Journal of Controlled Release最新文献

{"title":"Overcoming P-glycoprotein-mediated multidrug resistance in cancer cells through micelle-forming PHPMA-b-PPO diblock copolymers for doxorubicin delivery","authors":"Martin Kaňa, Alena Braunová, Daniil Starenko, Markéta Frejková, Jan Bouček, Blanka Říhová, Marek Kovář, Tomáš Etrych, Milada Šírová","doi":"10.1016/j.jconrel.2025.113645","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113645","url":null,"abstract":"Multidrug resistance (MDR) represents one of the major concerns in cancer therapy as it may cause reduced efficacy of chemotherapeutic drugs due to the overexpression of ABC transporters, particularly P-glycoprotein (P-gp). This study explores the potential of novel amphiphilic diblock (DB) copolymers composed of poly(<em>N</em>-(2-hydroxypropyl)methacrylamide)-based copolymers (PHPMA) and poly(propylene oxide) (PPO) to overcome MDR mechanisms. The DB copolymers and their doxorubicin (Dox) conjugates significantly increased Dox accumulation in P-gp positive cells, markedly sensitizing them to Dox cytotoxic activity. The underlying mechanisms included depletion of intracellular ATP with subsequent inhibition of P-gp mediated drug efflux, an altered mitochondrial membrane potential, and increased ROS production. Moreover, the DB-Dox conjugates inhibited tumor growth <em>in vivo</em> more effectively compared to the corresponding PHPMA-based drug delivery system. Copolymers with additionally loaded PPO in the micelle core demonstrated superior efficacy in terms of P-gp inhibition, ATP depletion, and chemosensitizing effect <em>in vitro</em>, as well as antitumor activity <em>in vivo</em>. DB copolymers effectively depleted ATP levels both <em>in vitro</em> and <em>in vivo</em> using patient-derived xenograft (PDX) models, underscoring their capacity to enhance the effectiveness of standard chemotherapy and translational potential.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"214 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of administration route and PEGylation on alpha-1 antitrypsin augmentation therapy","authors":"Xiao Liu, Bernard Ucakar, Kevin Vanvarenberg, Etienne Marbaix, Rita Vanbever","doi":"10.1016/j.jconrel.2025.113643","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113643","url":null,"abstract":"Patients suffering from emphysema associated with alpha1 antitrypsin (AAT) deficiency can benefit from augmentation therapy. AAT is administered to the patient once a week by intravenous infusion by a healthcare professional. However, only 2 % of the AAT dose reach the lungs following intravenous infusion. Inhalation of AAT might be a convenient and effective alternative to intravenous infusion. Yet, it has shown limited therapeutic efficacy in a recent clinical trial. Here, we assessed the impact of these routes of AAT administration on AAT pharmacokinetics, lung distribution and therapeutic efficacy in mice. PEGylation of the serpin was employed to improve its therapeutic value. Intravenous injection of AAT or its local administration to the lungs resulted in a similar exposure of the lung parenchyma to AAT with however an AAT dose delivered to the lungs 45-times lower than the injected dose. Conjugation of AAT to a 2-armed 40 kDa polyethylene glycol (PEG) chain prolonged its half-life in plasma and lungs 1.6-times, decreased its penetration in the lung tissue by both routes of administration but did not markedly affect the lung exposure to AAT. The PEG moiety in PEG-AAT was cleared more slowly than the protein moiety and high PEG quantities remained in the lung tissue and alveolar macrophages several days after intratracheal instillation. Pulmonary administration and PEGylation both improved AAT efficacy to prevent lung injury and inflammation in a murine model of chronic obstructive pulmonary disease where lung inflammation was induced by delivering porcine pancreatic elastase and lipopolysaccharide locally to the airways. Anti-AAT and anti-PEG antibodies were generated by AAT and PEG-AAT administration, as expected for a foreign protein. However, anti-PEG antibodies did not significantly contribute to the overall anti-drug antibody titers against the conjugate. AAT and PEG-AAT showed good stability to jet nebulization. This study provides new insights into the impact of administration route and PEGylation on lung exposure, clearance, therapeutic efficacy, and safety of AAT. It highlights that inhalation of AAT might effectively replace its intravenous infusion in augmentation therapy.