Molecular Pharmaceutics最新文献

{"title":"Large-Scale Compartmental Model-Based Study of Preclinical Pharmacokinetic Data and Its Impact on Compound Triaging in Drug Discovery","authors":"Peter Zhiping Zhang*,&nbsp;Jeanine Ballard,&nbsp;Facundo Esquivel Fagiani,&nbsp;Dustin Smith,&nbsp;Christopher Gibson and Xiang Yu*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0081310.1021/acs.molpharmaceut.4c00813","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00813https://doi.org/10.1021/acs.molpharmaceut.4c00813","url":null,"abstract":"<p >Reliable and robust human dose prediction plays a pivotal role in drug discovery. The prediction of human dose requires proper modeling of preclinical intravenous (IV) pharmacokinetic (PK) data, which is usually achieved either through noncompartmental analysis (NCA) or compartmental analysis. While NCA is straightforward, it loses valuable information about the shape of the PK curves. In contrast, compartmental analysis offers a more comprehensive interpretation but poses challenges in scaling up for high-throughput applications in discovery. To address this challenge, we developed computational frameworks, termed compartmental PK (CPK) and automated dose prediction (ADP), to enable automated compartmental model-based IV PK data modeling, translation, and simulation for human dose prediction in compound triaging and optimization. With CPK and ADP, we analyzed compounds with data collected at the MRL between 2013 and 2023 to quantitatively characterize the impact of different PK modeling and simulation methods on human dose prediction. Our study revealed that despite minimal impact on estimating animal PK parameters, different methods significantly impacted predicted human dose, exposure, and Cmax, driven more by different simulation assumptions than by the PK modeling itself. CPK–ADP therefore enables us to efficiently perform complex human dose predictions on a large scale while integrating the latest and best information available on absorption, distribution, and clearance to support decision-making in discovery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1230–1240 1230–1240"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528527","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-Labeled Glycopeptides as Effective Tools for Liver Function Imaging.","authors":"Maximilian Alexander Zierke, Christine Rangger, Kimia Samadikhah, Andreas Martin Schmid, Roland Haubner","doi":"10.1021/acs.molpharmaceut.4c01453","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01453","url":null,"abstract":"<p><p>[^99mTc]Tc-GSA, an albumin-based glycoprotein, is routinely used in Japan to measure the asialoglycoprotein receptor (ASGR) density via single photon emission tomography. Here we describe the development of ⁶⁸Ga-labeled peptide-based alternatives. Peptides were assembled on a solid support using a fragment coupling strategy. Glycosylation was carried out via a click chemistry approach resulting in a set of three peptides with increasing amounts of d-galactose (<i>n</i> = 3, 6, and 9) as well as one glycopeptide bearing nine <i>N</i>-acetylgalactosamine residues. ⁶⁸Ga-labeling of all compounds could be achieved in high radiochemical yields (>95%). Radiotracers exhibited high hydrophilicity, good metabolic stability in human serum and protein binding between 12 and 22%. The IC₅₀ values improved in the series tri-, hexa-, and nonamer with an IC₅₀ of 50 ± 30 pM for the latter one. In analogy, the <i>in vivo</i> biodistribution studies revealed increased liver uptake in the series of [⁶⁸Ga]Ga-<b>NODAGA-TriLysan</b> (9.4 ± 2.0% ID/g, 30 min p.i.), [⁶⁸Ga]Ga-<b>NODAGA-HexaLysan</b> (55.5 ± 7.4% ID/g, 30 min p.i.), and [⁶⁸Ga]Ga-<b>NODAGA-NonaLysan</b> (79.6 ± 8.0% ID/g, 30 min p.i.). [⁶⁸Ga]Ga-NODAGA-GalNAc-NonaLysan reached comparable liver uptake to [⁶⁸Ga]Ga-<b>NODAGA-NonaLysan</b>, but showed higher accumulation in nontarget organs. The impressive imaging properties of [⁶⁸Ga]Ga-<b>NODAGA-NonaLysan</b> were also confirmed by the PET/MR imaging studies in mice. Hence, [⁶⁸Ga]Ga-<b>NODAGA-NonaLysan</b> represents a new PET radiopharmaceutical with even better imaging properties than [^99mTc]Tc-GSA.