ACS Pharmacology and Translational Science最新文献

{"title":"Regulation of Different Types of Cell Death by Noncoding RNAs: Molecular Insights and Therapeutic Implications","authors":"Reshmi Kumari,&nbsp; and ,&nbsp;Satarupa Banerjee*,&nbsp;","doi":"10.1021/acsptsci.4c0068110.1021/acsptsci.4c00681","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00681https://doi.org/10.1021/acsptsci.4c00681","url":null,"abstract":"<p >Noncoding RNAs (ncRNAs) are crucial regulatory molecules in various biological processes, despite not coding for proteins. ncRNAs are further divided into long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) based on the size of their nucleotides. These ncRNAs play crucial roles in transcriptional, post-transcriptional, and epigenetic regulation. The regulatory roles of noncoding RNAs, including lncRNAs, miRNAs, and circRNAs, are essential in various modalities of cellular death, such as apoptosis, ferroptosis, cuproptosis, pyroptosis, disulfidptosis, and necroptosis. These noncoding RNAs are integral to modulating gene expression and protein functionality during cellular death mechanisms. In apoptosis, lncRNAs, miRNAs, and circRNAs influence the transcription of apoptotic genes. In ferroptosis, these noncoding RNAs target genes and proteins involved in iron homeostasis and oxidative stress responses. For cuproptosis, noncoding RNAs regulate pathways associated with the accumulation of copper ions, leading to cellular death. During pyroptosis, noncoding RNAs modulate inflammatory mediators and caspases, affecting the proinflammatory cell death pathway. In necroptosis, noncoding RNAs oversee the formation and functionality of necrosomes, thereby influencing the balance between cellular survival and death. Disulfidptosis is a unique type of regulated cell death caused by the excessive formation of disulfide bonds within cells, leading to cytoskeletal collapse and oxidative stress, especially under glucose-limited conditions. This investigation highlights the complex mechanisms through which noncoding RNAs coordinate cellular death, emphasizing their therapeutic promise as potential targets, particularly in the domain of cancer treatment.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1205–1226 1205–1226"},"PeriodicalIF":4.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Different Types of Cell Death by Noncoding RNAs: Molecular Insights and Therapeutic Implications.","authors":"Reshmi Kumari, Satarupa Banerjee","doi":"10.1021/acsptsci.4c00681","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00681","url":null,"abstract":"<p><p>Noncoding RNAs (ncRNAs) are crucial regulatory molecules in various biological processes, despite not coding for proteins. ncRNAs are further divided into long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) based on the size of their nucleotides. These ncRNAs play crucial roles in transcriptional, post-transcriptional, and epigenetic regulation. The regulatory roles of noncoding RNAs, including lncRNAs, miRNAs, and circRNAs, are essential in various modalities of cellular death, such as apoptosis, ferroptosis, cuproptosis, pyroptosis, disulfidptosis, and necroptosis. These noncoding RNAs are integral to modulating gene expression and protein functionality during cellular death mechanisms. In apoptosis, lncRNAs, miRNAs, and circRNAs influence the transcription of apoptotic genes. In ferroptosis, these noncoding RNAs target genes and proteins involved in iron homeostasis and oxidative stress responses. For cuproptosis, noncoding RNAs regulate pathways associated with the accumulation of copper ions, leading to cellular death. During pyroptosis, noncoding RNAs modulate inflammatory mediators and caspases, affecting the proinflammatory cell death pathway. In necroptosis, noncoding RNAs oversee the formation and functionality of necrosomes, thereby influencing the balance between cellular survival and death. Disulfidptosis is a unique type of regulated cell death caused by the excessive formation of disulfide bonds within cells, leading to cytoskeletal collapse and oxidative stress, especially under glucose-limited conditions. This investigation highlights the complex mechanisms through which noncoding RNAs coordinate cellular death, emphasizing their therapeutic promise as potential targets, particularly in the domain of cancer treatment.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1205-1226"},"PeriodicalIF":4.