Molecular Pharmaceutics最新文献

{"title":"Ceramide Profiling of Porcine Skin and Systematic Investigation of the Impact of Sorbitan Esters (SEs) on the Barrier Function of the Skin.","authors":"Hans Schoenfelder, Moritz Reuter, Dirk-Heinrich Evers, Michael E Herbig, Dominique Jasmin Lunter","doi":"10.1021/acs.molpharmaceut.4c01245","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01245","url":null,"abstract":"<p><p>The stratum corneum (SC) lipids provide the main barrier of the skin against the environment. Ceramides make up about half of the lipids by weight and are thus of particular interest. Emulsifiers are used in a multitude of topical formulations, e.g., to stabilize emulsions against coalescence. Investigations showed that some emulsifiers have the potential to impair skin barrier function. Sorbitan esters (SEs) are frequently used emulsifiers in pharmaceutical and cosmetic dermal formulations. Further, cholesterol and lecithin were used as natural alternatives. However, information on their impact on ceramides is very scarce. Thus, we first analyzed the SEs by LC-MS with regard to their composition. Then we developed an LC-MS method to identify and quantify the ceramides in porcine skin and subsequently investigated the impact of emulsifiers on the ceramide profile. Besides the LC-MS measurements, the effect of emulsifiers on the skin barrier function was investigated by trans-epidermal water loss (TEWL) measurements and confocal Raman spectroscopy (CRS). Throughout the experiments, water was used as a negative control and sodium lauryl sulfate (SLS) as a positive control. It was found that SEs are mixtures of mono-, di-, and triesters, partially with a complex fatty acid distribution. LC-MS measurements of the total ceramide content of the SC samples revealed the SE 60 and cholesterol-treated samples to be those showing the least ceramide depletion, implying a high skin tolerability in general. The TEWL measurements showed that SEs 40, 60, 80, and 120 showed no significant changes in skin barrier function. The lipid content, measured by CRS, was mostly decreased except for SE 120. Conformation, chain order, and SC thickness, also measured by CRS, showed no significant differences. These detailed investigations lead to the view that SEs are skin-friendly substances and can be used for topical applications, e.g., those commonly used to treat skin diseases.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603143","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":"Trans-Mediated, Cis-Inhibited Paradoxal Activity of <i>Clostridium perfringens</i> Enterotoxin (c-CPE) in Modulating Epithelial Permeability.","authors":"Julieta M Sanchez, Marianna T P Favaro, Hèctor López-Laguna, Eloi Parladé, Angela Di Somma, Isolda Casanova, Ugutz Unzueta, Ramón Mangues, Esther Vazquez, Eric Voltà-Durán, Antonio Villaverde","doi":"10.1021/acs.molpharmaceut.4c01205","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01205","url":null,"abstract":"<p><p>In the context of transdermal delivery, favoring the drug permeability of epithelia through convenient formulations would open new opportunities for local versus systemic drug delivery, envisaging higher patient comfort and an enhanced therapeutic effect. Ligands of tight junctions are interesting agents that enhance epithelial permeability by relaxing the protein complexes that form them. The C-terminal domain of <i>Clostridium perfringens</i> enterotoxin (c-CPE), which binds claudins, one of the tight junction (TJ) components, has been explored here as a functional domain in modular recombinant proteins, to evaluate its ability to self-promote its paracellular epithelial passage in a Caco-2 cell monolayer model. c-CPE-containing fusion proteins bind cells in the absence of internalization and cytotoxicity and support the passage, in trans, of other fusion proteins devoid of c-CPE. However, c-CPE-carrying proteins fail to cross the epithelia by themselves, probably because their affinity for TJs immobilizes them in the intercellular space. Therefore, while recombinant c-CPE versions have been here confirmed as convenient epithelial-permeabilizing agents, a paradoxical behavior has been observed where this effect is only successful when applied in trans, specifically on entities that lack c-CPE. Then, c-CPE itself inhibits the paracellular mobility of carrier molecules, not being suited as a self-driver (in c-CPE-drug complexes) for drug delivery through epithelia.