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439389","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":"64Cu Radiolabeled PDGFRβ-Targeting Affibody for PET Imaging in Pancreatic Cancer","authors":"Zhao Li,&nbsp;Ruiman Geng,&nbsp;Yousheng Zhan,&nbsp;Ruomeng Liu,&nbsp;Mufeng Li,&nbsp;Nengwen Ke,&nbsp;Hao Yang,&nbsp;Xiaofeng Lu,&nbsp;Lin Li,&nbsp;Suping Li* and Huawei Cai*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0136810.1021/acs.molpharmaceut.4c01368","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01368https://doi.org/10.1021/acs.molpharmaceut.4c01368","url":null,"abstract":"<p >Pancreatic cancer is a malignant solid tumor that contains a significant number of cancer-associated fibroblasts (CAFs). Clinical trials have confirmed that CAF-targeted radionuclide therapy can suppress tumor growth and extend the survival of patients; therefore, quantifying CAFs by molecular imaging of CAF biomarkers is helpful for assessing disease progression and therapeutic responses of pancreatic cancer. In our previous study, we found that platelet-derived growth factor receptor beta (PDGFRβ) was highly expressed on various fibroblast cells, and a novel affibody (Z_PDGFRβ) with highly specific binding to PDGFRβ had been developed. Herein, we verified the high expression of PDGFRβ on CAFs in pancreatic cancer tissues, and the Z_PDGFRβ affibody was radiolabeled with ⁶⁴Cu to obtain a [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ conjugate with radiochemical purity higher than 95%. Biodistribution studies showed that tumor uptake of [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ reached the peak of 7.28 ± 0.92 at 6 h postinjection, and the tumor-to-pancreas ratio continuously increased to reach the peak of 25.9 ± 8.18 at 24 h postinjection. Positron emission tomography (PET) imaging with [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ showed ideal tumor uptake and imaging capability in mice bearing both subcutaneous xenografts and <i>in situ</i> grafts. Our results demonstrated that the [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ conjugate could be applied as a promising PDGFRβ-targeted radiotracer for PET imaging of pancreatic cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1633–1640 1633–1640"},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528503","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":"⁶⁴Cu Radiolabeled PDGFRβ-Targeting Affibody for PET Imaging in Pancreatic Cancer.","authors":"Zhao Li, Ruiman Geng, Yousheng Zhan, Ruomeng Liu, Mufeng Li, Nengwen Ke, Hao Yang, Xiaofeng Lu, Lin Li, Suping Li, Huawei Cai","doi":"10.1021/acs.molpharmaceut.4c01368","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01368","url":null,"abstract":"<p><p>Pancreatic cancer is a malignant solid tumor that contains a significant number of cancer-associated fibroblasts (CAFs). Clinical trials have confirmed that CAF-targeted radionuclide therapy can suppress tumor growth and extend the survival of patients; therefore, quantifying CAFs by molecular imaging of CAF biomarkers is helpful for assessing disease progression and therapeutic responses of pancreatic cancer. In our previous study, we found that platelet-derived growth factor receptor beta (PDGFRβ) was highly expressed on various fibroblast cells, and a novel affibody (Z_PDGFRβ) with highly specific binding to PDGFRβ had been developed. Herein, we verified the high expression of PDGFRβ on CAFs in pancreatic cancer tissues, and the Z_PDGFRβ affibody was radiolabeled with ⁶⁴Cu to obtain a [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ conjugate with radiochemical purity higher than 95%. Biodistribution studies showed that tumor uptake of [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ reached the peak of 7.28 ± 0.92 at 6 h postinjection, and the tumor-to-pancreas ratio continuously increased to reach the peak of 25.9 ± 8.18 at 24 h postinjection. Positron emission tomography (PET) imaging with [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ showed ideal tumor uptake and imaging capability in mice bearing both subcutaneous xenografts and <i>in situ</i> grafts. Our results demonstrated that the [⁶⁴Cu]Cu-NOTA-Z_PDGFRβ conjugate could be applied as a promising PDGFRβ-targeted radiotracer for PET imaging of pancreatic cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431972","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":"Insights from Computational Studies of Polymeric Systems for Nucleic Acid Delivery.","authors":"Jesse Dylan Ziebarth, Hossain Shadman, Yongmei Wang","doi":"10.1021/acs.molpharmaceut.4c00994","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00994","url":null,"abstract":"<p><p>The safe and efficient delivery of nucleic acids into cells is a critical step in the success of gene and cell therapies. Although viral vectors are the predominant tools in current gene and cell therapy practices, they present significant challenges including high costs and safety concerns. Nonviral delivery systems for nucleic acids show immense potential for future medicine, particularly as nucleic acid therapeutics continue to be developed for the treatment of a wide range of diseases, including cancer. Significant research efforts, both experimental and computational, have been devoted to the development, characterization, and understanding of nonviral delivery processes. While numerous reviews have documented these research advancements, few have specifically addressed the contributions from computational studies. In this review, we provide an overview of the insights gained from computational and theoretical studies of polymeric systems for nucleic acid delivery. We also highlight future directions where computational and experimental approaches could synergize to advance the field.