Molecular Pharmaceutics最新文献

{"title":"Beyond Barriers, Big Crystallization Hurdles: Atropisomerism in Beyond Rule of Five Compounds Explored by Computational and NMR Studies.","authors":"Nikolaos Angelos Stamos, Benjamin Ries, Regina Schneider, Pavleta Tzvetkova, Florian Montel, Christian Jandl, Ulrike Werthmann","doi":"10.1021/acs.molpharmaceut.5c00204","DOIUrl":"10.1021/acs.molpharmaceut.5c00204","url":null,"abstract":"<p><p>Stereochemical purity, stability, and selection of a suitable solid-state form are pivotal factors in pharmaceutical development, particularly for complex beyond Rule of 5 (bRo5) compounds. In this study, we explore the intricate interplay between atropisomerism and crystallization using two model bRo5 compounds, namely, ACBI1 and BI201335, both violating three of four Lipinski's rules. One of the tool compounds exhibits Class 2 atropisomeric behavior, and the other is devoid of it. A diverse array of crystallization methods, including solution-phase crystallization, cocrystallization, and salt formation, were applied, revealing the critical role of atropisomerism-induced stereochemistry in polymorphism and nucleation outcomes. <i>In silico</i> torsion profile calculations and NMR studies were employed to elucidate the rotational energy barriers and confirm the presence or absence of atropisomerism. This comprehensive analysis highlights the significance of understanding stereochemical phenomena such as atropisomerism in designing and developing bRo5 compounds. By integrating advanced analytical techniques and crystallization strategies, this work provides novel insights into tailoring pharmaceutical properties for next-generation therapeutics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3268-3285"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952381","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":"Simple Quantification of Sticking Propensities of Pharmaceuticals with Mechanochemistry.","authors":"Marta Brocca, Helen Blade, Sten O Nilsson Lill, Aurora J Cruz-Cabeza","doi":"10.1021/acs.molpharmaceut.5c00124","DOIUrl":"10.1021/acs.molpharmaceut.5c00124","url":null,"abstract":"<p><p>Punch sticking poses significant challenges in tablet manufacturing and the need for effective solutions is ever-growing. Direct sticking assessment methods often rely on bulky, material-consuming equipment such as compactor emulators, only available in manufacturing sites, and thus inaccessible for most research labs. Consequently, there only exists limited data on sticking propensities of pharmaceuticals in the literature, significantly limiting our understanding of the issue and how it impacts drug manufacturing. A novel, easy, material-sparing, and lab-friendly method to evaluate sticking trends across diverse systems is presented here. The method employs a mechanochemical technique (ball mill grinding) to measure the materials' adherence to a stainless-steel substrate (milling ball). After optimization of the operating parameters such as relative humidity pretreatment of materials, a best practice protocol was developed. We measured the sticking propensities of 19 diverse molecular crystalline systems consisting of active pharmaceutical ingredients (APIs), API precursors, and common excipients. The method was effective at differentiating and quantifying the sticking ability of our diverse set of systems, which were classified into low sticking (<30 g/m²), medium sticking (30-60 g/m²), and high sticking (>60 g/m²) propensities. For example, p-nitrobenzoic acid and (R,S)-ibuprofen were found to stick with low propensities to the milling ball (<30 g/m²), while D-mannitol was found to stick significantly (>100 g/m²). Formulations of the pure materials with microcrystalline cellulose (MCC) were also tested and can be extensively explored with this method. Crucially, the operating parameters of the method (such as the milling times, relative humidity pretreatment of materials, or the material of the milling ball) can be easily adjusted to suit the systems and problem of interest. Our method is robust, nondestructive, and highly versatile and allows for fast quantification of sticking propensities of many systems with small quantities of material. The method has the potential to transform the way we study sticking tendencies of pharmaceuticals, enabling the assessment of sticking propensities significantly early in the development pipeline before manufacturing problems arise.