Drug Delivery and Translational Research最新文献

{"title":"Low-intensity pulsed ultrasound enhances delivery of 30 nm Q10 for improving mental and memory disorder in APP/PS1 mice.","authors":"Qi Luo, Xuanjie Ye, Jinan Xu, Zihui Sun, Panpan Wang, Haishu Chen, Tingting Gao, Qiangfeng Deng, Ziwen Wang, Qin Wang, Xiaoxiao Chen, Zhuowen Zhao, Yiqing Wu, Chuang Yang, Wanjia Lyv, Xingzhou Lyv, Ye Li, Hang Zhao, Ke Jiang, Ziqi Gu, Jing Lin, Yu Sun, Tao Tan, Haiyun Xu, Zhiqian Tong","doi":"10.1007/s13346-025-01814-y","DOIUrl":"10.1007/s13346-025-01814-y","url":null,"abstract":"<p><p>Patients with Alzheimer's disease (AD) often experience mental and memory disorders with poor outcomes. Coenzyme Q10 can degrade formaldehyde (FA) and improve Alzheimer-related symptoms, but its ability to cross the blood-brain barrier (BBB) is limited. This study investigated whether low-intensity pulsed ultrasound (LIPUS) enhances 30 nm Q10 delivery and improve symptoms in AD model mice. Here, 30 nm Q10 was prepared by encapsulating Q10 in liposomes coupled with PEG, creating PEG-Q10@NPs under 30 nm in diameter. Wild-type mice and APPswe/PS1dE9 mice (a familial AD model) received 30 nm Q10 via intraperitoneal injection, or a combination of 30 nm Q10 and LIPUS (50 or 100 100 mW/cm²). Then the mice's anxiety-like and depression-like behaviors and biochemical index were evaluated. We found that the combination therapy of LIPUS at 100 mW/cm² and 30 nm Q10 was more effective in ameliorating psychosis in AD mice than individual treatments with 30 nm Q10. This effectiveness was linked to higher levels of brain Q10, serotonin (5-HT), and dopamine (DA), along with lower levels of FA and plaques. Especially, excessive FA directly inactivated 5-HT and DA in vitro. The enhanced cellular uptake of Q10 and improved BBB permeability facilitated by LIPUS were confirmed in both cultured cells and wild-type mice. Unexpectedly, LIPUS at the different intensity only partially alleviated anxiety and depression symptoms and memory deficits in AD mice. Hence, this combination therapy of LIPUS and 30 nm Q10 is an innovative strategy for ameliorating mental and cognitive disorders in AD.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3497-3516"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced localized pressure-mediated non-viral gene delivery.","authors":"James E Dixon, Vanessa Wellington, Alaa Elnima, Amelie Savers, Lia A Blokpoel Ferreras, Aveen R Jalal, Hoda M Eltaher","doi":"10.1007/s13346-025-01827-7","DOIUrl":"10.1007/s13346-025-01827-7","url":null,"abstract":"<p><p>Topically applied therapies must not only be effective at the molecular level but also efficiently access the target site which can be on milli/centimetre-scales. This bottleneck is particularly inhibitory for peptide and nucleic acid macromolecule drug delivery strategies, especially when aiming to target wounded, infected, and poorly perfused tissues of significant volume and geometry. Methods to drive fluid-flow or to enhance physical distribution of such formulations after local administration in accessible tissues (skin, eye, intestine) would be transformative in realizing the potential of such therapeutics. We previously developed a technology termed Glycosaminoglycan (GAG)-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding peptides and cell penetrating peptides (CPPs) in the form of nanoparticles. Herein, we demonstrate that the most simplistic GET formulation is relatively poor in diffusing into tissue matrix (tested in collagen scaffolds). Changing nanoparticle physicochemical properties can enhance penetration, however the use of a pressure differential, generating fluid-flow significantly enhances effective gene delivery over milli/centimetre scales. We adapted clinically used pressure systems to administer both negative (Negative pressure (NP) wound therapy; NPWT) and positive pressures (PP; Insufflator). Pressure differences generated enhanced distribution, and we were able to show for the first-time localized gene transfer in vitro in cell scaffolds and enhanced transfection of ex vivo skin explants. The ability to simply control intra-tissue localization of gene delivery on milli/centimetre scales using pressure application will facilitate new drug delivery strategies for accessible tissues. Importantly site-specific enhancement of penetration and activity of novel nanotechnologies and gene therapeutics could be transformative for future regenerative medicine strategies.