Molecular Pharmaceutics最新文献

{"title":"Development of Thermally Stable mRNA-LNP Delivery Systems: Current Progress and Future Prospects.","authors":"Urmila Kafle, Hoang Quan Truong, Cao Thuy Giang Nguyen, Fanfei Meng","doi":"10.1021/acs.molpharmaceut.4c00826","DOIUrl":"10.1021/acs.molpharmaceut.4c00826","url":null,"abstract":"<p><p>The success of mRNA-LNP-based COVID-19 vaccines opens a new era for mRNA-LNP-based therapy. This breakthrough is expected to catalyze the development of more mRNA-LNP-based medicines, not only for preventive vaccines but also for therapeutic purposes. Despite the promising outlook, there are fundamental challenges impeding the progress and widespread application of mRNA-LNP formulations. One of the significant challenges is their thermal instability, requiring these products to be stored at ultralow temperatures for long-term stability. The specific requirements present significant challenges for the storage, transportation, and distribution of mRNA-LNP formulations. To effectively prepare for future infectious disease outbreaks and broaden the application of mRNA-LNP-based therapies for other illnesses, improving the thermostability of mRNA-LNP formulations is critical. In this review, we discuss the potential factors contributing to the thermal instability of mRNA-LNP formulations and examine the roles of key components such as ionizable lipids, cholesterol, pH, buffers, and stabilizing agents like sugars in maintaining their thermal stability, with the goal of providing insights that can guide the future development of thermally stable mRNA-LNP formulations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5944-5959"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612758","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]Cu-NOTA-Trastuzumab and [⁸⁹Zr]Zr-DFO-Trastuzumab in Xenografts with Varied HER2 Expression.","authors":"Cristina Simó, Shayla Shmuel, Alex Vanover, Patrícia M R Pereira","doi":"10.1021/acs.molpharmaceut.4c00777","DOIUrl":"10.1021/acs.molpharmaceut.4c00777","url":null,"abstract":"<p><p>Positron emission tomography (PET) has potential as a complementary technique to biomarker analysis, especially for human epidermal growth factor receptor 2 (HER2)-expressing tumors characterized by high heterogeneity. In this study, zirconium-89 (⁸⁹Zr) and copper-64 (⁶⁴Cu) labeled trastuzumab were employed to monitor varying levels of tumoral HER2 expression. Additionally, we studied the use of the cholesterol-depleting lovastatin as a pharmacological approach to enhance cell-surface HER2 expression in tumors with moderate to low HER2 levels, aiming to increase antibody accumulation in these tumor types. Both ⁸⁹Zr- and ⁶⁴Cu-labeled trastuzumab effectively monitor HER2 expression levels in xenografts exhibiting varying HER2 expression. No significant difference in tumor uptake was observed between ⁸⁹Zr- or ⁶⁴Cu-labeled trastuzumab, and tumor uptake for both radioimmunoconjugates positively correlated with HER2 protein levels. These findings underscore the potential of PET to monitor HER2 protein levels across heterogeneous tumors. Furthermore, our results suggest that further optimization of statin dosing and timing could offer a promising strategy to enhance trastuzumab accumulation in HER2-high, HER2-moderate, and HER2-low tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6311-6322"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542899","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":"Modeling and Simulations in Latin-American Generic Markets: Perspectives from Chilean Local Industry, Regulatory Agency, and Academia.","authors":"Mauricio A García, Claudio Paulos, Manuel Ibarra Viñales, Robin Michelet, Miguel Ángel Cabrera-Pérez, Alexis Aceituno, Michelle Bone, Mauricio Ibacache, Luis Ignacio Cortínez, Marcelo Guzmán","doi":"10.1021/acs.molpharmaceut.4c00764","DOIUrl":"10.1021/acs.molpharmaceut.4c00764","url":null,"abstract":"<p><p>In the last 20 years, modeling and simulations (M&S) have gained increased attention in pharmaceutical sciences. International industry and world-reference agencies have used M&S to make cost-efficient decisions through the model-informed drug development (MIDD) framework. Modeling tools include biopredictive dissolution models, physiologically based pharmacokinetic models (PBPK), biopharmaceutic models (PBBM), and virtual bioequivalence, among many others. Regulatorily, health agencies are becoming more and more open to accept the use of M&S to support regulatory applications, including setting dissolution specifications, quality-by-design (QbD), postapproval changes (SUPAC), etc. Nonetheless, the potential of M&S has been only barely explored in Latin America (Latam) across different actors: industry, regulatory agencies, and even academia. In this manuscript, we discuss the challenges and opportunities for implementing M&S