Molecular Pharmaceutics最新文献

{"title":"EGCG Metal–Polyphenol Frameworks for Controlling Nitric Oxide Release in the Treatment of MRSA-Infected Wounds","authors":"Jia-Xi Chen,&nbsp;, ,&nbsp;Xin-Hui Zhou,&nbsp;, ,&nbsp;Wei-Qiu Wen,&nbsp;, ,&nbsp;Ze-Ting Huang,&nbsp;, ,&nbsp;Jie Xuan,&nbsp;, ,&nbsp;Ping Gui,&nbsp;, ,&nbsp;Wei-Hua Peng*,&nbsp;, ,&nbsp;Xi-Ren Wu*,&nbsp;, and ,&nbsp;Guan-Hai Wang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00905","DOIUrl":"10.1021/acs.molpharmaceut.5c00905","url":null,"abstract":"<p >Drug-resistant bacteria have become the main pathogens in hospitals. Due to their resistance, traditional antibiotics are increasingly limited in treating resistant bacteria. To overcome this problem, a metal–polyphenol framework (MPN) loaded with a nitric oxide donor (S-nitrosoglutathione (GSNO)) was designed for the treatment of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-infected wounds. The MPN forms a framework structure through chelation between epigallocatechin gallate (EGCG) and Fe³⁺, encapsulating the GSNO. The results demonstrated that under 808 nm laser irradiation, the photothermal-triggered release of NO could inhibit MRSA and eliminate biofilms. EGCG has the ability to scavenge ROS and inhibit inflammation, effectively inducing macrophage polarization from M1 to M2, promoting angiogenesis and wound healing. In summary, this work designed a simple and effective drug delivery system, providing a promising therapeutic strategy for controlling MRSA infection and promoting tissue regeneration.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6174–6184"},"PeriodicalIF":4.5,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a CD9-Targeted Radiopharmaceutical for Imaging and Radionuclide Therapy in CD9-Positive Glioma","authors":"Longfei Fan,&nbsp;, ,&nbsp;Xiumin Shi,&nbsp;, ,&nbsp;Haoyue Jiang,&nbsp;, ,&nbsp;Wan Chen,&nbsp;, ,&nbsp;Maolin Liang,&nbsp;, ,&nbsp;Guanglin Wang,&nbsp;, ,&nbsp;Wenbin Li,&nbsp;, ,&nbsp;Feng Wang*,&nbsp;, ,&nbsp;Ran Zhu*,&nbsp;, and ,&nbsp;Mingrong Zhang,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c01203","DOIUrl":"10.1021/acs.molpharmaceut.5c01203","url":null,"abstract":"<p >High expression of CD9 (cluster of differentiation 9) is closely associated with the poor prognosis of glioma, and it is necessary to develop targeted radiopharmaceuticals for diagnosis and treatment. The therapeutic efficacy of peptide-based drugs is often limited by their rapid metabolism. This study aims to develop an integrated theranostic radiopharmaceutical capable of in vivo CD9 targeting by modifying peptides with maleimide. The CD9-binding molecule DOTA-M-P was synthesized and labeled with ⁶⁸Ga and ¹⁷⁷Lu by using an indirect labeling method. Construction of a CD9-overexpressing cell line (U87-CD9) to simulate an in vivo and in vitro model of the invasive glioma subtype before the affinity of DOTA-M-P for the CD9 protein was assessed through cellular assays. In vivo small animal PET/CT and SPECT/CT imaging and biodistribution studies were conducted to verify pharmacokinetics and tumor-targeting retention capabilities. DNA damage assays and Western blot analyses were employed to explore the therapeutic mechanisms. Radioligand therapy studies were performed to evaluate the therapeutic efficacy. Then OLINDA/EXM was employed to estimate the effective dose to human organs from ¹⁷⁷Lu-DOTA-M-P for assessing its dose safety. In vitro cellular assays demonstrated that DOTA-M-P exhibits a moderate affinity for CD9. In vivo imaging studies demonstrated the modest targeting and retention capabilities of DOTA-M-P. Biodistribution experiments indicated that DOTA-M-P is primarily metabolized via the kidneys. Mechanistic studies suggested that ¹⁷⁷Lu-DOTA-M-P induces DNA damage, thereby activating the mitochondrial apoptotic pathway. Targeted radioligand therapy results revealed that a single dose of 18.5 MBq of ¹⁷⁷Lu-DOTA-M-P significantly inhibited U87-CD9 tumor growth. The effective doses for all human organs were estimated