Molecular Pharmaceutics最新文献

{"title":"Lipid Nanoparticles-Mediated mRNA Delivery to the Eye Affected by Ionizable Cationic Lipid.","authors":"Siyu Dong, Zhaoqi Pan, Mengchun Chang, Juanjuan Zhou, Mengke Zhang, Yashuang Chen, Ting Li, Ziwen Chen, Yuwan Gao, Sitao Xie, Wencan Wu, Xiangsheng Liu","doi":"10.1021/acs.molpharmaceut.5c00248","DOIUrl":"10.1021/acs.molpharmaceut.5c00248","url":null,"abstract":"<p><p>Ionizable lipid serves as the key functional component in lipid nanoparticles (LNPs) for efficient mRNA delivery. This study aims to systematically evaluate clinically approved ionizable lipid DLin-MC3-DMA and SM102-based LNPs for ocular mRNA delivery, with a comprehensive assessment of their physicochemical characteristics, delivery efficiency, and biodistribution patterns within the ocular microenvironment. Enhanced green fluorescence protein or Luc encoding mRNA-loaded LNPs were formulated using microfluidic mixing technology and characterized by dynamic light scattering, ζ-potential measurements, and cryogenic transmission electron microscopy imaging. The two LNP systems with different ionizable cationic lipids demonstrated distinct capabilities for <i>in vitro</i> mRNA transfection and intraocular mRNA delivery following intravitreal administration. Notably, the SM102-LNPs exhibited superior performance compared to the MC3-LNPs, characterized by significantly higher transfection efficiency in retinal cells <i>in vitro</i>, and more efficient ocular expression with minimal systemic distribution <i>in vivo.</i> Safety assessment demonstrated that intravitreal administration of SM102-LNPs maintained excellent long-term biocompatibility throughout a five-month study period. The superior performance of SM102-LNPs establishes a promising platform for ocular mRNA therapeutics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3297-3307"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951233","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":"Design and Preclinical Evaluation of Novel uPAR-Targeting Radiopeptides Modified with an Albumin-Binding Entity.","authors":"Darja Beyer, Christian Vaccarin, Jerome V Schmid, Luisa M Deberle, Xavier Deupi, Roger Schibli, Cristina Müller","doi":"10.1021/acs.molpharmaceut.5c00135","DOIUrl":"10.1021/acs.molpharmaceut.5c00135","url":null,"abstract":"<p><p>Several studies have focused on the development and application of radiolabeled DOTA-AE105 for targeting the urokinase-type plasminogen activator receptor (uPAR), which is expressed on various cancer types. The aim of this project was to design and evaluate novel uPAR-targeting radiopeptides with improved pharmacokinetic properties in view of their therapeutic application. Five peptides (uPAR-01, uPAR-02, uPAR-03, uPAR-04, and uPAR-05) were synthesized based on the AE105 peptide backbone, a DOTA chelator, and the 4-(<i>p</i>-iodophenyl)butanoate moiety as an albumin binder. The peptides were obtained in 20-29 synthetic steps using solid-phase peptide synthesis with a 6-34% overall yield. In saline, the ¹⁷⁷Lu-labeled peptides (100 MBq/nmol) were stable (>93% intact radiopeptides) in the presence of l-ascorbic acid over 24 h. The new radiopeptides were also stable (>98% intact radiopeptides) in mouse and human blood plasma, while only ∼13% of [¹⁷⁷Lu]Lu-DOTA-AE105 was intact after a 4 h incubation period. The uPAR-binding affinities (<i>K</i>_D values) determined with uPAR-transfected human embryonic kidney cells (HEK-uPAR) ranged from 10 to 57 nM and were, thus, similar to that of [¹⁷⁷Lu]Lu-DOTA-AE105 (<i>K</i>_D: 20 ± 1 nM). Compared to [¹⁷⁷Lu]Lu-DOTA-AE105, the radiopeptides showed the anticipated increased binding affinity to plasma proteins both in mouse (31- to 104-fold) and human blood plasma (43- to 136-fold). The tissue distribution of the novel radiopeptides in nude mice bearing HEK-uPAR xenografts showed substantial activity retention in the blood (12-16% IA/g and 4.5-13% IA/g at 4 and 24 h p.i., respectively), while [¹⁷⁷Lu]Lu-DOTA-AE105 was rapidly cleared (<0.1% IA/g at 4 h p.i.). As a result, the accumulation of the new radiopeptides in HEK-uPAR xenografts (3.6-11% and 3.1-10% IA/g at 4 and 24 h p.i., respectively) was increased in comparison to that of [¹⁷⁷Lu]Lu-DOTA-AE105 (<1% IA/g at 4 h p.i.). Importantly, the metabolic stability of the new radiopeptides in mice was enhanced as compared to that of [¹⁷⁷Lu]Lu-DOTA-AE105. [¹⁷⁷Lu]Lu-uPAR-02 showed the most promising tissue distribution profile with over 10-fold higher activity retention in the HEK-uPAR xenograft than observed after injection of [¹⁷⁷Lu]Lu-DOTA-AE105. As a result, the xenograft-to-kidney ratio of [¹⁷⁷Lu]Lu-uPAR-02 was >3-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-AE105.