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient Small-Molecule Reversal Agents for Anticoagulant Fondaparinux","authors":"Daniel Carbajo,&nbsp;Yolanda Pérez,&nbsp;Gabriela F. Castelo,&nbsp;Eva Prats,&nbsp;Jordi Bujons and Ignacio Alfonso*,&nbsp;","doi":"10.1021/acsptsci.4c0074710.1021/acsptsci.4c00747","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00747https://doi.org/10.1021/acsptsci.4c00747","url":null,"abstract":"<p >Fondaparinux is a highly anionic synthetic heparinoid pentasaccharide used as an anticoagulant for specific clinical conditions and surgeries. As a non-natural small-molecule drug, it presents pharmacokinetic and pharmacodynamic advantages, as well as high stability and low immunogenicity, when compared with different forms of heparin. However, its broader usage is hampered by different factors like price, existence of alternative anticoagulants, or, specifically in this case, the lack of an effective antidote that is highly recommendable for avoiding uncontrolled bleeding. In this work, we describe two synthetic small molecules derived from spermine (3AC and 3FF) that efficiently revert the anticoagulant activity of fondaparinux. In an <i>in vitro</i> enzymatic assay related to blood coagulation, the spermine derivatives show potent activity as fondaparinux antidotes, with higher activity than ciraparantag (a small molecule in the clinical phase as an anticoagulant antidote) and much higher activity than protamine, the only approved antidote for unfractioned heparin but inefficient against fondaparinux. Remarkably, naked-eye <i>ex vivo</i> tests demonstrated their efficacy in freshly extracted mice blood. Mechanistic studies show that both small molecules strongly bind fondaparinux in buffered water, as detected by fluorescence and NMR spectroscopy and confirmed by molecular dynamics simulations. Thus, these spermine derivatives are promising reversal agents against heparinoid anticoagulants with a wide range of molecular weights, overcoming the drawbacks of those antidotes based on biomacromolecules.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1333–1346 1333–1346"},"PeriodicalIF":4.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient Small-Molecule Reversal Agents for Anticoagulant Fondaparinux.","authors":"Daniel Carbajo, Yolanda Pérez, Gabriela F Castelo, Eva Prats, Jordi Bujons, Ignacio Alfonso","doi":"10.1021/acsptsci.4c00747","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00747","url":null,"abstract":"<p><p>Fondaparinux is a highly anionic synthetic heparinoid pentasaccharide used as an anticoagulant for specific clinical conditions and surgeries. As a non-natural small-molecule drug, it presents pharmacokinetic and pharmacodynamic advantages, as well as high stability and low immunogenicity, when compared with different forms of heparin. However, its broader usage is hampered by different factors like price, existence of alternative anticoagulants, or, specifically in this case, the lack of an effective antidote that is highly recommendable for avoiding uncontrolled bleeding. In this work, we describe two synthetic small molecules derived from spermine (3AC and 3FF) that efficiently revert the anticoagulant activity of fondaparinux. In an <i>in vitro</i> enzymatic assay related to blood coagulation, the spermine derivatives show potent activity as fondaparinux antidotes, with higher activity than ciraparantag (a small molecule in the clinical phase as an anticoagulant antidote) and much higher activity than protamine, the only approved antidote for unfractioned heparin but inefficient against fondaparinux. Remarkably, naked-eye <i>ex vivo</i> tests demonstrated their efficacy in freshly extracted mice blood. Mechanistic studies show that both small molecules strongly bind fondaparinux in buffered water, as detected by fluorescence and NMR spectroscopy and confirmed by molecular dynamics simulations. Thus, these spermine derivatives are promising reversal agents against heparinoid anticoagulants with a wide range of molecular weights, overcoming the drawbacks of those antidotes based on biomacromolecules.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1333-1346"},"PeriodicalIF":4.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of SARS-CoV-2 Nsp14-Methyltransferase (MTase) Inhibitors by Harnessing Scaffold-Centric Exploration of the Ultra Large Chemical Space.","authors":"Sourav Pal, Quinlin M Hanson, Sarah C Ogden, Emily M Lee, Natalia J Martinez, Alexey V Zakharov","doi":"10.1021/acsptsci.5c00111","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00111","url":null,"abstract":"<p><p>The global impact of SARS-CoV-2 underscores the need for antiviral treatments beyond vaccines. This study targets Nsp14-MTase, a viral protein essential for replication. Initial quantitative high-throughput screening (qHTS) of ∼15,000 compounds from the selected NCATS in-house libraries identified 135 active hit molecules, reflecting a hit-rate of 1.04%. To enhance the search for promising antiviral agents, we expanded this screening campaign with two rounds of machine learning (ML)-based virtual screening of ∼130,000 compounds. The first iteration yielded 72 active compounds encompassing 27 chemotypes with an IC₅₀ ranging from 1.45 μM to 33.27 μM, increasing the hit-rate 28-fold over the initial qHTS screen. Scaffold clustering of those hits revealed 27 chemotypes. The second iteration added 30 more hits (IC₅₀: 2.18 μM-30.79 μM) across 12 new chemotypes. Initial structure-activity relationship (SAR) exploration around selected chemotypes identified <b>NCGC00606183</b> (IC₅₀: 0.41 μM) as the most potent hit. Hit-to-lead optimization using scaffold-centric exploration against the ultra large Enamine REAL Space (∼5.6 billion compounds) in HPC clusters identified 78 analogs, with 56 showing potent biochemical activity (IC₅₀: 0.12 μM-18.23 μM) and cellular activity (0.27 μM-23.07 μM) in fully infectious SARS-CoV-2 live virus assays.