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3219-3230"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955654","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":"Synthesis, Molecular Docking, and Biological Activity of New EGFR-Targeted Photosensitizers Based on Cationic Porphyrins Encapsulated into Pluronic F127 Micelles.","authors":"Yulia S Bortnevskaya, Nikita S Zakharov, Vadim S Senkov, Margarita A Gradova, Natalia Yu Karpechenko, Elena D Nikolskaya, Mariia R Mollaeva, Nikita G Yabbarov, Alexander S Novikov, Natal'ya A Bragina, Kseniya A Zhdanova","doi":"10.1021/acs.molpharmaceut.5c00247","DOIUrl":"10.1021/acs.molpharmaceut.5c00247","url":null,"abstract":"<p><p>The development of new effective photosensitizers (PS) for photodynamic therapy (PDT) is one of the important tasks in medical and organic chemistry. PSs inhibiting epidermal growth factor receptors (EGFR) overexpressed in cancer cells are of particular importance. In this work, we proposed the design and molecular docking of novel hybrid photosensitizers based on <i>meso</i>-aryl-substituted porphyrins and the Erlotinib molecule, a clinically approved tyrosine kinase inhibitor. The spacer length between the macrocycles and Erlotinib, hydrophilicity, and hydrophobicity of the porphyrin ring substituents were varied in the obtained compounds to evaluate structure-activity relationships (SAR). Photophysical and photochemical characteristics were studied for all of the received compounds in the presence of solubilizers suitable for the creation of dosage forms. Nanomicelles based on Pluronic F127 were obtained and characterized for the received compounds. In vitro biological tests on three cancer cell lines, MCF-7 (breast carcinoma), A431 (epidermoid carcinoma), MDA-MB-231 (breast adenocarcinoma), and normal NKE cells (human kidney epithelial cells) were performed, which showed low dark toxicity as well as light-induced activity of conjugates in the nanomolar range. Confocal microscopy experiments showed preferred accumulation of <b>UB-2</b> and a lower accumulation of <b>UB-3</b> PSs. In the case of <b>UB-3</b>, we observed a pronounced colocalization with early endosome antigen (EEA1). Also, cell apoptosis and inhibition of phosphorylation of EGFR were demonstrated for the <b>UB-3</b> compound. Thus, the proposed design of targeting PS containing cationic pyridyl moieties and a linker between the porphyrin macrocycle and Erlotinib can contribute to antitumor PDT.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3308-3330"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956544","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":"Impact of Storage Conditions on the Physical Stability of Amorphous Solid Dispersions Containing Two Structurally Similar Drugs.","authors":"Travis W Jarrells, Xiaoda Yuan, Eric J Munson","doi":"10.1021/acs.molpharmaceut.4c01279","DOIUrl":"10.1021/acs.molpharmaceut.4c01279","url":null,"abstract":"<p><p>The physical stability of two structurally similar drugs, indomethacin (IND) and indomethacin methyl ester (INDME), was investigated by comparison of thermodynamic, kinetic, and structural factors affecting crystallization. The impact of drug loading, storage temperature relative to the glass transition temperature (<i>T</i>_g), and hydrogen bonding ability has been explored for their relative importance as the cause for crystallization in amorphous solid dispersions (ASDs). IND or INDME and polyvinylpyrrolidone (PVP) K12 ASDs were formulated at varying drug loadings via cryomilling and melt-quenching. Differential scanning calorimetry was used to assign storage temperatures in the supercooled liquid and glassy states based on the <i>T</i>_g of each dispersion. The crystallization onset time (<i>t</i>_c) was monitored using powder X-ray diffraction while Fourier-transform infrared spectroscopy monitored changes in hydrogen bonding. IND formed strong homogeneous and IND-PVP hydrogen bonds while there was scarce evidence of INDME hydrogen bonding. The <i>t</i>_c of IND and INDME ASDs was inversely related to drug loading and storage temperature. However, systems with 80% IND or