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602944","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":"Biopharmaceutics Aspects of Sugar Alcohols: Implementation of Patient-Centricity in Pharmaceutical Development and Clinical Use.","authors":"Kazuki Matsui","doi":"10.1021/acs.molpharmaceut.4c01309","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01309","url":null,"abstract":"<p><p>Sugar alcohols such as mannitol and sorbitol are frequently used as pharmaceutical excipients in oral dosage forms. Their versatility stems from extensive evidence of use in humans. However, investigations over many years have clearly indicated their osmolarity-derived biopharmaceutics effects on oral drug absorption. Despite this, these accumulated insights have not been fully integrated into pharmaceutical formulation development or clinical use, leading to suboptimal industrial and clinical practices. This review provides a comprehensive summary of the biopharmaceutics of sugar alcohols, detailing their mechanisms of action and the magnitude of their osmotic effects on the oral absorption of various drugs. Additionally, the review discusses the implications for bioequivalence studies, BCS-based biowaiver guidelines, drug-excipient interactions in pediatric polypharmacy, and pharmaceutical compounding. The aim is to guide future successful and patient-centric pharmaceutical formulation development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583949","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":"Hypoxia-Targeted Responsive Delivery of Doxorubicin and Digoxin for Synergistic Treatment of Triple-Negative Breast Cancer.","authors":"Lingyan Weng, Min Zhao, Zhongping Chen, Li Zhu","doi":"10.1021/acs.molpharmaceut.4c01325","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01325","url":null,"abstract":"<p><p>To enhance the therapeutic efficacy and safety of triple-negative breast cancer (TNBC) treatment, we developed a hypoxia-responsive drug delivery system utilizing digoxin (DIG) to inhibit HIF-1α and sensitize TNBC to doxorubicin (DOX). DIG, a cardiac steroid with a well-characterized pharmacological mechanism, was encapsulated in micelles composed of methoxy-polyethylene glycol (mPEG) and poly(lactic acid) (PLA) copolymers, incorporating an azobenzene (AZO) trigger for hypoxia-sensitive drug release. The loading ratio of DOX to DIG was optimized based on DIG's minimum effective dose. In vitro and in vivo studies demonstrated that the micelles efficiently delivered their payload to hypoxic tumor regions, enabling rapid drug release. DIG-mediated HIF-1α inhibition enhanced TNBC sensitivity to DOX, leading to significant suppression of both primary tumor growth and pulmonary metastasis. This study presents a promising and clinically feasible strategy for TNBC and other hypoxia-driven malignancies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583950","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":"ImmunoPET Imaging of Trop2 Expression in Bladder Cancer Using [⁶⁴Cu]Cu-NOTA-Trodelvy.","authors":"Wenpeng Huang, Tianyao Wang, Fangfang Chao, Qi Yang, Jason C Mixdorf, Liming Li, Jonathan W Engle, Yu Fan, Lei Kang, Weibo Cai","doi":"10.1021/acs.molpharmaceut.5c00069","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00069","url":null,"abstract":"<p><p>Trop2 exhibits significantly elevated expression in numerous solid malignancies, playing a crucial role in tumor advancement, whereas its presence in healthy tissues is minimal. In this study, we investigated Trop2 expression in bladder cancer models using [⁶⁴Cu]Cu-NOTA-Trodelvy for immunoPET imaging. In HT-1376 models, [⁶⁴Cu]Cu-NOTA-Trodelvy effectively visualized tumor as early as 12 h p.i. (10.30 ± 1.45% ID/g), with tumor uptake increasing and peaking at 48 h p.i. (13.73 ± 1.16% ID/g), highlighting its potential for tumor imaging. Control groups also demonstrated low tumor uptake (5.27 ± 1.14% ID/g at 48 h in the blocking group; 6.33 ± 0.74% ID/g at 48 h in UM-UC-3; 4.50 ± 0.30% ID/g at 48 h in the [⁶⁴Cu]Cu-NOTA-IgG group). Long-term fluorescence imaging further confirmed the tumor uptake rate in the IRDye 800CW-Trodelvy group was significantly higher than in the IRDye 800CW-Trodelvy blockade group (<i>P</i> < 0.001). Our findings demonstrated that [⁶⁴Cu]Cu-NOTA-Trodelvy enables specific and prolonged tumor accumulation in bladder cancer models, providing precise and noninvasive monitoring of Trop2 expression.