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3679-3694"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local delivery of an adenosine receptor agonist reduces inflammation associated with contact hypersensitivity.","authors":"Elizabeth R Bentley, Stacia Subick, Jake Doran, Julie Kobyra, Stephen C Balmert, Steven R Little","doi":"10.1007/s13346-025-01831-x","DOIUrl":"10.1007/s13346-025-01831-x","url":null,"abstract":"<p><p>Allergic contact dermatitis (ACD), a T-cell mediated inflammatory skin condition, is prompted by multiple, subsequent exposures to contact allergens (e.g., nickel). Current treatment approaches for ACD include repeated topical application or systemic delivery of immunosuppressants. These treatment strategies have many limitations, including non-specific mechanism of actions and the occurrence of side effects due to their delivery method. For this reason, we developed a novel therapeutic approach that is based upon adenosine (Ado) receptor signaling, a known anti-inflammatory pathway. Specifically, we developed a polymer microparticle-based controlled release system capable of presenting IBMECA (IBMECA-MPs), an Ado receptor agonist, to the local environment. In this study, we first sought to study the immunosuppressive effects of IBMECA on immune cells implicated in the pathogenesis of ACD (e.g., dendritic cells) in vitro. Subsequently, we examined the effects of enhancing adenosine signaling in contact hypersensitivity (CHS), an in vivo model of ACD, through local administration of IBMECA-MPs. We observed that IBMECA-MPs were capable of reducing the inflammatory response associated with CHS by reducing maturation markers of antigen-presenting cells, altering cytokine secretion, and reducing relative frequencies of effector T cell populations. To our knowledge, this is the first demonstration of therapeutic efficacy of IBMECA in CHS, as well as the first proof-of-principle demonstration of IBMECA application in the context of a local drug delivery system. Ultimately, this delivery system has the potential to be adapted for use in other T-cell mediated inflammatory conditions (e.g., transplant rejection), suggesting broader implications of this study.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3737-3752"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in vivo assessment of diosmetin-loaded lactoferrin-modified liposomes for brain delivery in intracerebral hemorrhage therapy.","authors":"Yingjiang Gu, Hanyue Luo, Jun Zhu, Hao Ma, Yang Zhang, Jinshan Xing, Yuzhou Liu, Yu Cai, Wenxia Sun, Pei Luo","doi":"10.1007/s13346-025-01826-8","DOIUrl":"10.1007/s13346-025-01826-8","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high morbidity, mortality, and disability rates, largely due to neuroinflammation. Diosmetin, a natural flavonoid, has known neuroprotective effects in cerebral ischemia/reperfusion models but has been less studied in ICH. Our previous study developed diosmetin-loaded lactoferrin-modified long-circulating liposomes (Lf-Dios-Lcl), which penetrate the BBB and improve diosmetin bioavailability and brain distribution. In this study, we found that diosmetin reduced the levels of proinflammatory cytokines (IL-1β and TNF-α) and increased the level of the anti-inflammatory cytokine IL-10 in LPS-induced BV2 cells, promoting microglial polarization toward the anti-inflammatory M2 phenotype. In ICH model rats, Lf-Dios-Lcl (1 mg/kg) effectively reduced neuroinflammation, decreased IL-1β and TNF-α levels, increased IL-10 levels, and increased the proportion of CD206-positive microglia in brain tissues. Moreover, Lf-Dios-Lcl significantly downregulated p-p38 expression, suggesting that p38 signaling activation was inhibited. Overall, Lf-Dios-Lcl demonstrated brain-targeting properties and antineuroinflammatory effects by modulating microglial polarization via the p38 pathway.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3664-3678"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: Inhaled biologics for respiratory diseases: clinical potential and emerging technologies.","authors":"Nur Adania Shaibie, Nur Dini Fatini Mohammad Faizal, Fhataheya Buang, Teerapol Srichana, Mohd Cairul Iqbal Mohd Amin","doi":"10.1007/s13346-025-01985-8","DOIUrl":"https://doi.org/10.1007/s13346-025-01985-8","url":null,"abstract":"","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinically translatable anti-fibrotic nanosuspension for inhaled treatment of idiopathic pulmonary fibrosis.","authors":"Daiheon Lee, Byoungjae Kong, Gijung Kwak, Bokyung Kang, Carter Swaby, Rachel Fanaroff, Venkataramana Sidhaye, Jung Soo