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"43 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Micelle into gel thermosensitive intra-articular hydrogels for osteoarthritis management","authors":"Helena Rouco, Maria Permuy, Fernando Muñoz, José Antonio Vázquez, José R. Caeiro, Mariana Landin, Patricia Diaz-Rodriguez","doi":"10.1016/j.jconrel.2025.113639","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113639","url":null,"abstract":"Osteoarthritis (OA) is a chronic and degenerative joint disease with a rising incidence worldwide. Current therapeutic approaches primarily focus on symptom relief through systemic administration, which raises safety concerns related to side effects and long-term use. In this context, the local administration of natural compounds with anti-inflammatory and anti-arthritic properties, such as β-Lapachone constitutes an interesting alternative. In this work, we prepared and characterized injectable thermosensitive hybrid hydrogels loaded with β-Lapachone. A comprehensive characterization of the hydrogel systems was performed, including micellar diameter, mechanical properties at different temperatures, the ability to control drug release and microstructure. The anti-inflammatory activity of the free drug, as well as that of the blank or loaded hydrogels was then evaluated <em>ex vivo</em>, using OA cartilage explants. Additionally, <em>in vivo</em> studies were carried out in a rabbit model of OA to assess their clinical potential. The results suggest that the hydrogel systems possess a composite microstructure integrating micelles, together with a temperature-responsive stiffness and the ability to modulate drug release. In addition, β-Lapachone-loaded hydrogels display an interesting immunomodulatory potential <em>ex vivo</em>, as they were able to efficiently reduce the secretion of several proinflammatory mediators, such as IL-6, MMP9, MMP13 and CXCL8. Furthermore, the drug-loaded hydrogels were found to improve <em>in vivo</em> cartilage and bone histomorphometric markers, such as subchondral bone thickness, as well as early signs of cartilage damage, such as the fibrillation index. Therefore, the developed β-Lapachone-loaded thermosensitive hydrogels constitute a promising alternative for OA management.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"55 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the impact of lipid nanoparticle compositions on the delivery and T cell response of circRNA vaccine","authors":"Yasir Alshehry, Xiang Liu, Yu Zhang, Guizhi Zhu","doi":"10.1016/j.jconrel.2025.113617","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113617","url":null,"abstract":"Circular RNA (circRNA) is an emerging class of vaccines for various diseases, such as cancer immunotherapy. For cancer therapeutic vaccines, it is critical to deliver circRNA to lymphoid tissues such as lymph nodes (LNs) and dendritic cells (DCs) and then elicit antigen-specific T cell responses. Lipid nanoparticles (LNPs) have shown great success for mRNA vaccines and may also have great potential as nanocarriers for circRNA vaccines. Here, we studied the impact of LNP composition on the efficiency of immune delivery, protein expression, and the T cell responses for circRNA vaccine. First, we used model mRNA and circRNA encoding firefly luciferase (mRNA-fLuc) to study protein expression and used two small circRNA vaccines to study T cell responses. We investigated a combination of six ionizable lipids, three helper lipids, and six different molar ratios of cholesterol and β-sitosterol for their impact on the physicochemical properties of RNA LNPs, <em>in vitro</em> DC transfection, <em>in vivo</em> protein expression in draining LNs, and antigen-specific T cell responses. Among these ionizable lipids, SM-102 was the most effective for DC transfection and enabling circRNA vaccines to elicit T cell responses. DOPE and β-sitosterol incorporation in LNPs resulted in efficient protein expression, albeit β-sitosterol incorporation appeared to be associated with reduced T cell response. Overall, circRNA was efficiently delivered to DCs and macrophages in mouse draining lymph nodes by LNPs of SM-102 (50 %), cholesterol (38.5 %), DOPE (10 %), and DMG-PEG2000 (1.5 %), resulting in the induction of potent antigen-specific CD8⁺ T cell response in mice. These findings may provide insights into designing the compositions of LNPs as the carrier for circRNA therapeutics and vaccines.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"27 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of silica nanoparticles with varied physicochemical properties on the survival and functionality of saturated macrophages","authors":"Sushanto Kumar Saha, Cansu Umran Tunc, Nitish Khurana, Jason William Grunberger, Hamidreza Ghandehari","doi":"10.1016/j.jconrel.2025.113640","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113640","url":null,"abstract":"Silica nanoparticles (SNPs) have shown potential as nanocarriers in diagnostic, imaging, and drug delivery applications. To use SNPs for systemic drug delivery, it is important to have a detailed understanding of how these particles interact with the mononuclear phagocytic system (MPS). Whether or not SNPs may saturate the macrophages, thereby influencing their function and impairing innate immune responses, remains poorly understood. In this work, we defined macrophage saturation using RAW 264.7 macrophages as a model and studied four SNPs with variations in size and porosity. We further explored the downstream effects of SNP uptake by macrophages, including apoptosis/necrosis, cell cycle progression, membrane integrity, and phagocytic activity. The data demonstrate that SNPs do not alter major cellular functions at their respective nontoxic, saturating concentrations.