Molecular Pharmaceutics最新文献

{"title":"Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis.","authors":"Xun Li, Asuka A Orr, Mohammad M Sajadi, Anthony L DeVico, Daniel J Deredge, Alexander D MacKerell, Stephen W Hoag","doi":"10.1021/acs.molpharmaceut.4c00973","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00973","url":null,"abstract":"<p><p>N49P9.6-FR-LS and PGT121 are promising antibodies with significant therapeutic potential against HIV infection, but they are prone to precipitation at concentrations greater than 12 to 13 mg/mL. This study evaluates the influence of six excipients─arginine, alanine, sucrose, trehalose, methionine, and glutamate─on the biophysical stability of antibodies. We employed a comprehensive approach, combining computational mAb-excipient interaction analysis via the site-identification by ligand competitive saturation (SILCS) method with extensive experimental characterization. Our experimental matrix included viscosity measurements across temperature gradients, particle size distribution, zeta potential, pH value, and solution appearance, alongside a short-term stability product study at 30 °C and 65% relative humidity, with assessments at t₀ (initial), t₁ (14 days), and t₂ (28 days). Results indicated that sucrose, arginine, alanine, and trehalose provided varying degrees of stabilization for both antibodies. Conversely, glutamate destabilized PGT121 but stabilized N49P9.6-FR-LS, while methionine had a negative effect on N49P9.6-FR-LS but a positive one on PGT121. SILCS-Biologics analysis suggested that stabilization by these excipients is linked to their ability to occupy regions involved in self-protein interactions. Debye-Hückel-Henry charge calculations further indicated that neutral excipients like sucrose and trehalose could alter mAb charges by affecting buffer binding, influencing aggregation propensity. These findings offer valuable insights for optimizing antibody formulations, ensuring enhanced product stability and therapeutic efficacy for HIV treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539360","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":"<i>In Vitro</i> Drug Release and <i>Ex Vivo</i> Dermal Drug Permeation Studies of Selected Commercial Benzoyl Peroxide Topical Formulations: Correlation Between Human and Porcine Skin Models.","authors":"Murilo de Souza Brighenti, Lilian Rosário da Silva Montanheri, Marcelo Dutra Duque, Newton Andreo-Filho, Patricia Santos Lopes, Maria Teresa Junqueira Garcia, Lorraine Mackenzie, Vânia Rodrigues Leite-Silva","doi":"10.1021/acs.molpharmaceut.4c01058","DOIUrl":"10.1021/acs.molpharmaceut.4c01058","url":null,"abstract":"<p><p><i>In vitro</i> release testing (IVRT) serves as a crucial tool to assess the quality, physicochemical behavior, and performance of semisolid formulations already available on the market. <i>In vitro</i> skin permeation studies (IVPT) are widely used to evaluate the safety and efficacy profiles of topical drugs, utilizing biological membranes prepared from <i>ex vivo</i> human and porcine skin tissues. This study aimed to develop and validate a discriminative IVRT method to evaluate various marketed topical benzoyl peroxide formulations. Additionally, IVPT was employed to assess skin permeation and retention profiles of these formulations, comparing porcine skin results with those obtained by using <i>ex vivo</i> human skin tissues. Physicochemical differences among the evaluated benzoyl peroxide formulations were identified, with the poloxamer-based formulation exhibiting a higher release rate. IVPT using both porcine and human skin differentiated retention and skin permeation profiles, with the poloxamer-based formulation demonstrating greater skin retention capacity compared to the other formulations evaluated. Similar conclusions on benzoyl peroxide retention and cutaneous permeation were drawn from both porcine and human skin IVPT tests, confirming the correlation between the two models.