Suk","doi":"10.1007/s13346-025-01973-y","DOIUrl":"https://doi.org/10.1007/s13346-025-01973-y","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic pulmonary fibrosis, irreversible lung function decline, and high mortality rate. Oral nintedanib (NTB) is one of the rare anti-fibrotic drugs clinically available for managing the condition but suffers from poor bioavailability and lung delivery efficiency as well as numerous off-target adverse effects. To address these critical limitations, we developed a nanosuspension (NS) formulation of NTB (NTB-NS) for inhaled treatment of IPF. The formulation is composed entirely of FDA-approved materials, including NTB and polysorbate 80, a surfactant approved for respiratory use in a clinic, and can be freeze-dried to a powder form for long-term storage and remote shipping without perturbing the physicochemical properties and drug activity. NTB-NS locally administered via oropharyngeal administration exhibited favorable pharmacokinetics over the standard oral administration of nintedanib esylate (NTB-esy), resulting in comprehensive anti-inflammatory and anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrosis. Notably, locally administered NTB-NS, but not oral NTB-esy, normalized several key lung function parameters in the model despite the use of 60-fold and 3-fold lower dose and dosing frequency, respectively. The findings here may open a new avenue for the treatment of IPF and potentially other fibrotic lung diseases in the clinic.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Dual phage-incorporated electrospun polyvinyl alcohol-eudragit nanofiber matrix for rapid healing of diabetic wound infected by Pseudomonas aeruginosa and Staphylococcus aureus.","authors":"Kokkarambath Vannadil Suchithra, Asif Hameed, Suprith Surya, Sajida Mahammad, Ananthapadmanabha Bhagwath Arun","doi":"10.1007/s13346-025-01979-6","DOIUrl":"https://doi.org/10.1007/s13346-025-01979-6","url":null,"abstract":"","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vacuum compression-molded polyvinyl alcohol microneedles for sustained three-day transdermal delivery of palonosetron hydrochloride.","authors":"Meheli Ghosh, Sharvari M Kshirsagar, Thomas Kipping, Ajay K Banga","doi":"10.1007/s13346-025-01980-z","DOIUrl":"https://doi.org/10.1007/s13346-025-01980-z","url":null,"abstract":"<p><p>This study introduces vacuum compression molding (VCM) as a novel, solvent-free method for fabricating palonosetron hydrochloride (PAL HCl)-loaded polyvinyl alcohol (PVA) microneedles (MNs), addressing limitations of conventional micromolding such as extended drying times, batch variability, and solvent residues. PAL HCl-a hydrophilic 5-HT3 receptor antagonist (MW: 332.85 g/mol) with a low therapeutic dose-was selected for its clinical relevance in managing chemotherapy-induced nausea and vomiting (CINV). The microneedle platform offers advantages over PAL HCl's existing oral and injectable dosage forms, including pain-free application and improved patient compliance. The aim of this research is to develop and evaluate a scalable VCM-based fabrication approach for PAL HCl-loaded PVA microneedles, with the goal of achieving sustained, three-day in vitro transdermal drug delivery for improved CINV management. Ten PVA grades (varying in molecular weight and viscosity) were screened to optimize microneedle fabrication. Three formulations-M1 (particle-engineered PVA 4-88), M4 (PVA 5-88), and M5 (PVA 8-88)-demonstrated optimal mechanical strength, uniform geometry (SEM imaging), and reliable skin penetration (~ 200 μm depth in dermatomed human skin). Physicochemical characterization (FTIR, DSC) confirmed the amorphous state of PAL HCl within the PVA matrix and the absence of chemical interactions. In vitro release testing revealed biphasic profiles: an initial burst release for 8 h followed by sustained release over 72 h. Cumulative release inversely correlated with PVA molecular weight and viscosity, with M1 achieving 100% release, compared to M4 (74%) and M5 (67%). Permeation studies demonstrated M1's superior performance (257.56 ± 29.73 µg/sq cm), exceeding passive diffusion by 8.8-fold and significantly outperforming M4 (64.99 ± 30.23 µg/ sq cm) and M5 (39.03 ± 20.20 µg/sq cm). These results validate VCM as a scalable, tunable platform for fabricating PAL HCl-drug-loaded microneedles, offering sustained transdermal delivery with clinical potential for CINV management.