Frontiers in drug delivery最新文献

{"title":"Multiscale physics-based in silico modelling of nanocarrier-assisted intravascular drug delivery","authors":"Nicolae-Viorel Buchete, Iwona Cicha, Sutapa Dutta, Panagiotis Neofytou","doi":"10.3389/fddev.2024.1362660","DOIUrl":"https://doi.org/10.3389/fddev.2024.1362660","url":null,"abstract":"A rational design of drug nanocarriers supported by in silico modelling tools can improve the efficacy of nanosystem-based intravascular drug delivery (IVDD). Computational model development stems from the vision of replacing conventional (pre)clinical trials with advanced simulations and applies to the development of more efficient nanocarriers for intravascular therapies. To establish a standardized framework for in silico preclinical trials, it is necessary to include in silico tools that can model each experimental stage of a preclinical trial for a respective nanocarrier system and give accurate and verifiable results. This review paper highlights the status of intravascular drug delivery supported by nanocarriers and discusses the modelling stages of a physics-based multiscale modelling framework that should be developed, validated and exploited to address the need for an effective preclinical assessment of nanocarriers for IVDD.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140266885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Choice of adjuvant and antigen composition alters the immunogenic profile of a SARS-CoV-2 subunit vaccine","authors":"William R. Lykins, J. Pollet, Jessica A. White, B. Keegan, Leroy Versteeg, U. Strych, Wen-Hsiang Chen, R. Mohamath, Gabi Ramer-Denisoff, Sierra Reed, Sam Beaver, Alana Gerhardt, Emily A. Voigt, M. Tomai, Robert Sitrin, Robert K. M. Choy, Frederick J. Cassels, P. Hotez, M. Bottazzi, Christopher B. Fox","doi":"10.3389/fddev.2024.1342518","DOIUrl":"https://doi.org/10.3389/fddev.2024.1342518","url":null,"abstract":"Introduction: Since their introduction, adjuvanted recombinant subunit vaccines against COVID-19 have played a pivotal role in protecting global populations. Optimizing the immune response’s quality, amplitude, and durability to these vaccines depends on the appropriate adjuvant choice and dose in combination with the selected antigen.Methods: Here, we employed a preclinical mouse model to study the adaptive humoral and cellular immune responses to a SARS-CoV-2 receptor binding domain (RBD) antigen formulated with one of four different immune agonists [GLA, 3M-052, CpG-1826 (CpG), and dmLT], in combination with one of two different immune-stimulating formulations, a stabilized squalene emulsion (SE) or aluminum hydroxide (Alum). Using a weighted desirability index, we established an immunogenicity ranking for each adjuvant in combination with the RBD antigen.Results: We found that formulations of the RBD with Alum in combination with either 3M-052 or CpG led to at least a 2-log increase in serum IgG production and a 1.3- to 2.2-log increase in the number of bone marrow-derived antibody-secreting cells compared to the RBD formulated with Alum without an additional agonist. In contrast, the RBD formulated with SE in combination with 3M-052 or CpG did not elicit an IgG response greater than the unadjuvanted control. Additionally, RBD formulated with 3M-052 or CpG on Alum generated a 0.8- or 1.6-log lower splenocyte IL-5 response (a pro-Th2 marker), respectively, than Alum without an additional agonist. When formulated with 3M-052-Alum, a bivalent vaccine containing the original lineage (Wuhan-Hu-1) and the Delta variant (B.1.617.2) RBD antigens led to a more than 2-log increase in neutralizing antibodies against an Omicron variant (B.1.1.529) pseudovirus in vaccinated animals compared to animals that received the monovalent RBD antigen.Discussion: Our results suggest that optimal immune responses to subunit antigens may be achieved through an orthogonal approach that applies adjuvant formulation, antigen combination, and advances in rational vaccine development techniques.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139795152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Choice of adjuvant and antigen composition alters the immunogenic profile of a SARS-CoV-2 subunit vaccine","authors":"William R. Lykins, J. Pollet, Jessica A. White, B. Keegan, Leroy Versteeg, U. Strych, Wen-Hsiang Chen, R. Mohamath, Gabi Ramer-Denisoff, Sierra Reed, Sam Beaver, Alana Gerhardt, Emily A. Voigt, M. Tomai, Robert Sitrin, Robert K. M. Choy, Frederick J. Cassels, P. Hotez, M. Bottazzi, Christopher B. Fox","doi":"10.3389/fddev.2024.1342518","DOIUrl":"https://doi.org/10.3389/fddev.2024.1342518","url":null,"abstract":"Introduction: Since their introduction, adjuvanted recombinant subunit vaccines against COVID-19 have played a pivotal role in protecting global populations. Optimizing the immune response’s quality, amplitude, and durability to these vaccines depends on the appropriate adjuvant choice and dose in combination with the selected antigen.Methods: Here, we employed a preclinical mouse model to study the adaptive humoral