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3242-3254"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951572","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 Pathogen-Mimicking Monkeypox Virus Nanovaccine Inspired by Assembly of Viral Antigens with β-Glucan and Dendrimer.","authors":"Lucheng Xiao, Lijia Hu, Xiaofan Zhao, Lijuan Shen, Weili Yu, Yilong Yang, Jinming Qi, Tao Hu","doi":"10.1021/acs.molpharmaceut.4c01535","DOIUrl":"10.1021/acs.molpharmaceut.4c01535","url":null,"abstract":"<p><p>Monkeypox (mpox) is a zoonotic viral disease transmitted by the monkeypox virus (MPXV). Viral protein-based nanovaccines hold promise in preventing the infection of MPXV. MPXV-derived antigens (A29L, A35R, and M1R) were capable of eliciting protective immunity and suffered from low immunogenicity. Adjuvants and delivery systems were critical to improving the immunogenicity of antigens. In this study, a pathogen-mimicking nanovaccine was developed by conjugation of poly(amidoamine) (PAMAM) dendrimers with deoxycholic acid to form cationic nanoparticles as a delivery platform. The three antigens were individually conjugated with carboxylated β-glucan, a polysaccharide adjuvant, and subsequently self-assembled onto dendrimer nanoparticles via electrostatic interactions. The resulting nanovaccine induced robust antigen-specific antibody production, stimulated splenic levels of Th1- and Th2-type cytokines, and enhanced secretion of IFN-γ and IL-4 by CD4⁺ and CD8⁺ T cells. Additionally, it promoted the maturation of dendritic cells, activated T and B cells, and enhanced cytotoxic T cell activity. Notably, the vaccine stimulated the formation of B and T memory cells, providing long-term immune protection. Crucially, the vaccine conferred cross-protection against the lethal ectromelia virus (ECTV) challenge in mice while exhibiting no significant organ toxicity. These findings suggest that the vaccine is a promising candidate to deal with life-threatening mpox infections.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3033-3044"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952949","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":"Molar Ratio-Dependent Crystallization in Coamorphous Celecoxib-Carbamazepine Systems: The Interplay of Thermodynamics and Kinetics.","authors":"Minqian Luo, An Chen, Shiyu Shan, Minshan Guo, Ting Cai","doi":"10.1021/acs.molpharmaceut.5c00278","DOIUrl":"10.1021/acs.molpharmaceut.5c00278","url":null,"abstract":"<p><p>Coamorphous drug delivery systems have emerged as a promising formulation strategy to enhance the solubility, oral bioavailability, and physical stability of poorly water-soluble drugs. The molar ratio of components in coamorphous systems plays a critical role in determining their physical stability. In this study, we investigated the crystallization behavior of coamorphous celecoxib-carbamazepine (CEL-CBZ) systems at different molar ratios. The growth rates of CEL crystals, CBZ crystals, and CEL-CBZ cocrystals were observed to exhibit distinct dependencies on the molar ratio of coamorphous systems, primarily due to their unique thermodynamic driving forces, despite sharing the same kinetic factor. The influence of the molar ratio on the crystallization of coamorphous systems arises from the interplay between its effects on molecular mobility and thermodynamic driving forces, leading to either cooperative or competing effects. Both the crystal growth and crystallization tendency results reveal that thermodynamics plays a more dominant role than kinetics in the crystallization of coamorphous CEL-CBZ systems across various molar ratios. This study provides fundamental insights into the mechanism by which the molar ratio influences the crystallization of coamorphous systems, highlighting the complex crystallization behavior of multicomponent amorphous systems as an interplay between kinetics and thermodynamics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3401-3413"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953318","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":"Synthesis and Biological Evaluation of ¹³¹I-Risedronate with Bone Targeting Activity.","authors":"Zehui Lin, Wangxi Hai, Pengfei Pan, Jin-Hong Lin, Biao Li, Ji-Chang Xiao","doi":"10.1021/acs.molpharmaceut.5c00300","DOIUrl":"10.1021/acs.molpharmaceut.5c00300","url":null,"abstract":"<p><p>Current radiopharmaceuticals for treating bone metastatic tumors have various limitations. We focus on developing a universal, economical, efficient, and safe novel radiopharmaceutical for bone metastasis treatment. ¹³¹I is a well-established medical radionuclide commonly used for both treatment and diagnosis. Risedronate exhibits strong bone-targeting properties with moderate bone retention. This study explored the combination of these two components and evaluated its biological properties in animal experiments. Based on the experimental results, ¹³¹I-risedronate demonstrated high bone-targeting efficiency, low uptake in nontarget organs, and rapid clearance. Notably, at 3 days postadministration, significant bone retention was observed, indicating its potential for sustained therapeutic effects. Additionally, its biodistribution and therapeutic effect can be effectively monitored by SPECT/CT imaging.