RSC Pharmaceutics最新文献

{"title":"Prodrug nanotherapy demonstrates in vivo anticryptosporidial efficacy in a mouse model of chronic Cryptosporidium infection†","authors":"Amalendu P. Ranjan, Daniel J. Czyzyk, Griselle Martinez-Traverso, Aygul Sadiqova, Margarita Valhondo, Deborah A. Schaefer, Krasimir A. Spasov, William L. Jorgensen, Jamboor K. Vishwanatha, Michael W. Riggs, Alejandro Castellanos-Gonzalez and Karen S. Anderson","doi":"10.1039/D4PM00093E","DOIUrl":"10.1039/D4PM00093E","url":null,"abstract":"<p >The gastrointestinal disease cryptosporidiosis, caused by the genus <em>Cryptosporidium</em>, is a common cause of diarrheal diseases in children, particularly in developing countries and frequently fatal in immunocompromised individuals. <em>Cryptosporidium hominis</em> (<em>Ch</em>)-specific bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) has been a molecular target for inhibitor design. (<em>Note that this bifunctional enzyme has also been referred to as TS-DHFR in previous literature since the functional biochemical reaction first involves the conversion of methylene tetrahydrofolate to dihydrofolate at the TS site</em>.) While nanomolar inhibitors of <em>Ch</em> DHFR-TS have been identified at the biochemical level, effective delivery of these compounds to achieve anticryptosporidial activity in cell culture and <em>in vivo</em> models of parasite infection remains a major challenge in developing new therapies. Previous studies, using a nanotherapy approach, have shown a promising <em>Ch</em> DHFR-TS inhibitor, 906, that can successfully target <em>Cryptosporidium</em> parasites in cell culture with nanomolar anticryptosporidial activity. This formulation utilized poly(lactic-<em>co</em>-glycolic acid) (PLGA) nanoparticles (NPs) loaded with 906 (NP-906) and conjugated with a <em>Cryptosporidium</em> monoclonal antibody (MAb) on the nanoparticle surface to specifically target the glycoprotein GP25–200 in excysting oocysts. However, a limitation for <em>in vivo</em> use is antibody susceptibility to gastric acidity. To address this gap, a prodrug diethyl ester form of 906 (MAb-NP-Prodrug) was synthesized that allowed higher compound loading in the MAb-coated PLGA nanoparticles. An oral formulation was prepared by loading lyophilized MAb-NP-Prodrug into gelatin capsules with an enteric coating for gastric stability. Proof-of-concept studies with this oral formulation demonstrated antiparasitic activity in a chronic mouse model of <em>Cryptosporidium</em> infection. Efficacy was observed after a low daily dose of 2 × 8 mg kg<small>⁻¹</small> for 5 days, when examined 6 and 20 days postinfection, offering a new avenue of drug delivery to be further explored.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 5","pages":" 963-975"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight into central nervous system targeted nanostructured lipid carriers via the nose to brain pathway","authors":"Mridusmita Das, Anupam Sarma, Himakshi Baruah and Debojeet Basak","doi":"10.1039/D4PM00057A","DOIUrl":"https://doi.org/10.1039/D4PM00057A","url":null,"abstract":"<p >In nanomedicine, targeting the central nervous system (CNS) is one of the biggest challenges. The presence of the blood–brain barrier (BBB) leads to the failure of drugs to reach the brain; hence, CNS-related diseases are challenging to treat. Various invasive and noninvasive methods have been established to overcome the difficulty of passing through the BBB. Delivery of drugs by using nanoparticles through the nasal route is one of the noninvasive methods developed to treat CNS disorders. The nose to brain pathway allows direct transport to the brain without crossing the BBB. Among the nanocarriers designed to target the CNS, nanostructured lipid carriers (NLC) are the focus of this review. NLCs appeared as a newer generation of solid lipid nanoparticles (SLN) developed to get over SLN's limitations. They are novel pharmaceutical preparations made of lipids, surfactants and co-surfactants that are physiologic and biocompatible. Liquid lipids (oil) are added to the solid lipid to create a matrix which results in structural flaws in the solid lipids and creates a less ordered crystalline framework that prevents leakage of the drug and provides high drug loading. The imperfection in the internal arrangement of NLCs aids more drug accommodation. A systematic search was performed across the main databases like PubMed, Springer, Scopus, Taylor and Francis, Google Scholar and Wiley. The search applied terms and keywords related to nose to brain delivery, nanostructured lipid carriers and neurodegenerative diseases. This review discusses the anatomy of the nose, associated pathways, advantages and limitations of NLCs, and preparation techniques and recent developments of NLCs delivered <em>via</em> the nose to brain route. The reported records demonstrated the feasibility and potential of NLCs for innovative uses for treatment in the future <em>via</em> the nose to brain route.