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1366-1400"},"PeriodicalIF":4.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of SARS-CoV-2 Nsp14-Methyltransferase (MTase) Inhibitors by Harnessing Scaffold-Centric Exploration of the Ultra Large Chemical Space","authors":"Sourav Pal,&nbsp;Quinlin M. Hanson,&nbsp;Sarah C. Ogden,&nbsp;Emily M. Lee,&nbsp;Natalia J. Martinez and Alexey V. Zakharov*,&nbsp;","doi":"10.1021/acsptsci.5c0011110.1021/acsptsci.5c00111","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00111https://doi.org/10.1021/acsptsci.5c00111","url":null,"abstract":"<p >The global impact of SARS-CoV-2 underscores the need for antiviral treatments beyond vaccines. This study targets Nsp14-MTase, a viral protein essential for replication. Initial quantitative high-throughput screening (qHTS) of ∼15,000 compounds from the selected NCATS in-house libraries identified 135 active hit molecules, reflecting a hit-rate of 1.04%. To enhance the search for promising antiviral agents, we expanded this screening campaign with two rounds of machine learning (ML)-based virtual screening of ∼130,000 compounds. The first iteration yielded 72 active compounds encompassing 27 chemotypes with an IC₅₀ ranging from 1.45 μM to 33.27 μM, increasing the hit-rate 28-fold over the initial qHTS screen. Scaffold clustering of those hits revealed 27 chemotypes. The second iteration added 30 more hits (IC₅₀: 2.18 μM–30.79 μM) across 12 new chemotypes. Initial structure–activity relationship (SAR) exploration around selected chemotypes identified <b>NCGC00606183</b> (IC₅₀: 0.41 μM) as the most potent hit. Hit-to-lead optimization using scaffold-centric exploration against the ultra large Enamine REAL Space (∼5.6 billion compounds) in HPC clusters identified 78 analogs, with 56 showing potent biochemical activity (IC₅₀: 0.12 μM–18.23 μM) and cellular activity (0.27 μM–23.07 μM) in fully infectious SARS-CoV-2 live virus assays.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1366–1400 1366–1400"},"PeriodicalIF":4.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D Hepatocyte Model with Composite Nanofibers That Reproduced Human In Vivo Drug Clearance Profiles.","authors":"Rudolph Park, Chengpeng Chen","doi":"10.1021/acsptsci.5c00149","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00149","url":null,"abstract":"<p><p>This study presents a novel in vitro 3D hepatocyte model that contains a nanofibrous scaffold designed to mimic the extracellular matrix (ECM) of the human liver, both structurally and biochemically. A modular 3D-printed device housing the ECM scaffold was also developed, readily fitting in well plates. HepaRG hepatocytes cultured on the scaffold exhibited enhanced metabolic activity compared to traditional 2D cultures, indicating improved hepatocyte functionality. Drug clearance studies with lidocaine, clozapine, and fluoxetine demonstrated significantly faster clearance rates on the scaffold, closely aligning with in vivo results from the literature, while 2D cultures showed limited metabolic capacity. This model offers a physiologically relevant platform for hepatocyte studies. The findings underscore the model's potential to advance preclinical drug development by replicating liver-specific functions in vitro.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1424-1434"},"PeriodicalIF":4.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D Hepatocyte Model with Composite Nanofibers That Reproduced Human In Vivo Drug Clearance Profiles","authors":"Rudolph Park,&nbsp; and ,&nbsp;Chengpeng Chen*,&nbsp;","doi":"10.1021/acsptsci.5c0014910.1021/acsptsci.5c00149","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00149https://doi.org/10.1021/acsptsci.5c00149","url":null,"abstract":"<p >This study presents a novel in vitro 3D hepatocyte model that contains a nanofibrous scaffold designed to mimic the extracellular matrix (ECM) of the human liver, both structurally and biochemically. A modular 3D-printed device housing the ECM scaffold was also developed, readily fitting in well plates. HepaRG hepatocytes cultured on the scaffold exhibited enhanced metabolic activity compared to traditional 2D cultures, indicating improved hepatocyte functionality. Drug clearance studies with lidocaine, clozapine, and fluoxetine demonstrated significantly faster clearance rates on the scaffold, closely aligning with in vivo results from the literature, while 2D cultures showed limited metabolic capacity. This model offers a physiologically relevant platform for hepatocyte studies. The findings underscore the model’s potential to advance preclinical drug development by replicating liver-specific functions in vitro.