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1365-1372"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121785","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":"Mucin Mimics and Impacts the Function of Polymeric Inhibitors in Stabilizing Drug Supersaturation.","authors":"Victus Kordorwu, Steven Castleberry, Steve Lustig, Rebecca L Carrier","doi":"10.1021/acs.molpharmaceut.4c01102","DOIUrl":"10.1021/acs.molpharmaceut.4c01102","url":null,"abstract":"<p><p>Many drugs entering clinical trials today are poorly water-soluble and rely on supersaturating formulations, such as amorphous solid dispersions (ASD) to enhance their bioavailability. The <i>in vivo</i> performance of these formulations is often investigated through biorelevant dissolution testing using simulated intestinal fluid. Often overlooked in biorelevant dissolution is the presence of mucus within the intestinal environment and its possible role in affecting the formulation performance. In this study, the impact of mucins, the main structural glycoproteins of mucus, on the precipitation of two model compounds, carvedilol and nifedipine, from supersaturated solutions was investigated. The presence of mucin within the supersaturated environment was demonstrated to significantly alter the rate of drug precipitation <i>in vitro</i>. The impact of mucin on precipitation was then compared to commercially available polymer precipitation inhibitors hydroxypropyl methylcellulose (HPMC) and Kollidon VA 64, which are commonly used in ASD formulations. Surprisingly, when present at the same concentration (0.2% (w/v)), mucin reduces drug precipitation to an extent comparable to that of polymer precipitation inhibitors. Additionally, we observed that the presence of mucin in the supersaturated environment altered the precipitation inhibitory effects of HPMC and Kollidon VA64, suggesting that mucin could play an important and complicated role in formulation performance in the intestine.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1396-1407"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466574","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":"Correction to \"Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy\".","authors":"Jing Huang, Kaiyu Wang, Shan Wu, Jin Zhang, Xiayu Chen, Sibei Lei, Jieping Wu, Ke Men, Xingmei Duan","doi":"10.1021/acs.molpharmaceut.5c00046","DOIUrl":"10.1021/acs.molpharmaceut.5c00046","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1727-1728"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057472","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 \"Enhancing the Antitumor Effect of Doxorubicin with Photosensitive Metal-Organic Framework Nanoparticles against Breast Cancer\".","authors":"Qianqian Jiang, Mengmeng Zhang, Quanwei Sun, Dengke Yin, Zihua Xuan, Ye Yang","doi":"10.1021/acs.molpharmaceut.5c00049","DOIUrl":"10.1021/acs.molpharmaceut.5c00049","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1729-1731"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397607","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":"Nitroaromatic Compounds Dictate Electrochemical Properties of <i><i>Escherichia coli</i></i> by Manipulating the Cellular Membrane.","authors":"Neha Yadav, Santosh K Misra","doi":"10.1021/acs.molpharmaceut.4c01537","DOIUrl":"10.1021/acs.molpharmaceut.4c01537","url":null,"abstract":"<p><p>Nitroaromatic compounds (NACs) are generally used as starting materials and/or generated as byproducts during the manufacturing of dyes, fertilizers, and therapeutic agents. Though NACs are beneficial when used appropriately, inadequate management, disposal, and application methods have led to their introduction to bacterial ecosystems where NACs act as mutagenic agents and may even contribute to antimicrobial resistance. Many of these bacterial systems are known to have different pathways to adapt to the presence of NACs such as altering the lipid composition of cellular membranes and intracellular degradation of NACs. In general, these processes require sophisticated techniques and skilled human resources to detect the changes by conventional characterization techniques. Hence, alternative methods are needed to investigate the short-term effects of NACs on bacterial cells with better precision. Herein, we report that bacterial cells adapt to the presence of NACs initially by incorporation in the cellular membrane, which can be predicted by further altered electrical and electrochemical properties of the cells. It was observed that the whole cell bacteria were negatively charged entities that could generate varying levels of surface charges on being incubated with model NACs of biomedical importance viz. niclosamide and <i>p</i>-nitrophenol. Such variations were also reflected in dye entrapment assays performed by using lipidic membranes collected from NAC-treated bacterial cells after the cells. Further studies with gel electrophoresis and differential pulse voltammetry revealed the significant alterations in electrochemical properties of NAC-incubated bacterial cells. Overall, results indicate that bacterial adaptation to NACs was found to be closely linked to variations in the electrochemical properties of the bacterial cells. These outcomes advance our understanding of influences imparted by NACs during bacterial infections and might facilitate the way for developing therapies to combat antibacterial resistance in the near future.