and cellular immune responses to a SARS-CoV-2 receptor binding domain (RBD) antigen formulated with one of four different immune agonists [GLA, 3M-052, CpG-1826 (CpG), and dmLT], in combination with one of two different immune-stimulating formulations, a stabilized squalene emulsion (SE) or aluminum hydroxide (Alum). Using a weighted desirability index, we established an immunogenicity ranking for each adjuvant in combination with the RBD antigen.Results: We found that formulations of the RBD with Alum in combination with either 3M-052 or CpG led to at least a 2-log increase in serum IgG production and a 1.3- to 2.2-log increase in the number of bone marrow-derived antibody-secreting cells compared to the RBD formulated with Alum without an additional agonist. In contrast, the RBD formulated with SE in combination with 3M-052 or CpG did not elicit an IgG response greater than the unadjuvanted control. Additionally, RBD formulated with 3M-052 or CpG on Alum generated a 0.8- or 1.6-log lower splenocyte IL-5 response (a pro-Th2 marker), respectively, than Alum without an additional agonist. When formulated with 3M-052-Alum, a bivalent vaccine containing the original lineage (Wuhan-Hu-1) and the Delta variant (B.1.617.2) RBD antigens led to a more than 2-log increase in neutralizing antibodies against an Omicron variant (B.1.1.529) pseudovirus in vaccinated animals compared to animals that received the monovalent RBD antigen.Discussion: Our results suggest that optimal immune responses to subunit antigens may be achieved through an orthogonal approach that applies adjuvant formulation, antigen combination, and advances in rational vaccine development techniques.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139854998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Future theranostic strategies: emerging ovarian cancer biomarkers to bridge the gap between diagnosis and treatment","authors":"Weranga Rajapaksha, Riya Khetan, Ian R. D. Johnson, Anton Blencowe, Sanjay Garg, Hugo Albrecht, T. Gillam","doi":"10.3389/fddev.2024.1339936","DOIUrl":"https://doi.org/10.3389/fddev.2024.1339936","url":null,"abstract":"Ovarian cancers are a complex and heterogenic group of malignancies that are difficult to detect, diagnose and treat. Fortunately, considerable knowledge of ovarian cancer specific biomarkers has been generated, that is pertinent to the development of novel theranostic platforms by combining therapies and diagnostics. Genomic and proteomic data has been invaluable in providing critical biomolecular targets for ovarian cancer theranostic approaches. Exploitation of the wealth of biomarker research that has been conducted offers viable targets as beacons for ovarian cancer detection, diagnosis, and therapeutic targeting. These markers can be used in theranostics, a treatment strategy that combines therapy and diagnostics and is common in nuclear medicine, where radionuclides are used for both diagnosis and treatment. The development of theranostics has taken substantial focus in recent years in the battle against ovarian cancer. Yet to date only one theranostic technology has emerged in clinical practice. However, given the wealth of ovarian cancer biomarkers the field is poised to see the emergence of revolutionary disease treatment and monitoring outcomes through their incorporation into the development of theranostic strategies. The future of ovarian cancer treatment is set to enable precise diagnosis, targeted treatment, and vigilant monitoring. This review aims to assess the status of ovarian cancer diagnostic tools and biomarkers in practice, clinical development, or pre-clinical development, highlighting newly emerging theranostic applications.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139819786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Future theranostic strategies: emerging ovarian cancer biomarkers to bridge the gap between diagnosis and treatment","authors":"Weranga Rajapaksha, Riya Khetan, Ian R. D. Johnson, Anton Blencowe, Sanjay Garg, Hugo Albrecht, T. Gillam","doi":"10.3389/fddev.2024.1339936","DOIUrl":"https://doi.org/10.3389/fddev.2024.1339936","url":null,"abstract":"Ovarian cancers are a complex and heterogenic group of malignancies that are difficult to detect, diagnose and treat. Fortunately, considerable knowledge of ovarian cancer specific biomarkers has been generated, that is pertinent to the development of novel theranostic platforms by combining therapies and diagnostics. Genomic and proteomic data has been invaluable in providing critical biomolecular targets for ovarian cancer theranostic approaches. Exploitation of the wealth of biomarker research that has been conducted offers viable targets as beacons for ovarian cancer detection, diagnosis, and therapeutic targeting. These markers can be used in theranostics, a treatment strategy that combines therapy and diagnostics and is common in nuclear medicine, where radionuclides are used for both diagnosis and treatment. The development of theranostics has taken substantial focus in recent years in the battle against ovarian cancer. Yet to date only one theranostic technology has emerged in clinical practice. However, given the wealth of ovarian cancer biomarkers the field is poised to see the emergence of revolutionary disease treatment and monitoring outcomes through their incorporation into the development of theranostic strategies. The future of ovarian cancer treatment is set to enable precise diagnosis, targeted treatment, and vigilant monitoring. This review aims to assess the status of ovarian cancer diagnostic tools and biomarkers in practice, clinical development, or pre-clinical development, highlighting newly emerging theranostic applications.