to be below the single-dose limit (21 CFR 361.1) established by U.S. regulatory standards, demonstrating a favorable safety profile for clinical translation. We developed a CD9-targeted peptide precursor, DOTA-M-P, enabling dual-functional radionuclide imaging and therapy for glioma, with human dose estimates supporting personalized regimens and theranostic applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6368–6380"},"PeriodicalIF":4.5,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voices in Molecular Pharmaceutics: Meet Professor Pradeep Pant, Who Designs Precision DNA and RNA Aptamers to Target Disease-Related Proteins Using AI and Molecular Simulations to Fast-Track New Therapeutics.","authors":"Pradeep Pant","doi":"10.1021/acs.molpharmaceut.5c01306","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01306","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[18F]BIBD-239: A First-in-Human PET Radiotracer with Dual Diagnostic Utility for Glioma Grading and Myocardial Imaging","authors":"Xin Wang,&nbsp;, ,&nbsp;Xiaotong Li,&nbsp;, ,&nbsp;Wei Zheng,&nbsp;, ,&nbsp;Yongzhong Zhang,&nbsp;, ,&nbsp;Xuebo Cheng,&nbsp;, ,&nbsp;Yajing Liu,&nbsp;, ,&nbsp;Lu Zhang,&nbsp;, ,&nbsp;Hualong Chen,&nbsp;, ,&nbsp;Lin Ai*,&nbsp;, and ,&nbsp;Zehui Wu*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c01088","DOIUrl":"10.1021/acs.molpharmaceut.5c01088","url":null,"abstract":"<p >To verify its application potential in the field of cardiac and cerebral disease diagnosis, the first human experiment of [¹⁸F]BIBD-239 was reported. Synthesized via a GMP-compliant automated process on a CFN-MPS200 synthesizer (per Chinese Pharmacopoeia 2020), it achieved radiochemical purity &gt;95%, nondecay-corrected yield &gt;15%, and molar activity &gt;120 GBq/μmol (total synthesis time 80 ± 5 min) under optimized conditions (95 °C, 10 min). Preclinical studies in rats confirmed TSPO-specific binding. First-in-human studies (6 healthy volunteers, 1 high-grade glioma (HGG), 1 low-grade glioma (LGG)) showed it rapidly crossed the blood–brain barrier with low normal brain retention and high sustained myocardial uptake without in vivo defluorination. HGG had higher tumor-to-background ratios (3.09) than LGG (2.33), with uptake beyond MRI-enhanced regions, correlating with histopathology. The whole-body effective dose (0.0145 ± 0.0018 mSv/MBq) was lower than [¹⁸F]FDG. [¹⁸F]BIBD-239 has robust synthesis, favorable pharmacokinetics, and TSPO-specific binding, enabling dual utility in noninvasive glioma grading and glucose-independent myocardial imaging, supporting translation in neuro-oncology and cardiovascular assessment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6339–6348"},"PeriodicalIF":4.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voices in <i>Molecular Pharmaceutics</i>: Meet Professor Hui Xiong, Who Develops Targeted and Personalized Nanotherapeutics to Revolutionize Cancer Treatment.","authors":"Hui Xiong","doi":"10.1021/acs.molpharmaceut.5c01309","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01309","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tween 80-Modified Chitosan Nanoparticles via Ionotropic Gelation for Enhanced Brain Delivery of Chrysin and Improved Anxiolytic Efficacy in Preclinical Models","authors":"Payal Dey,&nbsp;, ,&nbsp;Somesh Narayan,&nbsp;, and ,&nbsp;Kalpana Nagpal*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00611","DOIUrl":"10.1021/acs.molpharmaceut.5c00611","url":null,"abstract":"<p >The natural polyphenol “Chrysin,” an antianxiety compound, has limited brain uptake due to the restricted crossing of the blood–brain barrier (BBB). In this study, we formulated Chrysin-encapsulated chitosan nanoparticles (CNPs) and Tween 80-coated CNPs (cCNPs) to improve Chrysin’s uptake in the brain and enhance the antianxiety effects. The CNP and cCNP nanoformulations were physicochemically characterized for calculating their particle size, polydispersity index (PDI), drug entrapment efficiency (EE %), and zeta