greater exhibited a deviation from the exponential relationship in <i>t</i>_c as <i>T</i>_g was approached. At high drug loadings, IND crystallized faster at temperatures near and slightly below <i>T</i>_g than at temperatures above <i>T</i>_g. IND has a greater thermodynamic driving force for crystallization relative to INDME at all temperatures above <i>T</i>_g. However, this is offset by a reduction in molecular mobility due to extensive hydrogen bonding with PVP. Near <i>T</i>_g, IND still has extensive translational mobility driven by the formation of IND-IND dimers during nucleation and crystallization and is proposed as a possible cause of the increased IND crystallization kinetics. Increased drug loading and temperature provide a larger thermodynamic driving force for crystallization and reduce the crystallization onset time. However, their relative contributions may change with decreasing temperature to the point where crystallization onset time above <i>T</i>_g may not be extrapolated below <i>T</i>_g. For the first time, diffusionless crystallization is observed in systems above 2% polymer to which a difference in thermodynamics, driven by hydrogen bond formation, is thought to be the cause. A better understanding of the causes of destabilization and their relative significance toward causing crystallization will help to make better informed decisions during formulation and storage.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2927-2938"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956696","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":"Exploration of Bicyclic Peptide Ligands for Immune-Specific PET Imaging: Targeting Tumor PD-L1 with [¹⁸F]AlF-BCY10959.","authors":"Xiaobo Wang, Jianyang Fang, Fei Kang, Jia Wang, Meng Niu, Hengyi Ou, Jiajun Ye, Mingru Zhang, Jie Dong, Guiyu Li, Zhiguo Liu, Wenbin Zeng, Jing Wang","doi":"10.1021/acs.molpharmaceut.5c00442","DOIUrl":"10.1021/acs.molpharmaceut.5c00442","url":null,"abstract":"<p><p>As a new modality of ligands, bicyclic peptides hold great promise in the discovery of novel programmed death ligand 1 (PD-L1) targeted radiotracers, which have not yet been reported. In this study, first-in-class bicyclic peptide-based radiotracers [¹⁸F]AlF-BCY509 and [¹⁸F]AlF-BCY10959 were developed and evaluated for PET imaging of tumor PD-L1 expression. The automatic radiosynthesis was achieved with robust radiochemical yields (55.1-90.2%) and high molar activity (42.5-90.8 GBq/μmol). Cell-based assays demonstrated high specificity and affinity of [¹⁸F]AlF-BCY509 and [¹⁸F]AlF-BCY10959 with IC₅₀ values of 9.36 ± 1.35 and 7.12 ± 1.24 nM and <i>K</i>_D values of 11.41 ± 1.04 and 8.09 ± 0.85 nM. In PET imaging, the accumulation of [¹⁸F]AlF-BCY10959 in PD-L1-positive tumors with moderate retention over 120 min was discovered, with the tumor uptake of 14.74 ± 1.67%ID/cc and tumor-to-muscle ratio of 12.41 ± 1.07 at 30 min. The <i>in vivo</i> specificity was strictly verified by PD-L1-knockout and PD-L1-positive tumors with blocking. The biodistribution manifested a rapid distribution and fast clearance from the body, supporting the favorable pharmacokinetics of [¹⁸F]AlF-BCY10959. [¹⁸F]AlF-BCY10959 was excreted through the urinary and hepatobiliary systems, indicating the doomed radiation exposure organs. The effective doses of [¹⁸F]AlF-BCY10959 and [¹⁸F]-FDG were comparable, highlighting its safety for human use. In conclusion, [¹⁸F]AlF-BCY10959 provides an attractive option to detect PD-L1 expression and lays the groundwork to further develop promising bicyclic peptide tracers for clinical use.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3456-3467"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952387","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":"Stereochemistry of Phosphorothioate Linkages Impacts the Structure and Binding Affinity of Aptamers and DNAzymes.","authors":"Sasha B Ebrahimi, Matthew J Eibling, Steve S Englehart, John M Campbell, Aston Liu, Charlotte M Fare, Sujatha Sonti, Himanshu Bhattacharjee","doi":"10.1021/acs.molpharmaceut.5c00117","DOIUrl":"10.1021/acs.molpharmaceut.5c00117","url":null,"abstract":"<p><p>The introduction of chemical modifications to oligonucleotides has been pivotal to their emergence as effective therapeutic agents. Understanding