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An effort to enhance the clinical translatability of caprate-based tablet formulations in gastric peptide delivery.","authors":"Pierre-Louis Bardonnet, Zhigao Niu, Jenni Pessi, Maria Kazakou, Konstantinos Raptis, Reece McCabe, Anders Toftlev, René Rebollo, Zhuoran Wang, Li Fan, Nicolai Rytter Mortensen, Lars Bardtrum, Vincent Andersson, Per-Olof Wahlund, Mathias Norrman, Andrew James Benie, Jian Xiong Wu, Max Sauter, Damiano La Zara, Philip Christophersen, Philip Jonas Sassene","doi":"10.1007/s13346-025-01978-7","DOIUrl":"https://doi.org/10.1007/s13346-025-01978-7","url":null,"abstract":"<p><p>Sodium caprate (C10) is the most investigated permeation enhancer to promote oral peptide absorption. However, the clinical translation of C10-based formulations is possibly affected by low gastric pH. Here, we developed a C10-based immediate-release tablet containing meglumine as a pH modifier to mitigate stomach acidity and evaluated it both in dogs and clinically. To mitigate the difference in gastric pH between species, the C10-based formulations were evaluated in acid pre-treated dogs. The exposure was compared to results with sodium salcaprozate (SNAC)-based tablets previously tested in clinical trials. The benefit of meglumine in improving gastric peptide absorption in dogs was demonstrated for several peptide modalities. Ultimately, an oral PCSK9 inhibitor was chosen for test clinical trials. The lead formulation containing 40 mg of PCSK9 inhibitor, 200 mg of C10, 60 mg of meglumine and 60 mg of sorbitol showed a 57% increase in exposure compared to the benchmark SNAC formulation in animal studies 0.5 h post dosing. However, this benefit was not observed in humans to the same extent, where the C10-based formulations provided similar bioavailability to the SNAC-based formulation. Other factors than pH which are likely to influence the relative performance of C10- and SNAC-based formulations are also discussed in this article.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioavailability enhancement and neuropharmacological effects of Dauricine under intranasal administration to improve cognitive impairment via PI3K/AKT/mTOR pathway.","authors":"Ruiye Xie, Zhen Liu, Jingjing Zheng, Qiwen Tan, Haitao Wu, Yong Liang","doi":"10.1007/s13346-025-01975-w","DOIUrl":"https://doi.org/10.1007/s13346-025-01975-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder strongly associated with aging, and Dauricine (DAU) has demonstrated significant neuropharmacological properties for AD treatment. However, its bioavailability is significantly limited when administered orally, leaving the mechanisms underlying its effects on AD largely unexplored. In this study, a DAU-loaded thermosensitive gel was formulated for delivery via the nasal-nerve route, and its potential to enhance the bioavailability of DAU in rat plasma and cerebrospinal fluid (CSF) was assessed through a pharmacokinetic study. The anti-Alzheimer's disease (AD) mechanism of DAU was investigated using network pharmacology approaches, molecular docking, and dynamics simulations, complemented by in vivo experimental validation. DAU can be effectively incorporated into a thermosensitive gel and administered to the brain within 30 min via intranasal delivery. Following nasal administration, the pharmacokinetic parameters of DAU in cerebrospinal fluid and plasma were significantly elevated compared to oral administration (^**P < 0.01), indicating a substantial improvement in bioavailability at equivalent doses. Behavioral studies demonstrated that DAU (dose of 1 mg/kg and 2 mg/kg in gel) enhanced cognitive function in intracerebroventricular-streptozotocin (ICV-STZ) rats and decelerated aging processes by reversing oxidative stress and mitigating neuronal apoptosis. Additionally, DAU contributed to lowering blood glucose levels, increasing insulin-like growth factor 1 (IGF-1) content, and reducing insulin resistance. Network pharmacological analysis, molecular docking, molecular dynamics simulations, and in vivo experiments collectively suggested that DAU exerted significant therapeutic effects on Alzheimer's disease by inhibiting the PI3K/AKT/mTOR pathway. Our study demonstrates a significant enhancement in the bioavailability of DAU in the brain via nasal-nerve delivery route and also this research is the first to report that DAU ameliorates cognitive impairment in ICV-STZ rats through the PI3K/AKT/mTOR pathway. Our findings contribute to the scientific understanding of DAU's potential in Alzheimer's disease treatment and offer a novel experimental foundation for the development of anti-Alzheimer's drugs.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}