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1424–1434 1424–1434"},"PeriodicalIF":4.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous, Seconds-Resolved Doxorubicin Measurements in the Blood and Subcutaneous Interstitial Fluid Identify Quantitative Pharmacokinetic Relationships between the Two.","authors":"Nicole A Emmons, Jennifer M Gibson, Matthew H McDonough, Julian Gerson, Murat Kaan Erdal, Kaylyn Leung, Lisa C Fetter, Kevin W Plaxco, Tod E Kippin","doi":"10.1021/acsptsci.5c00062","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00062","url":null,"abstract":"<p><p>The kinetics with which chemotherapeutics distribute into solid tissues, including their sites of both action and toxicity, remains poorly characterized. This is due to the limited temporal resolution of traditional methods of measuring drug concentrations in the body, all of which employ sample collection (e.g., via a blood draw or microdialysis) followed by benchtop analysis. Here, we have used electrochemical aptamer-based (EAB) sensors to perform simultaneous, 12 s resolution, nanomolar-precision measurements of the chemotherapeutic doxorubicin in the jugular vein (plasma) and subcutaneous space (interstitial fluid) of live rats. The resulting data sets identify predictively strong correlations between its plasma and solid-tissue pharmacokinetics in terms of both cumulative (area under the curve) and maximum exposure. In contrast, the correlations between delivered body-mass-adjusted and body-surface-area-adjusted doses and drug exposure in both the plasma and solid tissue are relatively poor. The latter observation highlights the need for therapeutic drug monitoring, and the former observation shows the potential value of employing subcutaneous EAB sensors as a convenient, minimally invasive, high-precision means of performing such monitoring. The high time density of our two-compartment data sets also provides unprecedented opportunities to model the distribution of a drug from the central compartment to a distal physiological compartment. We find that the preferred description of doxorubicin transport into the solid tissues for five of our six data sets is a three-compartment model composed of the vein (plasma), the interstitial fluid, and an unobserved third compartment distal to the interstitial fluid, with this additional compartment presumably representing intracellular fluid.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1347-1358"},"PeriodicalIF":4.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous, Seconds-Resolved Doxorubicin Measurements in the Blood and Subcutaneous Interstitial Fluid Identify Quantitative Pharmacokinetic Relationships between the Two","authors":"Nicole A. Emmons,&nbsp;Jennifer M. Gibson,&nbsp;Matthew H. McDonough,&nbsp;Julian Gerson,&nbsp;Murat Kaan Erdal,&nbsp;Kaylyn Leung,&nbsp;Lisa C. Fetter,&nbsp;Kevin W. Plaxco* and Tod E. Kippin*,&nbsp;","doi":"10.1021/acsptsci.5c0006210.1021/acsptsci.5c00062","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00062https://doi.org/10.1021/acsptsci.5c00062","url":null,"abstract":"<p >The kinetics with which chemotherapeutics distribute into solid tissues, including their sites of both action and toxicity, remains poorly characterized. This is due to the limited temporal resolution of traditional methods of measuring drug concentrations in the body, all of which employ sample collection (e.g., via a blood draw or microdialysis) followed by benchtop analysis. Here, we have used electrochemical aptamer-based (EAB) sensors to perform simultaneous, 12 s resolution, nanomolar-precision measurements of the chemotherapeutic doxorubicin in the jugular vein (plasma) and subcutaneous space (interstitial fluid) of live rats. The resulting data sets identify predictively strong correlations between its plasma and solid-tissue pharmacokinetics in terms of both cumulative (area under the curve) and maximum exposure. In contrast, the correlations between delivered body-mass-adjusted and body-surface-area-adjusted doses and drug exposure in both the plasma and solid tissue are relatively poor. The latter observation highlights the need for therapeutic drug monitoring, and the former observation shows the potential value of employing subcutaneous EAB sensors as a convenient, minimally invasive, high-precision means of performing such monitoring. The high time density of our two-compartment data sets also provides unprecedented opportunities to model the distribution of a drug from the central compartment to a distal physiological compartment. We find that the preferred description of doxorubicin transport into the solid tissues for five of our six data sets is a three-compartment model composed of the vein (plasma), the interstitial fluid, and an unobserved third compartment distal to the interstitial fluid, with this additional compartment presumably representing intracellular fluid.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1347–1358 1347–1358"},"PeriodicalIF":4.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}