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431977","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":"Glassy Drug Microneedle Array Design: Drug Glass-Forming Ability and Stability.","authors":"Mohamed Elkhashab, Ziad Sartawi, Waleed Faisal, Abina Crean","doi":"10.1021/acs.molpharmaceut.4c01067","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01067","url":null,"abstract":"<p><p>Glassy microneedles, composed only of drug, provide an intradermal alternative to oral or parenteral drug delivery. Compared to microneedles composed of drug-polymer solid dispersions, they offer higher drug loading while possessing mechanical strength for skin penetration. However, their microneedle structure and associated mechanical strength are reliant on the component glass stability. This study investigates relationships between the glass stability of drug-only microneedles and drug glass-forming ability (GFA), determined by differential scanning calorimetry (DSC) analysis. The glass stability of microneedles fabricated from six drugs was evaluated at 2-8 °C under nitrogen, 25 °C/60% relative humidity (RH), and 40 °C/75% RH. Drug glass stability was determined by visual assessment of microneedle appearance, together with DSC and powder X-ray diffraction analysis of the drug melt cooled outside the microneedle molds. Glassy microneedle structure was retained for all drugs stored at 2-8 °C under nitrogen for 3 months. Drug GFA classes informed glass stability under dry (nitrogen) environments at temperatures below their glass transition temperature. Under controlled humidity conditions, all glass microneedles crystallized, except for itraconazole. Drug GFA did not inform microneedle glass stability when exposed to water vapor during storage due to water absorption and glass plasticization. Itraconazole's glass stability was attributed to the interaction of absorbed water with liquid crystalline phases present in the itraconazole glass. The results highlight how glassy microneedle stability is informed by storage below <i>T</i>_g and glass interaction with moisture vapor. Results also demonstrate how the skin penetration efficiency of glassy microneedles is maintained during storage by selecting stabilizing storage conditions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431975","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":"Insights from Computational Studies of Polymeric Systems for Nucleic Acid Delivery","authors":"Jesse Dylan Ziebarth,&nbsp;Hossain Shadman and Yongmei Wang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0099410.1021/acs.molpharmaceut.4c00994","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00994https://doi.org/10.1021/acs.molpharmaceut.4c00994","url":null,"abstract":"<p >The safe and efficient delivery of nucleic acids into cells is a critical step in the success of gene and cell therapies. Although viral vectors are the predominant tools in current gene and cell therapy practices, they present significant challenges including high costs and safety concerns. Nonviral delivery systems for nucleic acids show immense potential for future medicine, particularly as nucleic acid therapeutics continue to be developed for the treatment of a wide range of diseases, including cancer. Significant research efforts, both experimental and computational, have been devoted to the development, characterization, and understanding of nonviral delivery processes. While numerous reviews have documented these research advancements, few have specifically addressed the contributions from computational studies. In this review, we provide an overview of the insights gained from computational and theoretical studies of polymeric systems for nucleic acid delivery. We also highlight future directions where computational and experimental approaches could synergize to advance the field.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1160–1173 1160–1173"},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528589","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":"Glassy Drug Microneedle Array Design: Drug Glass-Forming Ability and Stability","authors":"Mohamed Elkhashab,&nbsp;Ziad Sartawi,&nbsp;Waleed Faisal and Abina Crean*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0106710.1021/acs.molpharmaceut.4c01067","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01067https://doi.org/10.1021/acs.molpharmaceut.4c01067","url":null,"abstract":"<p >Glassy microneedles, composed only of drug, provide an intradermal alternative to oral or parenteral drug delivery. Compared to microneedles composed of drug–polymer