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"17 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In situ peptide assembly for cell membrane rewiring in tumor therapy","authors":"Yu Ma, Qiaochu Jiang, Xiaoyang Liu, Xianbao Sun, Gaolin Liang","doi":"10.1016/j.jconrel.2025.113637","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113637","url":null,"abstract":"Peptide assembly on the cell membrane is capable of endowing cells with novel biological properties that are distinct from their original states, thereby playing a pivotal role in the regulation of diverse cellular biological events. In practical biomedical scenarios, in order to make peptide assembly more precisely meet the requirements of cells at different physiological stages and conditions to achieve desired effects of cell function regulation, it becomes particularly crucial to conduct precise <em>in situ</em> spatiotemporal control of peptide assembly on the cell membrane, thus attracting great attentions. Particularly for tumor treatment, this artificially manipulated cell surface engineering can achieve excellent anti-tumor effects by altering the cell membrane structure, influencing receptor clustering or interfering with relevant signal pathways. Of note, membrane-anchoring peptides play a key role in these processes. In this review, we focus on three main types of membrane-anchoring peptides, elaborating in detail on how their assembly regulation mechanisms influence the cell membrane remodeling effect, and further exert therapeutic effects on tumors. On this basis, we further introduce a variety of tumor treatment strategies combined with <em>in situ</em> peptide assembly on the cell membrane, and discuss the current opportunities and challenges in this field, aiming to present the overall research panorama and trend of <em>in situ</em> peptide self-assembly on the cell membrane for efficient tumor treatment.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"89 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of focused ultrasound modulation of the blood-brain barrier in gray and white matter","authors":"Alessandro De Maio, Yuexi Huang, Fa-Hsuan Lin, Bojana Stefanovic, Greg J. Stanisz, Meaghan A. O'Reilly","doi":"10.1016/j.jconrel.2025.113631","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113631","url":null,"abstract":"<h3>Rationale</h3>Focused ultrasound (FUS) in combination with intravenous microbubbles is being studied clinically for modulation of the blood-brain barrier. Contrast-enhanced MRI can be used to visualize the enhanced permeability resulting from the treatment. However, contrast enhancement in the white matter (WM) are inconsistently observed compared to the gray matter (GM). Intrinsic tissue differences are believed to result in reduced treatment efficacy and insufficient drug delivery to the WM. In this study we evaluate the deposition of MRI contrast and clinically relevant antineoplastics in GM and WM tissues following single and repeated FUS and microbubble treatments.<h3>Methods</h3>The brains of Fischer-344 rats (<em>n</em> = 24) and Yorkshire pigs (<em>n</em> = 6) underwent FUS (rats: 580 kHz; pigs: 220 kHz) treatments targeting the internal capsule and thalamus, repeated at 30-min intervals. Definity microbubbles (rats: 20 μL/kg bolus; pigs: 4 μL/kg/5-min infusion) were administered intravenously for each sonication with MRI contrast to measure gadolinium-mediated signal change. Feedback-controlled algorithms were used to monitor treatments and modulate the pressure based on emitted microbubble signals to ensure safe and effective exposures. The delivery of methotrexate (MTX; 454.4 Da) and bevacizumab (BVZ; 149 kDa) was evaluated via immunofluorescence microscopy in rats, and respectively quantified via liquid chromatography mass spectrometry and enzyme-linked immunosorbent assay in pigs.<h3>Results</h3>Repeated FUS exposures successfully increased the vascular permeability of both gray and white matter tissues to MRI contrast and drugs of both small and large molecular sizes.In rats, single treatments showed statistically significant higher enhancements in the GM (23.5 ± 4.3 %; WM: 4.68 ± 3.75 %), however following a second sonication there were no between-tissue differences (GM: 38.0 ± 6.4 %; WM: 34.0 ± 8.7 %).In pigs, the smaller focus size relative to the brain enabled separate targeting of GM vs WM and the treatment controller used higher average power level in the WM to achieve the same cavitation dose. This resulted in no difference in gray and white matter permeability levels (to both contrast and pharmacological agents) after a single sonication. Repeated treatments sustained MRI enhancements for a longer time and enhanced drug deposition (MTX increased 6.5 and 8.3 folds after single and repeated treatment; BVZ increased 6.8 and 20.4 folds respectively).