potential. Further, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and in vitro release studies were performed. The obtained results indicated the reduced particle size of cCNP NPs (174.40 ± 2.51 nm) compared to CNPs (197.67 ± 4.94 nm) and showed an increased EE for cCNPs (86.8%) compared to CNPs (82.73%). The zeta potential of cCNPs was calculated to be −14.4 ± 1.20 mV, in contrast to +12.3 ± 0.50 mV for CNPs. TEM images exhibited the presence of spherical cCNPs. In vivo studies revealed a higher time in the light compartment in the light–dark model and increased time spent in the open arm in elevated and maze models. This demonstrates significantly enhanced antianxiety effects of cCNPs compared to CNPs and pure Chrysin. These findings were further validated by the significant reduction in plasma nitrite levels, without any impact on locomotor activity. Additionally, histopathological evaluation of liver, kidney, and brain tissues confirmed the safety of cCNPs, with no significant structural changes observed. This study augments the therapeutic efficacy of cCNPs through enhanced brain uptake by reduced particle size and facilitating adsorptive transcytosis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5959–5974"},"PeriodicalIF":4.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D Bioprinting and Artificial Intelligence for Tumor Microenvironment Modeling: A Scoping Review of Models, Methods, and Integration Pathways","authors":"Urszula Piotrowska*,&nbsp;, ,&nbsp;James Tsoi,&nbsp;, ,&nbsp;Pradeep Singh,&nbsp;, ,&nbsp;Avijit Banerjee,&nbsp;, and ,&nbsp;Marcin Sobczak,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c01062","DOIUrl":"10.1021/acs.molpharmaceut.5c01062","url":null,"abstract":"<p >Recent advances in cancer research emphasize the development of physiologically relevant models to better understand tumor behavior and therapeutic responses. The tumor microenvironment (TME) plays a pivotal role in tumor progression, metastasis, and treatment resistance. Three-dimensional (3D) bioprinting offers unique capabilities for constructing complex in vitro tumor models that closely replicate the TME heterogeneity and interactions. These biomimetic models surpass the limitations of traditional 2D cultures and reduce the reliance on animal testing. This review aimed to systematically map current research on 3D bioprinting and artificial intelligence (AI) applications in modeling TME across selected cancer types. The review was structured into three thematic domains: 3D bioprinting of TME models for selected cancer types, AI applications in 3D bioprinting regardless of clinical focus, and integration of AI with 3D bioprinting specifically for TME modeling. A comprehensive literature search was conducted in PubMed, covering publications from January 2020 to June 2025. The review was conducted in accordance with PRISMA-ScR guidelines and focused on peer-reviewed original research articles published in English. Included cancer types were colorectal cancer, oral cancer, breast cancer, and glioma. In total, 63 articles were screened for TME-specific 3D bioprinting, with 44 included. For AI applications in 3D bioprinting irrespective of cancer type, 67 records were identified and 14 met the inclusion criteria. Only one study explicitly integrated AI and 3D bioprinting for TME modeling, highlighting a critical research gap. These findings are illustrated in the PRISMA flowcharts for clarity. Despite growing interest in both 3D bioprinting and AI, their combined application for modeling of the tumor microenvironment remains limited. The reviewed literature demonstrates significant progress in bioink development, process optimization, and quality control through AI methods. However, further interdisciplinary research is necessary to realize the potential of AI in enhancing TME modeling for oncology applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5801–5823"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.5c01062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infill-Modulated, Bioerodible, and