11095-026-04211-3","DOIUrl":"https://doi.org/10.1007/s11095-026-04211-3","url":null,"abstract":"<p><p>Oral nanomedicine offers a promising strategy to enhance drug bioavailability, yet engineering strategies are most effectively evaluated not as isolated features but as sequential decision nodes, because a choice at one barrier mechanically constrains the strategy space at the next. This review presents a barrier-sequenced analytical framework that evaluates nanoparticle strategies at each stage by mechanistic causality, oral-specific evidence quality, and downstream design constraint. Within each barrier category, strategies were distinguish and validated by multiple oral in vivo studies from those supported by limited oral data or remaining at the proof-of-concept stage, and identified the physiological boundary conditions (fed versus fasted states, inflammatory disease, and chronic dosing) under which each principle holds. This review further maps how a formulation choice at one barrier mechanically constrains the strategy space at the next, revealing which multi-barrier combinations are compatible and which are antagonistic. Finally, This review assesses physiologically based pharmacokinetic modeling and machine learning against their current data prerequisites, framing them as hypothesis-generating aids with explicit infrastructure gaps rather than decision-grade design engines. By extracting generalizable design principles and their limits, this framework aims to guide mechanism-informed, patient-centered oral nanotherapies.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Composite Design-Optimized Dabigatran Etexilate Cubosomes for Sustained Oral Release and Enhanced In Vivo Pharmacokinetics.","authors":"Aashka H Bhatt, Hetal P Patel, Parvez S Shaikh, Priyanshi R Patel, Dhrumi K Naik, Hiren G Rathod, Bhavin A Vyas, Furqan A Maulvi","doi":"10.1007/s11095-026-04208-y","DOIUrl":"https://doi.org/10.1007/s11095-026-04208-y","url":null,"abstract":"<p><strong>Objectives: </strong>Dabigatran etexilate mesylate (DEM), a prodrug of the direct thrombin inhibitor dabigatran used for stroke prevention in nonvalvular atrial fibrillation, exhibits poor aqueous solubility, P-glycoprotein-mediated efflux, and limited oral bioavailability, which pose challenges for oral delivery. This study aimed to develop and optimize a cubosome-based nanocarrier system to enhance the oral bioavailability and sustain the release of DEM.</p><p><strong>Methods: </strong>DEM-loaded cubosomes were prepared using glycerol monooleate (GMO) and Poloxamer 407 by melt dispersion-emulsification. A Central Composite Design (CCD) was employed to optimize formulation variables based on particle size, entrapment efficiency, and drug release responses. Optimized formulations were characterized by dynamic light scattering, TEM, FT-IR, DSC, and XRD analyses. In vitro drug release and in vivo pharmacokinetic studies in Wistar rats were performed to evaluate sustained release behavior and relative oral bioavailability enhancement.</p><p><strong>Results: </strong>The optimized cubosomes exhibited nanoscale particle size (~ 19-30 nm), narrow size distribution, high entrapment efficiency (~ 87%), and sustained biphasic drug release up to 24 h. Structural characterization supported incorporation of DEM within the lipid matrix and reduced drug crystallinity. In vivo pharmacokinetic evaluation demonstrated prolonged plasma exposure and enhanced relative bioavailability compared with the marketed formulation, with approximately 2.28-fold higher relative bioavailability.</p><p><strong>Conclusions: </strong>The optimized cubosomal system effectively improved the oral delivery and sustained release of DEM. The formulation demonstrated enhanced relative bioavailability and prolonged systemic exposure, supporting further development for oral DEM delivery. Anticoagulant efficacy, gastrointestinal safety, and appropriate dosing regimens remain to be established.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Population-based Gastrointestinal Transit Model Using Individual-Level Imaging Data.","authors":"Feifan Xie, Yuxin Xie, Yehua Xie, Zeneng Cheng, Feiyan Liu","doi":"10.1007/s11095-026-04210-4","DOIUrl":"https://doi.org/10.1007/s11095-026-04210-4","url":null,"abstract":"<p><strong>Purpose: </strong>Gastrointestinal (GI) transit is a key determinant of oral drug absorption. Existing GI transit models derived from summary transit-time distributions provide limited characterization of inter-individual variability. This study aimed to develop a population-based GI transit model using individual-level imaging data.