how these modifications influence the higher-order structure of oligonucleotides is one of the key considerations during the drug development process. Here, we use a G-quadruplex (thrombin-binding aptamer) and stem/loop structure (dehydroepiandrosterone sulfate binding aptamer) as model cases to show for the first time that the stereochemistry of phosphorothioate linkages can affect the stability and function of oligonucleotides that depend on their intramolecular conformation for activity (e.g., aptamers and DNAzymes). Differences up to 15 °C in melting temperature are observed between stereochemical variants of the same sequence. Moreover, using a hemin-DNAzyme assay and small molecule recognizing fluorogenic aptamer, we illustrate that stereochemistry can be used to tune the binding affinity and activity of the oligonucleotides examined in this study toward non-nucleic acid targets. Taken together, these discoveries highlight the potential influence of stereochemistry on the structure and function of other phosphorothioate-containing oligonucleotides, revealing important considerations for future drug design.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3198-3207"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074854","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":"Correction to \"Theranostic Fibers for Simultaneous Imaging and Drug Delivery\".","authors":"Miao Jin, Deng-Guang Yu, Carlos F G C Geraldes, Gareth R Williams, S W Annie Bligh","doi":"10.1021/acs.molpharmaceut.5c00624","DOIUrl":"10.1021/acs.molpharmaceut.5c00624","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3518"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074907","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":"Lipid Nanoparticles-Mediated mRNA Delivery to the Eye Affected by Ionizable Cationic Lipid.","authors":"Siyu Dong, Zhaoqi Pan, Mengchun Chang, Juanjuan Zhou, Mengke Zhang, Yashuang Chen, Ting Li, Ziwen Chen, Yuwan Gao, Sitao Xie, Wencan Wu, Xiangsheng Liu","doi":"10.1021/acs.molpharmaceut.5c00248","DOIUrl":"10.1021/acs.molpharmaceut.5c00248","url":null,"abstract":"<p><p>Ionizable lipid serves as the key functional component in lipid nanoparticles (LNPs) for efficient mRNA delivery. This study aims to systematically evaluate clinically approved ionizable lipid DLin-MC3-DMA and SM102-based LNPs for ocular mRNA delivery, with a comprehensive assessment of their physicochemical characteristics, delivery efficiency, and biodistribution patterns within the ocular microenvironment. Enhanced green fluorescence protein or Luc encoding mRNA-loaded LNPs were formulated using microfluidic mixing technology and characterized by dynamic light scattering, ζ-potential measurements, and cryogenic transmission electron microscopy imaging. The two LNP systems with different ionizable cationic lipids demonstrated distinct capabilities for <i>in vitro</i> mRNA transfection and intraocular mRNA delivery following intravitreal administration. Notably, the SM102-LNPs exhibited superior performance compared to the MC3-LNPs, characterized by significantly higher transfection efficiency in retinal cells <i>in vitro</i>, and more efficient ocular expression with minimal systemic distribution <i>in vivo.</i> Safety assessment demonstrated that intravitreal administration of SM102-LNPs maintained excellent long-term biocompatibility throughout a five-month study period. The superior performance of SM102-LNPs establishes a promising platform for ocular mRNA therapeutics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3297-3307"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951233","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":"Design and Preclinical Evaluation of Novel uPAR-Targeting Radiopeptides Modified with an Albumin-Binding Entity.","authors":"Darja Beyer, Christian Vaccarin, Jerome V Schmid, Luisa M Deberle, Xavier Deupi, Roger Schibli, Cristina Müller","doi":"10.1021/acs.molpharmaceut.5c00135","DOIUrl":"10.1021/acs.molpharmaceut.5c00135","url":null,"abstract":"<p><p>Several studies have focused on the development and application of radiolabeled DOTA-AE105 for targeting the urokinase-type plasminogen activator receptor (uPAR), which is expressed on various cancer types. The aim of this project was to design and evaluate novel