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1707-1724"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389516","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":"⁶⁸Ga-FAPI Small Animal PET/CT in Rats with Peritoneal Fibrosis and the Therapeutic Effect of Sodium Butyrate.","authors":"Jingyi Chen, Zibei Wan, Mengxia Cao, Yuexi Huang, Yan Li, Weihua Wu, Chunmei Guo, Zhanwen Huang, Santao Ou","doi":"10.1021/acs.molpharmaceut.4c00998","DOIUrl":"10.1021/acs.molpharmaceut.4c00998","url":null,"abstract":"<p><p>Peritoneal fibrosis (PF) is a common complication in peritoneal dialysis patients with end-stage renal disease. This study established a rat model of PF, used ⁶⁸Ga-FAPI PET/CT imaging to visualize PF, and evaluated the therapeutic effects and mechanism of action of sodium butyrate. The rat model of PF (<i>n</i> = 20) was induced by hyperglycemic peritoneal dialysate combined with lipopolysaccharide, the control group (<i>n</i> = 20) was given the same amount of normal saline, and the intervention group (<i>n</i> = 20) was given sodium butyrate by intraperitoneal injection. At 2, 4, 6, and 8 weeks, a peritoneal equilibration test was performed, and peritoneal tissues were collected for histological staining. Three rats from each group were randomly selected for ⁶⁸Ga-FAPI small animal PET/CT imaging. Compared with control rats, model group rats presented a decreased ultrafiltration volume, increased maximum glucose transport (<i>P</i> < 0.05), increased peritoneal thickness and fibrosis area, and upregulated α-SMA, COL I, TGF-β1, Smad3, and p-Smad3 expression in peritoneal tissues (<i>P</i> < 0.05) in a time-dependent manner. The sodium butyrate group improved peritoneal transport function (<i>P</i> < 0.05), alleviated collagen deposition, and downregulated α-SMA, COL I, TGF-β1, Smad3, and p-Smad3 while increasing Smad7 expression in peritoneal tissues (<i>P</i> < 0.05). ⁶⁸Ga uptake was markedly increased in the model group (<i>P</i> < 0.05) but was reduced after sodium butyrate treatment (<i>P</i> < 0.05). The SUVmax was positively correlated with peritoneal thickness; maximum glucose transport; and α-SMA, COL I, and FAP-α expression (<i>r</i> = 0.871, 0.845, 0.843, 0.659, 0.926) but negatively correlated with ultrafiltration volume (<i>r</i>= -0.894). In summary, ⁶⁸Ga-FAPI PET/CT could be a promising noninvasive approach for assessing peritoneal fibrosis that is superior to and safer than peritoneal biopsy. Sodium butyrate may attenuate peritoneal fibrosis by regulating the TGF-β1/Smad3 signaling pathway.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1329-1338"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397606","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":"Targeted Oral Fixed-Dose Combination of Amphotericin B-Miltefosine for Visceral Leishmaniasis.","authors":"Raquel Fernández-García, David Walsh, Peter O'Connell, Luiz Felipe D Passero, Jéssica A de Jesus, Marcia Dalastra Laurenti, María Auxiliadora Dea-Ayuela, M Paloma Ballesteros, Aikaterini Lalatsa, Francisco Bolás-Fernández, Anne Marie Healy, Dolores R Serrano","doi":"10.1021/acs.molpharmaceut.4c01133","DOIUrl":"10.1021/acs.molpharmaceut.4c01133","url":null,"abstract":"<p><p>The incidence of visceral leishmaniasis (VL) remains a significant health threat in endemic countries. Fixed-dose combination (FDC) of amphotericin B (AmB) and miltefosine (MLT) is a promising strategy for treating VL, but the parenteral administration of AmB leads to severe side effects, limiting its use in clinical practice. Here, we developed novel FDC granules combining AmB in the core with a MLT coating using wet granulation followed by the fluidized bed technology. The granules maintained the crystalline structure of AmB throughout manufacturing, achieving an AmB loading of ∼20%. The MLT coating layer effectively sustained AmB release from 3 to 24 h following Korsmeyer-Peppas kinetics. The formulation demonstrated remarkable stability, maintaining >90% drug content for over a year at both 4 °C and room temperature under desiccated conditions. In vivo efficacy studies in <i>Leishmania infantum</i><i>-</i>infected hamsters showed 65-80% reduction in parasite burden in spleen and liver, respectively, suggesting potential as an oral alternative to current VL treatments. Uncoated and coated granules demonstrated comparable performance in key aspects, including <i>in vivo</i> efficacy and long-term stability.