</p><p><strong>Methods: </strong>Individual gastric emptying (GE), small intestinal (SI) transit, and colon arrival (CA) data from imaging studies of non-absorbed markers in healthy adults were extracted from the literature. A population-based GI transit model was developed using sequential Weibull GE and transit compartment models. Formulation type and prandial state were evaluated as covariates, and inter-individual variability was estimated on key transit parameters.</p><p><strong>Results: </strong>Individual data comprising 90 GE, 26 SI, and 39 CA profiles were included. The final model consisted of a Weibull GE component and a six-compartment SI transit model. Formulation type and prandial state significantly influenced GE. Mean GE time was 0.16 h for liquid formulations under fasted conditions, while mean SI transit time was 2.97 h with substantial inter-individual variability (CV = 50.0%).</p><p><strong>Conclusion: </strong>This population-based GI transit model, informed by individual imaging data, quantitatively captures both mean transit behavior and inter-individual variability and may facilitate mechanistic absorption frameworks for oral drug exposure prediction.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Design of a Trivalent Multi-Epitope mRNA Vaccine Candidate Against Western, Eastern, and Venezuelan Equine Encephalitis Viruses.","authors":"Rongliu Qin, Yuying Luo, Ziyou Zhou, Yizhong Xu, Xu Wu, Yanqun Hou, Jie Chen, Fei Zhu, Pinhua Pan","doi":"10.1007/s11095-026-04192-3","DOIUrl":"https://doi.org/10.1007/s11095-026-04192-3","url":null,"abstract":"<p><strong>Purpose: </strong>Western equine encephalitis virus (WEEV), Eastern equine encephalitis virus (EEEV), and Venezuelan equine encephalitis virus (VEEV) are mosquito-borne neurotropic alphaviruses that can cause severe encephalitis in humans and equids, yet no licensed vaccines are currently available for routine human prevention. This study aimed to computationally design a trivalent multi-epitope mRNA vaccine targeting WEEV, EEEV, and VEEV.</p><p><strong>Methods: </strong>Immunoinformatics and reverse vaccinology approaches were used to identify conserved cytotoxic T-lymphocyte, helper T-lymphocyte, and linear B-cell epitopes from the three viruses. Fifteen candidate constructs incorporating different immunomodulatory strategies were evaluated for predicted antigenicity, safety, stability, and solubility, and the construct with the most balanced overall profile was selected for further analysis. Secondary- and tertiary-structure prediction, molecular docking, molecular dynamics (MD) simulations, binding free-energy analysis, and immune simulation were subsequently performed.</p><p><strong>Results: </strong>WEV showed a favorable overall physicochemical and immunological profile, supporting its further structural and immunological characterization. Molecular docking demonstrated favorable interactions between WEV and TLR2, TLR3, and TLR4, with the strongest predicted HADDOCK score observed for TLR4. In contrast, molecular dynamics simulations and MM-PBSA analysis indicated greater dynamic stability and a more favorable estimated binding free energy for the WEV-TLR2 complex. In silico immune simulation predicted enhanced IgM and IgG production, B- and T-cell responses, memory-cell formation, and increased IFN-γ and IL-2 levels.</p><p><strong>Conclusions: </strong>WEV represents a computationally designed trivalent multi-epitope mRNA vaccine candidate against WEEV, EEEV, and VEEV. The present study provides a sequence-defined framework for the rational development of multivalent vaccines, and further in vitro and in vivo studies are warranted to evaluate antigen expression, immunogenicity, protective efficacy, and safety.