approaches in Latam. Perspectives of regional experts were shared in a workshop. Attendance (professionals from industry, regulator, academia, and clinicians) also shared their views via survey. The rational development of bioequivalent generics was considered the main opportunity for M&S in regional market, particularly the use of PBPK and PBBM. Nonetheless, a critical mass of modeling scientists is needed before Latin American industry and regulators can actually benefit from M&S. Collaborations (e.g., Academia-Industry and Academia-Regulatory) may be a path to develop applied research projects and train the future modelers. Reaching that critical mass, scientists from industry may apply modeling across generic drug development process and life cycle, while regulatory scientists may issue guidelines in local language to support regional industry. Only at that stage could the full potential of MIDD be reached in Latin American generic markets.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6100-6108"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491111","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":"The Future of Pharmaceutics: Showcasing Emerging Leaders in Drug Delivery","authors":"Chun-Wan Yen,&nbsp;Patrick O’Dwyer,&nbsp;Weijun Wei,&nbsp;Lauren A. Austin* and Orlagh M. Feeney*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0131610.1021/acs.molpharmaceut.4c01316","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01316https://doi.org/10.1021/acs.molpharmaceut.4c01316","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"5905–5906 5905–5906"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756432","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":"High-Speed Imaging-Based Particle Attribute Analysis of Spray-Dried Amorphous Solid Dispersions Using a Convolution Neural Network.","authors":"Hang Hu, Sampada Koranne, Colton M Bower, Daniel Skomski, Matthew S Lamm","doi":"10.1021/acs.molpharmaceut.4c01092","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01092","url":null,"abstract":"<p><p>Spray drying is a well-established method for preparing amorphous solid dispersion (ASD) formulations to improve the oral bioavailability of poorly soluble drugs. In addition to the characterization of the amorphous phase, particle attributes of spray-dried intermediates (SDIs), including particle size, morphology, and microstructure, need to be carefully studied and controlled for optimizing drug product performance. Although recent developments in microscopy technology have enabled the analysis of morphological attributes for individual SDI particles, a high-throughput method is highly desirable. In this work, a fingerprinting method exploiting high-speed dynamic imaging, laser diffraction (LD), and a convolutional neural network (CNN) was developed to characterize and quantify size and morphological distributions of particles in batches of spray-dried ASDs. This imaging technology enables the generation of hundreds of thousands of single-particle images in a few minutes that are analyzed by both unsupervised and supervised CNN models. The unsupervised data mining analysis demonstrated that a batch of SDI is a mixture of diverse particle subpopulations with varying sizes and morphological attributes. Motivated by this observation, we developed a CNN model that enabled rapid computation of the volumetric composition of the distinct particle subpopulations in a SDI batch, thus generating a morphological fingerprint. We implemented this high-speed imaging-based particle attribute analysis method to investigate SDIs containing hypromellose acetate succinate as a model system. The CNN fingerprint results enabled quantification of the changes in the morphological distribution of SDI batches prepared with variations in the spray drying process parameters, and the results were in line with the LD and electron microscopy data. Our experiments and analysis demonstrate the robustness and throughput of this fingerprinting approach for quantifying particle size and morphological distributions of individual SDI batches, which can help guide spray drying process development and thereby enable the development of a drug product with more robust process and optimized performance.