solid dispersions, they offer higher drug loading while possessing mechanical strength for skin penetration. However, their microneedle structure and associated mechanical strength are reliant on the component glass stability. This study investigates relationships between the glass stability of drug-only microneedles and drug glass-forming ability (GFA), determined by differential scanning calorimetry (DSC) analysis. The glass stability of microneedles fabricated from six drugs was evaluated at 2–8 °C under nitrogen, 25 °C/60% relative humidity (RH), and 40 °C/75% RH. Drug glass stability was determined by visual assessment of microneedle appearance, together with DSC and powder X-ray diffraction analysis of the drug melt cooled outside the microneedle molds. Glassy microneedle structure was retained for all drugs stored at 2–8 °C under nitrogen for 3 months. Drug GFA classes informed glass stability under dry (nitrogen) environments at temperatures below their glass transition temperature. Under controlled humidity conditions, all glass microneedles crystallized, except for itraconazole. Drug GFA did not inform microneedle glass stability when exposed to water vapor during storage due to water absorption and glass plasticization. Itraconazole’s glass stability was attributed to the interaction of absorbed water with liquid crystalline phases present in the itraconazole glass. The results highlight how glassy microneedle stability is informed by storage below <i>T</i>_g and glass interaction with moisture vapor. Results also demonstrate how the skin penetration efficiency of glassy microneedles is maintained during storage by selecting stabilizing storage conditions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1373–1383 1373–1383"},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c01067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528502","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":"Novel FAP-Targeted Heptamethine Cyanines for NIRF Imaging Applications","authors":"Rebecca Rizzo,&nbsp;Martina Capozza,&nbsp;Laura Conti,&nbsp;Lidia Avalle,&nbsp;Valeria Poli and Enzo Terreno*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0123210.1021/acs.molpharmaceut.4c01232","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01232https://doi.org/10.1021/acs.molpharmaceut.4c01232","url":null,"abstract":"<p >Fibroblast activation protein (FAP) is a pan-cancer target that is useful for imaging, ideally all epithelial cancers. This work aimed to develop, characterize, and validate two novel FAP-targeted probes for optical imaging, both in <i>vitro</i> and <i>in vivo</i>. IRDye800CW and FNIRTag heptamethine cyanines were conjugated to the NH precursor of the well-known FAP inhibitor FAPI-46, which is widely employed in nuclear medicine. In addition to synthesis, the dyes were characterized in terms of physicochemical properties, biodistribution, and imaging performances in a breast cancer tumor model. FAPI-FNIRTag showed a stronger fluorescence and higher photostability compared to FAPI-IRDye800CW. Notably, both compounds exhibited strong tumor accumulation in TUBO breast cancer-bearing mice 24 h postadministration, suggesting potential for further investigation as fluorescence-guided surgery (FGS) agents.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1518–1528 1518–1528"},"PeriodicalIF":4.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c01232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528576","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":"Novel FAP-Targeted Heptamethine Cyanines for NIRF Imaging Applications.","authors":"Rebecca Rizzo, Martina Capozza, Laura Conti, Lidia Avalle, Valeria Poli, Enzo Terreno","doi":"10.1021/acs.molpharmaceut.4c01232","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01232","url":null,"abstract":"<p><p>Fibroblast activation protein (FAP) is a pan-cancer target that is useful for imaging, ideally all epithelial cancers. This work aimed to develop, characterize, and validate two novel FAP-targeted probes for optical imaging, both in <i>vitro</i> and <i>in vivo</i>. IRDye800CW and FNIRTag heptamethine cyanines were conjugated to the NH precursor of the well-known FAP inhibitor FAPI-46, which is widely employed in nuclear medicine. In addition to synthesis, the dyes were characterized in terms of physicochemical properties, biodistribution, and imaging performances in a breast cancer tumor model. FAPI-FNIRTag showed a stronger fluorescence and higher photostability compared to FAPI-IRDye800CW. Notably, both compounds exhibited strong tumor accumulation in TUBO breast cancer-bearing mice 24 h postadministration, suggesting potential for further investigation as fluorescence-guided surgery (FGS) agents.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424623","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}