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583951","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":"Suppression of Liver Fibrogenesis with Photothermal Sorafenib Nanovesicles via Selectively Inhibiting Glycolysis and Amplification of Active HSCs.","authors":"Xianjing Xiang, Yaru Shao, Li Xiang, Qiangqiang Jiao, Wenhui Zhang, Yuting Qin, Yuping Chen","doi":"10.1021/acs.molpharmaceut.4c01135","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01135","url":null,"abstract":"<p><p>As the major driving factor of hepatic fibrosis, the activated hepatic stellate cells (aHSCs) rely on active glycolysis to support their aberrant proliferation and secretion of the extracellular matrix. Sorafenib (Sor) can combat liver fibrosis by suppressing HIF-1α and glycolysis, but its poor solubility, rapid metabolism, and low bioavailability restrict such a clinical application. Here, Sor was loaded onto polydopamine nanoparticles and then encapsulated by a retinoid-decorated red blood cell membrane, yielding HSC-targeted Sor nanovesicles (PDA/Sor@RMV-VA) with a high Sor-loading capacity and photothermally controlled drug release for antifibrotic treatment. These Sor RMVs not only exhibited a good particle size, dispersity and biocompatibility, prolonged circulation time, enhanced aHSC targetability, and hepatic accumulation both in vitro and in vivo, but also displayed a mild photothermal activity proper for promoting sorafenib release and accumulation in CCl₄-induced fibrotic mouse livers without incurring phototoxicity. Compared with nontargeting Sor formulations, PDA/Sor@RMV-VA more effectively downregulated HIF-1α and glycolytic enzyme in both cultured aHSCs and fibrotic mice and reversed myofibroblast phenotype and amplification of aHSCs and thus more significantly improved liver damage, inflammation, and fibrosis, all of which could be even further advanced with NIR irradiation. These results fully demonstrate the antifibrotic power and therapeutic potential of PDA/Sor@RMV-VA as an antifibrotic nanomedicine, which would support a new clinical treatment for hepatic fibrosis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571564","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":"Multitask Deep Learning Models of Combined Industrial Absorption, Distribution, Metabolism, and Excretion Datasets to Improve Generalization.","authors":"Joseph A Napoli, Michael Reutlinger, Patricia Brandl, Wenyi Wang, Jérôme Hert, Prashant Desai","doi":"10.1021/acs.molpharmaceut.4c01086","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01086","url":null,"abstract":"<p><p>The optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of compounds is critical to the drug discovery process. As such, machine learning (ML) models for ADME are widely used for prioritizing the design and synthesis of compounds. The effectiveness of ML models for ADME depends on the availability of high-quality experimental data for a diverse set of compounds that is relevant to the emerging chemical space being explored by the drug discovery teams. To that end, ADME data sets from Genentech and Roche were combined to evaluate the impact of expanding the chemical space on the performance of ML models, a first experiment of its kind for large-scale, historical ADME data sets. The combined ADME data set consisted of over 1 million individual measurements distributed across 11 assay end points. We utilized a multitask (MT) neural network architecture that enables the modeling of multiple end points simultaneously and thereby exploits information transfer between interconnected ADME end points. Both single- and cross-site MT models were trained and compared against single-site, single-task baseline models. Given the differences in assay protocols across the two sites, the data for corresponding end points across sites were modeled as separate tasks. Models were evaluated against test sets representing varying degrees of extrapolation difficulty, including cluster-based, temporal, and external test sets. We found that cross-site MT models appeared to provide a greater generalization capacity compared to single-site models. The performance improvement of the cross-site MT models was more pronounced for the relatively \"distant\" external and temporal test sets, suggesting an expanded applicability domain. The data exchange exercise described here demonstrates the value of expanding the learning from ADME data from multiple sources without the need to aggregate such data when the experimental methods are disparate.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575610","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 Dr. Herma Pierre, Dedicated to Developing Safer and More Effective Therapeutics.","authors":"Herma Pierre","doi":"10.1021/acs.molpharmaceut.5c00283","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00283","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575622","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 Sugar Molecular Weight on the Miscibility and Stability of Lyophilized and Spray-Dried Protein Formulations.","authors":"Hanh Thuy Nguyen, Mennatallah A Mohamed, Jing Ling, Yong Du, Kevin Kjoller, Yongchao Su, Lynne S Taylor","doi":"10.1021/acs.molpharmaceut.4c01488","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01488","url":null,"abstract":"<p><p>Poor