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 5","pages":" 904-927"},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00057a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive investigation of the biophysical approach for aptamer functionalized nanoparticles in cancer therapy: a review","authors":"Alanthatta Govindan Navaneeth and Subramani Karthikeyan","doi":"10.1039/D3PM00027C","DOIUrl":"https://doi.org/10.1039/D3PM00027C","url":null,"abstract":"<p >Aptamers stand out for their remarkable specificity and versatility, making them an invaluable tool in cancer therapy. When combined with nanoparticles, they form a dynamic platform for targeted drug delivery and diagnostics, leveraging enhanced cellular take up and the enhanced permeability and retention effect. This review explores both experimental and computational studies that probe the intricate interactions between aptamers and nanoparticles. By combining theoretical insights with empirical studies, this approach deepens our understanding of aptamer–nanoparticle conjugation, opening new avenues to enhance therapeutic efficacy and reduce off-target effects. Recent advancements in the field are critically analysed, spotlighting transformative studies that highlight the potential of this approach. Offering a comprehensive overview of current achievements and future prospects, this article aims to establish the pivotal role of aptamer-functionalized nanoparticles in personalized cancer treatment strategies.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 5","pages":" 879-903"},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d3pm00027c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconceptualising mucoadhesion for future medicines†","authors":"Michael T. Cook and David Shorthouse","doi":"10.1039/D4PM00149D","DOIUrl":"https://doi.org/10.1039/D4PM00149D","url":null,"abstract":"<p >The field of mucoadhesion has grown from a niche interest to a central consideration for the optimisation of mucosal medicines. As new therapies progress through development pipelines there are constantly emerging conditions which would benefit from the ability to target prolonged residence at mucosal sites. As such, there continues to be expansive investigation into mucoadhesion and the design of novel mucoadhesive materials for dosage form design. In this perspective piece, we give consideration to the recent progress in the field of mucoadhesive materials and make suggestion for reconsideration of current focus. Opinion on risks around current approaches to the development of mucoadhesive materials are described. Furthermore, challenges with translation are discussed, focussing on sensitisation and incompatibilities. Finally, the state of data in this field is critically assessed with a focus to <em>in vitro</em>–<em>in vivo</em> correlation and the formulation state space. It is intended that this manuscript challenges some important areas currently under investigation in the field.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 5","pages":" 949-957"},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00149d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-purpose resveratrol-quantum dots loaded albumin nanoparticles†","authors":"Deepankar Yadav, Priyanka Chaudhary, Priya Singh, Monu Gupta and Shubhini A. Saraf","doi":"10.1039/D4PM00100A","DOIUrl":"https://doi.org/10.1039/D4PM00100A","url":null,"abstract":"<p >Incorporating therapeutic and imaging capabilities into core–shell structured nanoparticles (NPs) has shown promising results in cancer treatment. This study aims to develop paddy husk carbon quantum dots (QDs) encapsulated in bovine serum albumin (BSA) nanoparticles with resveratrol (RSV) to enhance antioxidant activity and bioimaging potential. Carbon QDs, approximately 10 nm in size, were synthesized and characterized by UV-visible spectroscopy, photoluminescence spectroscopy, TEM, and FTIR. The optimized formulation was achieved using a full-factorial design, resulting in a combination of BSA with concentration of 219.004 mg, RSV with concentration of 8.271 mg, and 4 mL of ethanol. The nanoparticles exhibited a particle size of 125.6 nm, a zeta potential of −0.570 mV, 63.06% entrapment efficiency, and 7.173 mg drug content. <em>In vitro</em> assays showed that the nanoparticles enhanced RSV release under mildly acidic conditions, demonstrating efficacy as intracellular drug carriers. Cytotoxicity assays against MDA-MB-231 cells revealed dose- and time-dependent cytotoxicity, with 72% cell viability for the optimized formulation at the highest concentration tested. Antioxidant activity was 96% for the optimized formulation, compared to 35–45% for QDs and 80–85% for RSV alone, as measured by DPPH and H<small>₂</small>O<small>₂</small> assays. Confocal microscopy confirmed the superior imaging capability of the QDs. These findings indicate that QD- and resveratrol-loaded albumin nanoparticles (ANPs) have the potential to serve as effective cancer therapeutic agents and as biological imaging probes.