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Coarse-Grained Molecular Dynamics Perspective on the Release of 5-Fluorouracil from Liposomes.","authors":"Roxana-Maria Amărandi, Luminiţa Marin, Brînduşa Drăgoi, Andrei Neamţu","doi":"10.1021/acs.molpharmaceut.4c00328","DOIUrl":"10.1021/acs.molpharmaceut.4c00328","url":null,"abstract":"<p><p>Liposomes, small bilayer phospholipid-containing vesicles, are frequently used to ensure slow drug release for a prolonged and improved therapeutic effect. Nevertheless, current findings on the membrane affinity and permeability of the anticancer agent 5-fluorouracil (5-FU) are confounding, which leads to a lack of a clear understanding of how lipid composition impacts the distribution of 5-FU within liposomal structures and its delivery. In the current work, we report a comprehensive coarse-grained molecular dynamics (CGMD) investigation on the influence of cholesterol (CHOL) and the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) on the partitioning of 5-FU in 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphocholine (DPPC) double-bilayer systems, as well as its in vitro release from liposomes with identical lipid compositions. Our results show that 5-FU tends to accumulate at the water-lipid interface, in the vicinity of polar headgroups, without partitioning in the hydrophobic tail region. At the same time, the presence of CHOL proportionally increases the distribution of this drug in the interbilayer aqueous space, decreasing the drug's affinity toward the membrane polar head region, while DOTAP has only a slight effect on drug distribution. Thus, it is expected that 5-FU will be released slower from CHOL-containing DPPC liposomes but not DOTAP-containing vesicles. However, in vitro release studies showed that the release kinetics of 5-FU from DPPC vesicles is not influenced by the presence of CHOL and that the incorporation of 10 mol % DOTAP leads to the best release profile for 5-FU, highlighting the complexity of nanocarrier drug release kinetics. We hypothesize that the initial rapid release seen in dialysis experiments is not related to drug membrane permeability but rather to 5-FU adsorbed on the outer surface of liposomes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6137-6152"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612753","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":"The Future of Pharmaceutics: Showcasing Emerging Leaders in Drug Delivery.","authors":"Chun-Wan Yen, Patrick O'Dwyer, Weijun Wei, Lauren A Austin, Orlagh M Feeney","doi":"10.1021/acs.molpharmaceut.4c01316","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01316","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"5905-5906"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764848","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":"Divergent Proteomic Profiles and Uptake Mechanisms of Exosomes Derived from Human Dental Pulp Stem Cells, Endothelial Cells, and Fibroblasts.","authors":"Siqi Zhang, Jun Chen, Yipu Cao, Yifan Cui, Mei Zhang, Chongxia Yue, Bangcheng Yang","doi":"10.1021/acs.molpharmaceut.4c00911","DOIUrl":"10.1021/acs.molpharmaceut.4c00911","url":null,"abstract":"<p><p>Effective intercellular communication is crucial for tissue repair and regeneration, with exosomes playing a key role in mediating these processes by transferring proteins, lipids, and nucleic acids between cells. This study explored the mechanisms underlying the uptake of exosomes derived from human dental pulp stem cells (hDPSCs), human umbilical vein endothelial cells (HUVECs), and human fibroblasts (HFBs). Our findings revealed that hDPSCs exhibited the greatest capacity for exosome uptake across all three cell types. Moreover, exosomes originating from hDPSCs were also taken up in the highest amounts by all three cell types. Proteomic analysis uncovered significant differences in protein expression among exosomes from these different cell types, particularly in proteins related to endocytosis. Clathrin-dependent endocytosis emerged as the primary pathway for exosome uptake in hDPSCs and HUVECs, while HFBs appeared to use a different mechanism. Additionally, proteins such as fibronectin and tetraspanins were found to be highly expressed in hDPSC-derived exosomes, suggesting their potential involvement in exosome-cell interactions. This study offers new insights into exosome uptake mechanisms and highlights the potential of exosomes in advancing tissue engineering and regenerative medicine.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6353-6362"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612761","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":"Immuno-PET Imaging of CD93 Expression with ⁶⁴Cu-Radiolabeled NOTA-mCD93 ([⁶⁴Cu]Cu-NOTA-mCD93) and Insulin-Like Growth Factor Binding Protein 7 ([⁶⁴Cu]Cu-NOTA-IGFBP7).","authors":"Xiaoyan Li, Wenyu Song, Jonathan W Engle, Jason C Mixdorf, Todd E Barnhart, Yi Sun, Yuwen Zhu, Weibo Cai","doi":"10.1021/acs.molpharmaceut.4c00983","DOIUrl":"10.1021/acs.molpharmaceut.4c00983","url":null,"abstract":"<p><p>CD93 is overexpressed in multiple solid tumor types, serving as a novel target for antiangiogenic therapy. The goal of this study was to develop a ⁶⁴Cu-based positron emission tomography (PET) tracer for noninvasive imaging of CD93 expression. Antimouse-CD93 mAb (mCD93) and the CD93 ligand IGFBP7 were conjugated to a bifunctional chelator, <i>p</i>-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (<i>p</i>-SCN-NOTA) and labeled