stability of biological products such as proteins is a major challenge facing the biopharmaceutical industry. Poor stability is usually mitigated by formulating these products in the solid state, employing sugars as stabilizers. Several studies have pointed out the superior stabilizing ability of disaccharides, including sucrose and trehalose, as compared to polysaccharides such as dextrans. The aim of this study was to investigate the impact of excipient molecular weight on miscibility with a model protein, bovine serum albumin (BSA). Aqueous solutions containing a binary combination of a sugar-based stabilizer and BSA were dried using different methods (air drying to form films, spray drying, and lyophilization). The stabilizers tested varied in molecular weight and were dextran 6, 70, or 2000 kDa, hydroxypropyl methyl cellulose (HPMC), and trehalose. Miscibility was evaluated using a variety of techniques including confocal fluorescence microcopy, infrared and Raman microscopy, and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. The stability of BSA in dried mixtures subjected to accelerated storage conditions was also measured. BSA was more stable in the presence of dextran 2000 kDa compared to dextran 70 and 6 kDa, while stability was highest in trehalose and lowest in HPMC. From ssNMR spectroscopy, BSA-Dex 2000 kDa and BSA-trehalose were miscible over 20 and 5 nm length scales, BSA-Dex 6 kDa was miscible over a 20 nm length scale and phase-separated over a 5 nm length scale, while BSA-Dex 70 kDa and BSA-HPMC were phase-separated over both length scales. It was postulated that for dextran, the size of the polysaccharide relative to the size of the protein determined the extent of the system miscibility and stability. A smaller or similar polysaccharide size compared to that of the protein, as in the case of BSA-Dex 6 kDa and BSA-Dex 70 kDa, leads to depletion-induced phase separation. A much larger polysaccharide size compared to that of the protein allows the protein molecules to be trapped within a polysaccharide mesh, resulting in a miscible system. This study suggests that the impact of the relative size of the stabilizer and protein on miscibility is more complex than previously considered.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565509","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":"Miniaturized High-Throughput Amorphous Solid Dispersion Screening via Picoliter Volume 2D-Inkjet Printing of Formulation Microarrays.","authors":"Georgios Papakostas, Philip A Corner, Andrew L Hook, Stephanie C Brookes, Jonathan Booth, Jonathan C Burley, James F McCabe","doi":"10.1021/acs.molpharmaceut.4c01256","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01256","url":null,"abstract":"<p><p>Many new drug substances exhibit poor physicochemical properties and therefore require significant time and material resources to develop into safe and efficacious medicinal products. This typically involves exploring a large amount of compositional space and may require excessive amounts of drug compounds, which may not be adequate at the early stage of drug development. Scaled-down screening methods have been used as a cost-effective approach to the early-stage formulation. However, even the most material-efficient methods used in product development require milligrams or grams of drug material, which is often not available until relatively late in the lead optimization process. Herein, we report the application of picoliter inkjet printing of drugs and polymers from solution to create addressable formulation microarrays. This allows the efficient screening of drug-polymer compositions while only requiring micrograms or less of the drug substance. A total of eight model compounds, namely, carbamazepine, griseofulvin, saccharin, theophylline, 4-aminobenzoic acid, caffeine, salicylic acid, and benzocaine, were screened against seven commonly used amorphous solid dispersion (ASD) matrix polymers at 5% w/w composition intervals in the range of 5-80% w/w, with five replicates each. Each dispensed spot contains a total of only 1 μg of material (model compound and/or polymer). Across the tested ASD formulations, we ranked the different polymers based on their ability to hinder drug recrystallization across different compositions. Also, we identified distinct physicochemical behaviors in their crystallization kinetics, such as moisture resolubilization. We expect this approach to enable the rapid time- and material-efficient development of new amorphous solid dispersion formulations in an industrial setting.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571563","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}