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3508-3514"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956131","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":"Neuroprotective Riluzole-Releasing Electrospun Implants for Spinal Cord Injury.","authors":"Mathilde M Ullrich, Bhavana Pulipaka, Jing Yin, Jana Hlinková, Fangyuan Zhang, Michael W Chan, Fergal J O'Brien, Adrian Dervan, Karolina Dziemidowicz","doi":"10.1021/acs.molpharmaceut.4c01270","DOIUrl":"10.1021/acs.molpharmaceut.4c01270","url":null,"abstract":"<p><p>Spinal cord injury (SCI) results in paralysis, driven partly by widespread glutamate-induced secondary excitotoxic neuronal cell death in and around the injury site. While there is no curative treatment, the standard of care often requires interventive decompression surgery and repair of the damaged dura mater close to the injury locus using dural substitutes. Such intervention provides an opportunity for early and local delivery of therapeutics directly to the injured cord via a drug-loaded synthetic dural substitute for localized pharmacological therapy. Riluzole, a glutamate-release inhibitor, has shown neuroprotective potential in patients with traumatic SCI, and therefore, this study aimed to develop an electrospun riluzole-loaded synthetic dural substitute patch suitable for the treatment of glutamate-induced injury in neurons. A glutamate-induced excitotoxicity was optimized in SH-SY5Y cells by exploring the effect of glutamate concentration and exposure duration. The most effective timing for administering riluzole was found to be at the onset of glutamate release as this helped to limit extended periods of glutamate-induced excitotoxic cell death. Riluzole-loaded patches were prepared by using blend electrospinning. Physicochemical characterization of the patches showed the successful encapsulation of riluzole within polycaprolactone fibers. A drug release study showed an initial burst release of riluzole within the first 24 h, followed by a sustained release of the drug over 52 days to up to approximately 400 μg released for the highest loading of riluzole within fiber patches. Finally, riluzole eluted from electrospun fibers remained pharmacologically active and was capable of counteracting glutamate-induced excitotoxicity in SH-SY5Y cells, suggesting the clinical potential of riluzole-loaded dural substitutes in counteracting the effects of secondary injury in the injured spinal cord.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2905-2916"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074851","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":"Self-Assembled Peptide PROTAC Prodrugs Targeting FOXM1 for Cancer Therapy.","authors":"Huajie Zeng, Zhiguo Fang, Yinghua Feng, Tong Su, Weibing Miao, Zihua Wang","doi":"10.1021/acs.molpharmaceut.5c00219","DOIUrl":"10.1021/acs.molpharmaceut.5c00219","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) represent a promising strategy for addressing ″undruggable″ proteins in cancer therapy. However, challenges such as poor bioavailability, limited cellular permeability, and inadequate targeting hinder their effectiveness. Herein, we present a novel PROTAC prodrug, NFTP, designed for FOXM1 degradation, which leverages self-assembled peptides functionalized with an integrin α-6 ligand to enhance tumor targeting and proteolysis in vivo. NFTP effectively penetrates tumor cells, induces FOXM1 degradation, inhibits cancer cell survival and migration, and promotes apoptosis in vitro. In a 4T1 mouse xenograft model, NFTP demonstrated efficient FOXM1-targeted degradation, significant tumor growth inhibition, and low systemic toxicity. This self-assembling FOXM1 PROTAC platform demonstrates enhanced tumor-targeting precision and superior therapeutic performance in vivo, representing a promising paradigm shift in targeted cancer therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3286-3296"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074853","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":"Correction to \"Biological Fate Tracking of Nitric Oxide-Propelled Microneedle Delivery System Using an Aggregation-Caused Quenching Probe\".","authors":"Ziyao Chang, Yuhuan Wu, Yangyan Chen, Xuequn Bai, Tingting Peng, Chuanbin Wu, Xin Pan, Zhengwei