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Predictive Performance of Machine Learning and Population Pharmacokinetic Models for Valproic Acid Clearance and Trough Concentrations: An In-silico Simulation Study in Epilepsy Scenarios.","authors":"Janthima Methaneethorn, Supavadee Aramvith, Khanita Duangchaemkarn, Brad Reisfeld","doi":"10.1007/s11095-026-04206-0","DOIUrl":"https://doi.org/10.1007/s11095-026-04206-0","url":null,"abstract":"<p><strong>Purpose: </strong>While population pharmacokinetic (PopPK) models traditionally guide valproic acid (VPA) dosing, machine learning (ML) may better capture complex, nonlinear relationships. A direct comparison of their predictive performances remains poorly defined. This study compared the predictive performance of ML and PopPK models for VPA clearance and trough concentrations.</p><p><strong>Methods: </strong>PopPK and ML models were developed and validated using two independent simulated datasets. Trough concentration and clearance were each evaluated under a priori and a posteriori conditions and were compared against matched PopPK references.</p><p><strong>Results: </strong>For trough concentration, most ML models significantly outperformed PopPK population prediction (PRED) under a priori condition, while individual prediction (IPRED) significantly outperformed all ML models under a posteriori condition. For clearance, the best-performing ML model (kNN) significantly outperformed a population-typical prediction (CL PRED) under a priori condition, whereas the best-performing ML model (CatBoost) showed a small but statistically significant advantage over the empirical Bayes estimate for clearance (CL EBE) under a posteriori condition.</p><p><strong>Conclusions: </strong>Relative performance depended on the prediction target and available data. Under a priori condition, ML outperformed PopPK for both endpoints. Under a posteriori condition, PopPK remained superior for trough concentration, while ML performed comparably for clearance. Further real-world validation is needed.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into Poloxamer 188-Mediated Stabilization of AAV8 Capsids Using Coarse-Grained Molecular Dynamics.","authors":"Leila Sharifi, Jahanbakhsh Ghasemi, Leo Santisi, Shivangi Naik, Willow DiLuzio, Arani Chanda, Bodhisattwa Chaudhuri","doi":"10.1007/s11095-026-04187-0","DOIUrl":"https://doi.org/10.1007/s11095-026-04187-0","url":null,"abstract":"<p><strong>Purpose: </strong>Aggregation of adeno-associated virus (AAV) during manufacturing and storage remains a challenge in gene therapy formulation. This study evaluates how varying Poloxamer188 (P188) concentrations affect the structural stability and aggregation behavior of two full AAV8 capsids.</p><p><strong>Methods: </strong>Coarse-grained molecular dynamics simulations of AAV8 capsids with P188 were performed for 4000 ns at 300 K. Center-of-mass (COM) separation, residue-level contacts, surface coverage, van der Waals interactions, radius of gyration (Rg), relative shape anisotropy (k²), and simulation snapshots were analyzed.</p><p><strong>Results: </strong>Persistent capsid association was not observed in systems containing 10 or 24 P188 molecules (0.15% and 0.35% w/v), whereas systems containing 2 or 5 P188 molecules (0.03% and 0.07% w/v) showed delayed association relative to the surfactant-free system. Capsid surface coverage increased with P188 loading. Polyethylene oxide (EO) segments associated with the capsid surface early and persistently, followed by gradual polypropylene oxide (PO) engagement, indicating a preferential/sequential interaction mechanism. Higher P188 loadings showed negligible van der Waals attraction, consistent with steric shielding. Chain-resolved Rg and k² profiles indicated initial conformational rearrangement followed by stabilization of distinct surface-associated P188 conformations, with varying spatial extension and shape anisotropy.</p><p><strong>Conclusions: </strong>These findings provide mechanistic insight into the stabilizing effect of P188 on AAV via concentration-dependent surface coverage and steric hindrance that minimize capsid-capsid interactions associated with aggregation. The reported concentrations are nominal finite-box values defined by discrete P188 molecule counts and represent comparative simulation conditions rather than experimentally derived formulation thresholds. These findings provide a molecular basis for understanding P188-mediated AAV stabilization and for guiding formulation optimization.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}