Biocompatible Ocular Inserts for Tunable Acyclovir Release via Direct Powder Extrusion 3D Printing","authors":"Ankan Das,&nbsp;, ,&nbsp;Srushti Lekurwale,&nbsp;, ,&nbsp;Shriram Mahajan,&nbsp;, ,&nbsp;Sanjay K. Banerjee,&nbsp;, and ,&nbsp;Subham Banerjee*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00808","DOIUrl":"10.1021/acs.molpharmaceut.5c00808","url":null,"abstract":"<p >Conventional treatment of herpetic keratitis via eye drops or ointments is limited by rapid precorneal elimination, frequent dosing requirements, and poor patient adherence. To overcome these challenges, this study explores the use of single-step direct powder extrusion (DPE) 3D printing for the fabrication of sustained-release, dissolvable ocular inserts composed of acyclovir, hydroxypropyl methylcellulose acetate succinate-high flow (HPMCAS-HF), and polyethylene glycol (PEG) 6000. Inserts were printed with varying infill densities (30%, 60%, and 90%) to modulate microstructural properties, drug release profiles, and transcorneal permeation. Lower infill density (OI30) exhibited higher porosity, enabling rapid matrix erosion and diffusion-driven release (∼95% over 24 h), along with enhanced permeation flux (0.33 ± 0.01 μg/cm²/min) and permeation coefficient (1.14 ± 0.05 × 10^–2 cm/s). Conversely, high-density constructs (OI90) showed compact microstructure, slower erosion (∼40% at 10 h), and extended release (∼58% over 24 h) with reduced transcorneal permeation flux (0.15 ± 0.01 μg/cm²/min). All formulations followed Weibull release kinetics (<i>R</i>² &gt; 0.98), demonstrating a complex diffusion- and erosion-driven release behavior. The inserts maintained physiological pH, desired flexibility, and exhibited high biocompatibility in both <i>in vitro</i> and <i>ex vivo</i> studies, with no observable signs of irritancy in the hen’s egg test on chorioallantoic membrane (HET-CAM), excellent hemocompatibility, &gt;80% viability of ARPE-19 cells, and desired corneal tolerance. Apart from these, the 3D-printed ocular insert showed nearly 4-fold enhanced penetration and retention of Rhodamine B in the corneal layers compared to its aqueous solution during confocal laser scanning microscopy (CLSM) studies. These findings confirm the potential of DPE 3D printing for producing customizable, patient-centric, bioerodible ocular drug delivery systems offering sustained and tailored release, improved retention, and enhanced compliance for the management of keratitis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6092–6107"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reactive Oxygen Species-Mediated Mitochondrial-Targeted Therapeutics in Hepatic Disorders: Current Progress and Future Opportunities","authors":"Ashish Dhiman,&nbsp;, ,&nbsp;Yagni Shah,&nbsp;, ,&nbsp;Umesh Chaudhary,&nbsp;, and ,&nbsp;Kalpna Garkhal*,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00145","DOIUrl":"10.1021/acs.molpharmaceut.5c00145","url":null,"abstract":"<p >Reactive oxygen species (ROS) are key mediators of mitochondrial dysfunction, contributing to the onset and development of hepatic disorders, including nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and liver fibrosis. Mitochondria, as central regulators of cellular energy and metabolism, are both sources and targets of ROS, making them critical in understanding liver disease pathology. Current approaches include the development of mitochondria-specific antioxidants, therapeutic agents that enhance mitochondrial biogenesis, and nanotechnology-based delivery systems to improve precision targeting. Emerging approaches such as the modulation of mitochondrial dynamics and mitophagy hold significant potential to restore mitochondrial function and cellular homeostasis. The various causes of mitochondrial dysfunction, with a focus on ROS involvement in the pathogenesis of hepatic disorders, are discussed. Here, currently explored therapeutic remedies for mitochondrial dysfunction and their potential in translating them into clinical applications are covered. A discussion of recent advances in mitochondrial-targeted therapeutics for hepatic disorders is also included. The review concludes by identifying promising directions for future research, emphasizing the need for innovative strategies to exploit the interplay between ROS and mitochondrial dysfunction. These advances could pave the way for targeted, effective therapies for managing hepatic disorders.