Huang","doi":"10.1021/acs.molpharmaceut.5c00600","DOIUrl":"10.1021/acs.molpharmaceut.5c00600","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3516-3517"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074901","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":"Long-Acting Human PASylated Leptin Reaches the Murine Central Nervous System and Offers Potential for Optimized Replacement Therapy.","authors":"Volker Morath, Stefanie Maurer, Annette Feuchtinger, Rebecca Walser, Martin Schlapschy, Florian Bolze, Thomas Metzler, Johanna Bruder, Katja Steiger, Axel Walch, Martin Klingenspor, Arne Skerra","doi":"10.1021/acs.molpharmaceut.4c01503","DOIUrl":"10.1021/acs.molpharmaceut.4c01503","url":null,"abstract":"<p><p>Despite the multifaceted role of leptin for energy homeostasis and its broad therapeutic potential, the FDA/EMA-approved metreleptin constitutes the only leptin drug to date. To translate the promising results from previous studies on murine PASylated leptin with improved solubility and extended plasma half-life using PASylation technology─a biological alternative to PEGylation─we have developed a second-generation human leptin drug candidate and tested it rigorously <i>in vitro</i> and <i>in vivo</i>. To this end, the exposed hydrophobic Trp residue at position 100 in human leptin was replaced by Gln, which, together with the genetic fusion with a 600-residue PAS polypeptide, yielded a protein with high solubility, folding stability and receptor-stimulatory activity. In a pharmacokinetic (PK) study with wild-type mice, this modified human leptin showed an extended plasma half-life of 18.8 ± 3.6 h after subcutaneous (s.c.) injection. Furthermore, leptin-deficient mice were dosed s.c. with the modified human leptin carrying two different PAS fusion tags, PAS#1 or P/A#1, each comprising 600 residues. After only four doses, the disease phenotype, including morbid adiposity, hyperphagia, and hepatic steatosis, was completely reversed by both PASylated leptin versions, but not by the non-PASylated leptin if administered at the same dose. To assess its tissue distribution, P/A(200)-huLeptin^W100Q was doubly labeled with two fluorescent dyes, which were specifically attached to the leptin and the PAS moiety, respectively. Analysis of relevant mouse organs by light sheet fluorescence microscopy after clearance revealed colocalized signals in the kidney and liver, thus indicating general stability of the PAS-leptin fusion protein <i>in vivo</i>. However, discrete signals were observed in the hypothalamic region, only with leptin detectable in the choroid plexus, which implies cleavage of the PAS tag during transcytosis across the physiological barriers. This study should pave the way toward a second-generation leptin drug enabling prolonged dosing intervals.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"3017-3032"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951448","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 a ⁶⁸Ga-Labeled Single-Domain Antibody for Detecting Tumor TIGIT Expression.","authors":"Dinghu Weng, Rong Guo, Yu Gao, Shasha Xu, Yingying Li, Jun Zhou, Rui An, Haibo Xu","doi":"10.1021/acs.molpharmaceut.4c00900","DOIUrl":"10.1021/acs.molpharmaceut.4c00900","url":null,"abstract":"<p><p>Preclinical studies have shown that the expression of T cell immunoglobulin and the immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) in the tumor microenvironment is associated with the efficacy of anti-TIGIT-based immunotherapy. This study aimed to develop a TIGIT single-domain antibody (sdAb)-based positron emission tomography (PET) radiotracer, [⁶⁸Ga]Ga-NOTA-NABT3A1, and evaluate its characteristics. The NABT3A1 was modified with a NOTA derivative and radiolabeled with ⁶⁸Ga. In vitro stability of [⁶⁸Ga]Ga-NOTA-NABT3A1 was assessed in phosphate-buffered saline (PBS) and fetal bovine serum (FBS), along with its specificity for TIGIT stably transfected A375 Human melanoma cells (A375-TIGIT) was performed. In vivo imaging was conducted on A375-TIGIT tumor-bearing nude mice at different time points after the injection of [⁶⁸Ga]Ga-NOTA-NABT3A1. The synthesized [⁶⁸Ga]Ga-NOTA-NABT3A1 achieved a radiochemical yield of 70.56 ± 1.14% and purity levels of 95.80 ± 0.58% in PBS and 96.79 ± 1.69% in FBS at 2 h. Immuno-PET imaging revealed specific accumulation of [⁶⁸Ga]Ga-NOTA-NABT3A1 in A375-TIGIT tumor-bearing nude mice, with a maximum uptake of 3.86 ± 0.29% injected dose/g at 0.5 h. Biodistribution and immunohistochemical analyses confirmed the in vivo imaging results. In conclusion, we successfully synthesized an NABT3A1-derived PET radiotracer with the potential to noninvasively assess TIGIT expression in tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2849-2857"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951465","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}