<h3>Conclusions</h3>Feedback-controlled algorithms and the possibility to individually target gray and white matter highlighted the impact of tissue composition on treatment outcomes. Repeated FUS-mediated modulation of the brain microvasculature achieved higher levels of permeabilization to contrast and pharmacological agents in both gray and white matter.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ion-paired moxifloxacin nanocrystal formulation improves treatment and prevention of ocular infection","authors":"Matthew B. Appell, Kiersten Malmberg, Ashwin Pasupathy, Aditya Josyula, Jairo Ortiz, Peter J. McDonnell, Nakul Shekhawat, Kunal S. Parikh, Laura M. Ensign","doi":"10.1016/j.jconrel.2025.113634","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113634","url":null,"abstract":"Ocular infections may arise spontaneously or following penetrating globe injury or operation, such as corneal transplant or cataract extraction. Treatment and prophylaxis of bacterial infections using antibiotic eye drops requires a strict dosing regimen to avoid irreversible vision loss. At present, moxifloxacin eye drops are prescribed for use multiple times per day, leading to patient non-adherence, the emergence of bacterial resistance, and infection progression. The desire to avoid sub-lethal antibiotic dosing and visual impairment through inconsistent eye drop application motivates the development of a sustained release injectable formulation. Herein, we report the development of an ion-paired, nanocrystalline moxifloxacin formulation that provided increased intraocular antibiotic accumulation with a single subconjunctival injection compared to 3× daily eye drops. The sustained release functionality further led to improved or non-inferior prevention and treatment of <em>Staphylococcus aureus</em>-induced ocular infection in both rats and rabbits compared to gold standard intracameral moxifloxacin and moxifloxacin eye drops. By achieving therapeutically relevant moxifloxacin accumulation, this nanocrystalline moxifloxacin formulation may be a promising alternative to conventional therapies to achieve improved post-surgical infection prevention and bacterial keratitis treatment outcomes.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"58 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assembled granular hydrogels loaded with growth factors for enhanced mesenchymal stem cell therapy in abdominal wall defect repair","authors":"Liuxin Yang ,&nbsp;Fengya Jing ,&nbsp;Dandan Wei ,&nbsp;Xiaocong Zhao ,&nbsp;Yinghua Tao ,&nbsp;Tao Liu ,&nbsp;Tianzhu Zhang","doi":"10.1016/j.jconrel.2025.113630","DOIUrl":"10.1016/j.jconrel.2025.113630","url":null,"abstract":"<div><div>Abdominal wall defects caused by trauma, congenital rupture, and intra-abdominal infection remain challenging due to the large wound area and complex complications. Herein, an assembled mesenchymal stem cell (MSCs)-laden granular hydrogel (termed assembled GSD@FPs), loaded with basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF), is developed. This hydrogel is constructed through dynamic covalent cross-linking (<em>via</em> borate ester bonds) among dopamine-grafted gelatin methacrylamide (GelMA-DA), phenylborate-modified hyaluronic acid (HA-PBA), and epigallocatechin-3-gallate (EGCG), serving as multifunctional bulk building blocks for cell delivery and abdominal wall repair. The designed assembled granular hydrogels possess good rheological properties, self-healing, injectability, and tissue-adhesion properties. Detailed <em>in vitro</em> cell experiments are conducted, revealing that the GSD@FPs granular hydrogels can effectively promote cell proliferation, cell migration and angiogenesis. Furthermore, in abdominal wall defects, assembled GSD@FPs significantly accelerates the tissue healing process by simultaneously inhibiting the inflammatory response, promoting collagen deposition, and promoting cell proliferation and angiogenesis. Importantly, the assembled GSD@FPs granular hydrogels can also provide mechanical support and increase the thickness of regenerated tissue (1727.8 ± 169.6 μm for the control group, 3204.2 ± 278.5 μm for the assembled GSD@FPs group at 14 d). Eventually, the GSD granular hydrogels biodegraded, facilitating tissue remodeling and generating new muscle tissues. Therefore, this study provides a promising strategy with great potential for application in abdominal wall repair.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"381 ","pages":"Article 113630"},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inside back cover: Adrian Tabora Dychiao et al","authors":"","doi":"10.1016/S0168-3659(25)00226-3","DOIUrl":"10.1016/S0168-3659(25)00226-3","url":null,"abstract":"","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Page IBC"},"PeriodicalIF":10.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}