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"5715–5737"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Biodistribution, Immunogenicity, and Model-Informed-Based PK/PD Model of a Next-Generation Advanced Novel Gene Therapy for Hemophilia","authors":"Dehu Dou*,&nbsp;, ,&nbsp;Jing Lu,&nbsp;, ,&nbsp;Peixin Sangchen,&nbsp;, ,&nbsp;Chaorui Guo,&nbsp;, ,&nbsp;Deli Li,&nbsp;, ,&nbsp;Fengxia He,&nbsp;, ,&nbsp;Xi Zhu,&nbsp;, ,&nbsp;Xuefeng Zhang,&nbsp;, and ,&nbsp;Xijing Chen,&nbsp;","doi":"10.1021/acs.molpharmaceut.5c00918","DOIUrl":"10.1021/acs.molpharmaceut.5c00918","url":null,"abstract":"<p >Hemophilia B is an X-linked hereditary coagulation condition resulting from a defect in the factor IX gene. Gene-based delivery offers a promising alternative to protein-based medicines. The efficacy and safety may be influenced by several parameters, including the dosage of gene therapy, biological distribution, transduction efficiency, immunogenicity risk, or the molecular causes of inhibitor formation. The mechanism for determining the clinical first-in-human (FIH) dose of AAV-based gene therapy continues to pose challenges. This study aims to develop and validate a population pharmacokinetic and pharmacodynamics model (PK/PD) of VGB-R04 gene therapy for prediction of clinical dose. The pharmacodynamics, pharmacokinetic, and immunogenicity studies of VGB-R04 via intravenous injection in mice and cynomolgus monkeys were conducted to support an investigational new drug (IND) application. The end points included pharmacodynamic biomarkers, biodistribution, viral shedding, clinical pathology and histopathology, anti-AAV8 neutralizing antibodies, and anti-hFIX Padua protein antibody test. The peak concentration was noted 1 h after injection, subsequently exhibiting a distinct decline over time. The elimination rate of target genes in mice blood exceeded that in cynomolgus monkeys. The concentration in liver tissues indicated distinct liver tissue tropism. The elimination rate of target genes in mice livers exceeded that in cynomolgus monkeys. The plasma concentration of hFIX Padua protein exhibited a dose-dependent elevation in mice at doses of 8 × 10¹¹, 2.4 × 10¹², and 8 × 10¹² vg/kg. Cynomolgus monkeys exhibited significant elevation in plasma concentrations of hFIX Padua protein at 4 × 10¹³ vg/kg. A significant reduction in FIX activity and hFIX protein was observed in most of the animals starting about 4 weeks after dosing. In most animals, anti-hFIX Padua neutralizing antibody titers were detected at about week 4 of the monkeys and correlated with the preceding reductions in hFIX expression. Anti-AAV8 neutralizing antibodies can be detected in both species, but no antibodies against anti-hFIX Padua were found in mice. The research revealed the potential pharmacological and immunogenicity benefits, pharmacokinetic characteristics with target distribution, and possible safety of VGB-R04 in mice and cynomolgus monkeys following a single dosage. The model’s adequacy and robustness were assessed by VPC and bootstrap methods. Utilizing these data, we formulated a semimechanistic pharmacokinetic/pharmacodynamic quantitative model at a dosage of 4 × 10¹² vg/kg to enhance clinical translation, optimize clinical decision-making, and inform personalized therapy, despite the absence of suitable quantitative published data for developing pharmacokinetic models in gene therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 10","pages":"6381–6394"},"PeriodicalIF":4.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}