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139879624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Release of delta-9-tetrahydrocannabinol from polyvinyl alcohol hydrogels and its safe interaction with human skin fibroblasts","authors":"Shujun Cui, Ze Zhang, Denis Rodrigue, François Béland, Mahmoud Rouabhia","doi":"10.3389/fddev.2024.1303812","DOIUrl":"https://doi.org/10.3389/fddev.2024.1303812","url":null,"abstract":"This study aimed to design a THC-rich hydrogel to deliver cannabis derivatives topically. We developed hydrogels using polyvinyl alcohol (PVA) mixed with propylene glycol (PG), vegetable glycerin (VG), or both to facilitate the dissolution of delta-9-tetrahydrocannabinol (THC). The hydrogels showed a brown color, confirming the presence of the cannabinoid. They exhibit a porous structure and better mechanical properties than PVA alone. Indeed, the hydrogel containing PG, VG, or both showed elastic deformation behaviors with lower water content. FTIR analysis demonstrated the presence of THC with two specific peaks at 1,575 and 1,619 cm−1, confirming the presence of THC in the hydrogels. Human dermal fibroblast cultures onto the surface of all hydrogels confirmed the safety of the THC-rich hydrogel as the cell adhesion was comparable to the control (no THC). Furthermore, cells adhering to the hydrogels could proliferate, showing increased cell viability at 48 and 72 h, with a higher proliferation obtained with the THC-rich PVA-PG-VG hydrogels. Such cell behavior could be due to the release of the THC in the culture medium, as demonstrated by ultra-high performance liquid chromatography (UPLC), showing the presence of THC in the culture medium, ranging from 203 to 290 μg after 24 h of incubation of the hydrogels containing PG and VG or both. In comparison, the released THC from the PVA hydrogel was higher, reaching 852 μg. It is interesting to note that the THC release at 24, 48, and 72 h was slower with the hydrogels containing PG, VG, and both, compared to PVA alone. Overall, the present study has designed safe THC-rich PVA-PG-VG hydrogels as a functional delivery system for the topical use of cannabinoids to control tissue diseases, such as inflammation.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140475811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnological innovations in paediatric tuberculosis management: current trends and future prospects","authors":"Taiwo Oreoluwa Ajayi, M. Poka, B. Witika","doi":"10.3389/fddev.2023.1295815","DOIUrl":"https://doi.org/10.3389/fddev.2023.1295815","url":null,"abstract":"Paediatric Tuberculosis (TB) continues to be a major global cause of morbidity and mortality. Children are more prone to contracting TB, which can spread quickly to extrapulmonary infection sites. Although the pathophysiology of the disease, drug pharmacokinetics, and the therapeutic window in children differ from those of adults, the same drugs used to treat adult TB have long been utilised to treat paediatric TB infections. Since many current formulations such as tablets are unsuitable for children due to difficulty swallowing and risk of choking, adult medications are frequently used by breaking or crushing tablets to obtain a paediatric dose. This can result in inaccurate dosing due to pharmacokinetic differences in children which could subsequently lead to sub-therapeutic or toxic systemic concentrations. In addition, many of the medications used in the treatment of TB and most medicines in general, have a profoundly unpleasant taste to children causing them to reject and spit out medication which contributes to challenges with adherence, ultimately leading to treatment failure. The aforementioned demonstrates a huge need for the development of novel drug delivery formulations that are paediatric-friendly and address the limitations of current dosage forms. This review discusses the currently available oral paediatric formulations, recent developments of novel oral drug delivery systems studied to overcome the current problems associated with the treatment of tuberculosis in paediatrics and provides potential direction for future research through nanotechnology by using a SWOT analysis.