uPAR-targeting radiopeptides with improved pharmacokinetic properties in view of their therapeutic application. Five peptides (uPAR-01, uPAR-02, uPAR-03, uPAR-04, and uPAR-05) were synthesized based on the AE105 peptide backbone, a DOTA chelator, and the 4-(<i>p</i>-iodophenyl)butanoate moiety as an albumin binder. The peptides were obtained in 20-29 synthetic steps using solid-phase peptide synthesis with a 6-34% overall yield. In saline, the ¹⁷⁷Lu-labeled peptides (100 MBq/nmol) were stable (>93% intact radiopeptides) in the presence of l-ascorbic acid over 24 h. The new radiopeptides were also stable (>98% intact radiopeptides) in mouse and human blood plasma, while only ∼13% of [¹⁷⁷Lu]Lu-DOTA-AE105 was intact after a 4 h incubation period. The uPAR-binding affinities (<i>K</i>_D values) determined with uPAR-transfected human embryonic kidney cells (HEK-uPAR) ranged from 10 to 57 nM and were, thus, similar to that of [¹⁷⁷Lu]Lu-DOTA-AE105 (<i>K</i>_D: 20 ± 1 nM). Compared to [¹⁷⁷Lu]Lu-DOTA-AE105, the radiopeptides showed the anticipated increased binding affinity to plasma proteins both in mouse (31- to 104-fold) and human blood plasma (43- to 136-fold). The tissue distribution of the novel radiopeptides in nude mice bearing HEK-uPAR xenografts showed substantial activity retention in the blood (12-16% IA/g and 4.5-13% IA/g at 4 and 24 h p.i., respectively), while [¹⁷⁷Lu]Lu-DOTA-AE105 was rapidly cleared (<0.1% IA/g at 4 h p.i.). As a result, the accumulation of the new radiopeptides in HEK-uPAR xenografts (3.6-11% and 3.1-10% IA/g at 4 and 24 h p.i., respectively) was increased in comparison to that of [¹⁷⁷Lu]Lu-DOTA-AE105 (<1% IA/g at 4 h p.i.). Importantly, the metabolic stability of the new radiopeptides in mice was enhanced as compared to that of [¹⁷⁷Lu]Lu-DOTA-AE105. [¹⁷⁷Lu]Lu-uPAR-02 showed the most promising tissue distribution profile with over 10-fold higher activity retention in the HEK-uPAR xenograft than observed after injection of [¹⁷⁷Lu]Lu-DOTA-AE105. As a result, the xenograft-to-kidney ratio of [¹⁷⁷Lu]Lu-uPAR-02 was >3-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-AE105.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3242-3254"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951572","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":"A Pathogen-Mimicking Monkeypox Virus Nanovaccine Inspired by Assembly of Viral Antigens with β-Glucan and Dendrimer.","authors":"Lucheng Xiao, Lijia Hu, Xiaofan Zhao, Lijuan Shen, Weili Yu, Yilong Yang, Jinming Qi, Tao Hu","doi":"10.1021/acs.molpharmaceut.4c01535","DOIUrl":"10.1021/acs.molpharmaceut.4c01535","url":null,"abstract":"<p><p>Monkeypox (mpox) is a zoonotic viral disease transmitted by the monkeypox virus (MPXV). Viral protein-based nanovaccines hold promise in preventing the infection of MPXV. MPXV-derived antigens (A29L, A35R, and M1R) were capable of eliciting protective immunity and suffered from low immunogenicity. Adjuvants and delivery systems were critical to improving the immunogenicity of antigens. In this study, a pathogen-mimicking nanovaccine was developed by conjugation of poly(amidoamine) (PAMAM) dendrimers with deoxycholic acid to form cationic nanoparticles as a delivery platform. The three antigens were individually conjugated with carboxylated β-glucan, a polysaccharide adjuvant, and subsequently self-assembled onto dendrimer nanoparticles via electrostatic interactions. The resulting nanovaccine induced robust antigen-specific antibody production, stimulated splenic levels of Th1- and Th2-type cytokines, and enhanced secretion of IFN-γ and IL-4 by CD4⁺ and CD8⁺ T cells. Additionally, it promoted the maturation of dendritic cells, activated T and B cells, and enhanced cytotoxic T cell activity. Notably, the vaccine stimulated the formation of B and T memory cells, providing long-term immune protection. Crucially, the vaccine conferred cross-protection against the lethal ectromelia virus (ECTV) challenge in mice while exhibiting no significant organ toxicity. These findings suggest that the vaccine is a promising candidate to deal with life-threatening mpox infections.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3033-3044"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952949","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}