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1437-1448"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439392","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":"Boosting Natural Killer Cells' Immunotherapy with Amoxicillin-Loaded Liposomes.","authors":"Xiaohui Li, Huan Wei, Siyuan Wei, Zhixuan Wang, Jiachen Qi, Lixing Weng","doi":"10.1021/acs.molpharmaceut.4c00446","DOIUrl":"10.1021/acs.molpharmaceut.4c00446","url":null,"abstract":"<p><p>Natural killer (NK) cell immunotherapy is a significant category in tumor therapy due to its potent tumor-killing and immunomodulatory effects. This research delves into exploring the mechanisms underlying the ability of amoxicillin to boost NK cell cytotoxicity in NK cell immunotherapy. Amoxicillin significantly enhances the cytotoxic activity of NK-92MI cells against MCF-7 cells by triggering the initiation of a cytolytic program in target cell-deficient NK-92MI cells and augmenting the degranulation level of NK-92MI cells in the presence of target cells. The ability of NK cells to recognize target cells was increased upon exposure to amoxicillin at low concentration (10 ng/mL). Additionally, the utilization of amoxicillin loaded in liposome (AMO@Liposome) for NK cell immunotherapy in a mouse breast cancer model resulted in an increased antitumor effect in comparison to without the treatment of AMO@Liposome. RNA transcriptome analysis showed that amoxicillin upregulated differential genes related to the synaptic vesicle cycle pathway and calcium signaling pathway, and FOSB, TNFRSF18, and H4C1 were identified as critical players. These studies suggest that the strategy of using amoxicillin in NK cell immunotherapy has potential applications in the field of tumor therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1210-1219"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057470","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":"Antiplatelet Effects of DMPC-Based Synthetic High-Density Lipoproteins: Exploring Particle Structure and Noncholesterol Efflux Mechanisms.","authors":"Antonela Rodriguez, Minzhi Yu, May Thazin Phoo, Michael Holinstat, Anna Schwendeman","doi":"10.1021/acs.molpharmaceut.4c01000","DOIUrl":"10.1021/acs.molpharmaceut.4c01000","url":null,"abstract":"<p><p>Platelet activation is a key factor in the development of cardiovascular diseases. High-density lipoprotein (HDL) is known for its cardioprotective activities including antithrombotic actions. While HDL mimetics have been explored for their potential to regulate thrombosis, their influence on platelet activity remains unclear. This study explores the capacity of synthetic HDL (sHDL) to modulate platelet function and investigates the underlying mechanisms. We examined the effects of sHDL, formulated with various ApoA1 mimetic peptides (18A, 5A, and 22A) and full-length ApoA1 protein, all complexed with 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphocholine (DMPC), on platelet function. DMPC-based sHDL demonstrated pronounced antiplatelet effects across all formulations. Comparison with DMPC micelles showed that all sHDL molecules were more effective, highlighting the crucial role of the protein-phospholipid complex in reducing platelet reactivity. Further analysis revealed that DMPC sHDL dose-dependently inhibited various platelet functions, including aggregation, integrin activation, α-granule secretion, protein kinase C (PKC) activation, and platelet spreading. Mechanistic studies demonstrated that DMPC sHDL's antiplatelet effects are not entirely dependent on cholesterol efflux, despite effectively reducing total platelet cholesterol. Furthermore, sHDL's activity was found to be independent of scavenger receptor BI (SR-BI). Notably, inhibition of the CD36 receptor markedly attenuated sHDL's antiplatelet activity and uptake, suggesting a novel mechanism distinct from that of native HDL. In summary, DMPC sHDL modulates platelet function through a synergistic action between protein and phospholipid components, primarily via CD36 receptor engagement. These insights pave the way for novel antiplatelet therapies utilizing sHDL's distinct properties.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1305-1317"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070755","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}