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139445249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biodistribution of the saponin-based adjuvant Matrix-M™ following intramuscular injection in mice","authors":"Cecilia Carnrot, Berit Carow, Anna-Karin E. Palm, Eray Akpinar, Per-Henrik Helgesson, Ingrid Lekberg Osterman, Emelie Bringeland, Bryant Foreman, Nita Patel, Johan Bankefors, Louis Fries, Linda Stertman","doi":"10.3389/fddev.2023.1279710","DOIUrl":"https://doi.org/10.3389/fddev.2023.1279710","url":null,"abstract":"Novel adjuvants are extensively utilized in the development of safe and effective vaccines against emerging pathogens. Matrix-M™ adjuvant is a saponin-based adjuvant used in several active clinical development programs and in widespread use in the COVID-19 vaccine NVX-CoV2373. Here, we conducted a biodistribution study to better understand the mechanism of action and safety profile for Matrix-M™ adjuvant. Radiolabeled saponins or cholesterol were incorporated into Matrix-A™ particles, which represent 85% of Matrix-M™. Labeled Matrix-M™ adjuvant was given to mice by intramuscular injection with or without SARS-CoV-2 Spike protein. Radioactivity of the adjuvant components was quantified in local and systemic tissues at seven timepoints over a period of 1–168 h. The highest saponin levels were found at the 1-h timepoint at the injection site, in the draining (iliac) lymph nodes, and in urine. Saponins were rapidly cleared from these tissues, reaching very low levels by 48–72 h. Systemically, saponins were found at low levels in the plasma, kidneys, liver, and bone marrow, and were barely detectable in other investigated tissues. Cholesterol was also found at high levels at the injection site and in the draining lymph nodes. These levels declined rapidly at first, then plateaued at 24–48 h. Radiolabeled cholesterol was found at very low levels in other tissues at the earliest timepoints, until increasing and stabilizing after the 24-h timepoint, indicating entry into the endogenous cholesterol recycling pool. This study demonstrates a rapid distribution of Matrix-M™ adjuvant from the injection site to the draining lymph nodes, thus excluding a depot effect as central to the mechanism of action for this adjuvant. The diverging clearance patterns for saponins and cholesterol are suggestive of at least partial disassembly of the Matrix-particles, which has implications for the downstream effects of Matrix-M™ adjuvant on adaptive immune responses. Systemic exposure to toxicologically relevant tissues is very low.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135589356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mannose-functionalization of reconstituted high-density lipoprotein nanoparticles improves payload delivery and enhances M2-to-M1 phenotype reprogramming of RAW 264.7 macrophages polarized by B16-F10 melanoma cells","authors":"Akpedje S. Dossou, Morgan E. Mantsch, Nirupama Sabnis, Rance E. Berg, Rafal Fudala, Andras G. Lacko","doi":"10.3389/fddev.2023.1281066","DOIUrl":"https://doi.org/10.3389/fddev.2023.1281066","url":null,"abstract":"The targeting and conversion of the immunosuppressive (M2) tumor-associated macrophages (TAMs) to an immunostimulatory (M1) phenotype can induce tumor regression in advanced melanoma. We have previously characterized and reported the ability of reconstituted high-density lipoprotein nanoparticles (rHDL NPs) functionalized with DSPE-PEG-mannose (DPM) to deliver payload to macrophages. Herein, we investigate the modulation of macrophage phenotype and payload delivery mechanisms of the rHDL-DPM NPs in RAW 264.7 murine macrophages exposed to the conditioned medium (CM) from murine B16-F10 melanoma cells. The rHDL-DPM NPs loaded with the Stimulator of Interferon genes agonist, DMXAA, reduced protein levels of M2 markers. Through the mannose moiety, the rHDL-DPM-DMXAA NPs enhanced the production of interferon β and CXCL10 compared to the free DMXAA in the B16-F10 CM-educated RAW 264.7 macrophages. Compared to their non-mannosylated counterpart, the rHDL-DPM NPs delivered their payload more efficiently to the B16-F10 CM-educated RAW 264.7 macrophages. Mechanistically, both the scavenger receptor type B class 1 (SR-B1) and the mannose receptor (CD206) facilitated payload delivery to the macrophages via endocytic and non-endocytic mechanisms. Finally, the CM from rHDL-DPM-DMXAA NPs -treated macrophages enhanced paclitaxel (paclitaxel)-mediated cytotoxicity in B16-F10 cells. Together, these in vitro findings demonstrate the potential of the mannose-functionalized rHDL NPs in improving the targeting of M2-like TAMs and treatment outcomes when combined with immunotherapy or PTX in B16-F10 melanoma in vivo models.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135265840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frontiers in hepatic drug delivery-grand challenges","authors":"José M. Lanao","doi":"10.3389/fddev.2023.1265446","DOIUrl":"https://doi.org/10.3389/fddev.2023.1265446","url":null,"abstract":"SPECIALTY GRAND CHALLENGE article Front. Drug Deliv., 20 October 2023Sec. Hepatic Drug Delivery Volume 3 - 2023 | https://doi.org/10.3389/fddev.2023.1265446","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135570278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}