with ⁶⁴Cu. To evaluate the pharmacokinetic properties and tumor-targeting efficacy of [⁶⁴Cu]Cu-NOTA-mCD93 and [⁶⁴Cu]Cu-NOTA-IGFBP7, PET imaging and biodistribution were performed on both 4T1 murine breast tumor-bearing mice and MDA-MB-231 human breast tumor-bearing mice. The tumor model HT1080-FAP, which does not overexpress CD93, was used as a negative control. Fluorescent immunostaining was conducted on different tissues to correlate radiotracer uptake with CD93 expression. ⁶⁴Cu-labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the <i>in vivo</i> performance of [⁶⁴Cu]Cu-NOTA-IGFBP7 was superior to that of [⁶⁴Cu]Cu-NOTA-mCD93, and that the tracer [⁶⁴Cu]Cu-NOTA-IGFBP7 exhibited elevated tumor uptake values and excellent tumor retention in MDA-MB-231 mice, rather than in 4T1 murine mice. The MDA-MB-231 tumor uptake of [⁶⁴Cu]Cu-NOTA-IGFBP7 was 2.85 ± 0.15, 3.69 ± 0.60, 6.91 ± 0.88, and 6.35 ± 0.55%ID/g at 1, 4, 24, and 48 h p.i., respectively, which were significantly higher than that in the CD93-negative HT1080-FAP tumor (0.73 ± 0.15, 0.97 ± 0.31, 1.00 ± 0.07, and 1.02 ± 0.11%ID/g, respectively). The significant difference between positive and negative tumors indicated [⁶⁴Cu]Cu-NOTA-IGFBP7 was specifically binding to CD93. Biodistribution data as measured by gamma counting were consistent with the PET analysis. <i>Ex vivo</i> histology further confirmed the high CD93 expression on MDA-MB-231 tumor tissues. Herein, we prepared two novel radiotracers, [⁶⁴Cu]Cu-NOTA-mCD93 and [⁶⁴Cu]Cu-NOTA-IGFBP7, for the first immune-PET imaging of CD93 expression. Our results suggest that [⁶⁴Cu]Cu-NOTA-IGFBP7 is a more potential radiotracer for visualizing angiogenesis due to its sensitive, persistent, and CD93-specific characteristics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6411-6422"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612765","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":"New Insights on the Burst Release Kinetics of Spray-Dried PLGA Microspheres.","authors":"Kyprianos Michaelides, Mohamad Anas Al Tahan, Yundong Zhou, Gustavo F Trindade, David J H Cant, Yiwen Pei, Pawan Dulal, Ali Al-Khattawi","doi":"10.1021/acs.molpharmaceut.4c00686","DOIUrl":"10.1021/acs.molpharmaceut.4c00686","url":null,"abstract":"<p><p>Spray drying is one of the leading manufacturing methods for active pharmaceutical ingredients (APIs) owing to its rapid, single-step, and cost-effective nature. It also has the capacity to generate microspheres capable of controlled release of APIs including biomolecules and vaccines. However, one of the key challenges of spray-dried formulations especially with poly(lactic-<i>co</i>-glycolic acid) (PLGA)-based controlled-release injectables is burst release, where a significant fraction of the API is released prematurely within a short period of time following administration, leading to detrimental impact on the performance and quality of end products. This study uses a model API, bovine serum albumin (BSA) protein, to identify the sources of burst release that may affect the kinetics and performance of long-acting injectable microsphere formulations. Spray-dried microspheres with various formulations (i.e., variable BSA/PLGA ratios) were characterized in terms of their morphology, particle size, surface area, thermal properties, moisture content, as well as chemical compositions and their distributions to investigate the impact of spray drying on the burst release phenomenon. The results suggest that a relatively high initial release (85%) observed is mainly attributed to the protein distribution close to the particle surface. Morphology analysis provided evidence that the microspheres retained their spherical structure during the burst release phase. X-ray photoelectron spectroscopy, hard X-ray photoelectron spectroscopy, and argon cluster sputtering-assisted time-of-flight secondary ion mass spectrometry analysis suggest an enrichment of PLGA on particle surfaces with buried BSA protein. The statistically significant difference in particle size and surface area between three different formulations may be responsible for an initial variation in release but did not seem to alter the overall burst release profile. Considering the suggested source of burst release, the two-fluid spray-drying method, characterized by a single liquid feed delivering a preprepared emulsion, generated matrix-type microspheres with a surface layer of PLGA, as evidenced by surface analysis. The PLGA surface layer proved to be prone to degradation and pore formation, allowing for faster diffusion of BSA out of the microspheres, resulting in a burst release. Increasing the polymer concentration did not seem to halt this process.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6245-6256"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491112","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}