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 4","pages":" 806-819"},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00100a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A brief overview of quality by design approach for developing pharmaceutical liposomes as nano-sized parenteral drug delivery systems","authors":"Prachi Atre and Syed A. A. Rizvi","doi":"10.1039/D4PM00201F","DOIUrl":"https://doi.org/10.1039/D4PM00201F","url":null,"abstract":"<p >Liposomes are sophisticated drug delivery vehicles that have significantly broadened the range of therapeutic agents that can be selectively delivered along with controlled release. Liposomes are small vesicles (size optimizable) composed of a lipid bilayer that encapsulates hydrophilic as well as hydrophobic drugs. This advancement has led to the creation of liposomal nano-formulations for drugs with very poor water solubility and cell membrane permeability, resulting in improved therapeutic efficacy and reduced side effects. Liposomal formulations can also be engineered with ligands or antibodies to target specific cells or tissues, ensuring site-specific drug delivery and minimizing off-target side effects. These targeted liposomal formulations have shown promising potential in treating various diseases, such as cancer, infectious diseases, and inflammatory disorders. With continuous advancements in liposomal technology, researchers are exploring new ways to further optimize the liposomal formulations for enhanced drug stability, bioavailability, and targeted delivery to specific cells or tissues. The Quality by Design (QbD) approach is a systematic and scientific method for designing and developing pharmaceutical products, ensuring quality and consistency throughout the product lifecycle. Applied to the development of pharmaceutical liposomes, QbD facilitates the optimization of liposome formulations for targeted drug delivery, improved stability, and enhanced therapeutic outcomes. The creation of novel liposomal formulations with superior drug stability, bioavailability, and targeting capabilities will undoubtedly play a crucial role in shaping the future of medicine and improving patient care. This brief review provides an overview of the development of liposomes as nanocarrier systems for parenteral drug delivery, covering aspects such as quality manufacturing attributes, structure, preparation methods, characterization, clinical applications, and regulatory considerations.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 4","pages":" 675-688"},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00201f?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial coatings from gramicidin D nanoparticles and polymers","authors":"Livia Cestaro de Souza Camargo, Bianca Reche Bazan, Rodrigo Tadeu Ribeiro, Giovanna Maruyama Quinto, Andrea Caroline Bazzan Muniz and Ana Maria Carmona-Ribeiro","doi":"10.1039/D4PM00124A","DOIUrl":"https://doi.org/10.1039/D4PM00124A","url":null,"abstract":"<p >The microbicidal activity of gramicidin D molecules (Gr) assembled as nanoparticles (NPs) against <em>Staphylococcus aureus</em> was found to be superior to that of other Gr formulations in bilayers. In combination with the antimicrobial polymer poly(diallyl dimethyl ammonium chloride) (PDDA), water dispersions and coatings on glass exhibited a remarkably broadened spectrum of activity, achieving complete killing of Gram-negative bacteria, Gram-positive bacteria and fungi at reduced Gr and PDDA doses. In this work, combinations of Gr NPs and polymers were cast on glass (hydrophilic) or polyethylene (hydrophobic) surfaces, modeling common surfaces on biomedical materials, to evaluate the effect of polymer positive charge on the antimicrobial activity. Decreasing positive charges of three different polymers, namely PDDA, chitosan (CH) and polyacrylamide (PA), reduced or abolished microbicidal activity both in the presence and absence of Gr NPs. At 4.7 μg Gr and 25 μg polymer, microbicidal activity increased from PA to CH to PDDA at pH 6.3. The results suggested that the Gr/polymer antimicrobial coatings can be used on both hydrophobic and hydrophilic biomedical materials, effectively imparting them with efficient defense against a broad spectrum of microbes.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 5","pages":" 1033-1041"},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00124a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of drug release from polymeric nanoparticles in simulated saliva and gastric media by asymmetric flow field–flow fractionation (AF4)†","authors":"Haoran Wu, Alaia Homawoo, Saba Shariati, Carlos E. Astete, Debora F. Rodrigues, Cristina M. Sabliov, Elham H. Fini and Stacey M. Louie","doi":"10.1039/D4PM00175C","DOIUrl":"https://doi.org/10.1039/D4PM00175C","url":null,"abstract":"<p >Nanocarriers for oral drug delivery will encounter various biochemical environments throughout the digestive tract, which could induce different drug release behaviors. Conventional drug release assays can provide total drug release rates but have limited capability to identify drug release mechanisms in complex samples. The objective of this study is to compare the rates and mechanisms for release of an antibiotic, enrofloxacin, from poly(lactic-<em>co</em>-glycolic acid) (PLGA) nanoparticles in simulated saliva and simulated gastric fluid (SGF) by combining drug release profiling using asymmetric flow field–flow fractionation (AF4) with physical release models and density functional theory (DFT) analyses. At 30 °C, similar release profiles were observed in media with near-neutral pH, represented by saliva and phosphate buffered saline (PBS) as a comparative medium, whereas antibiotic release was accelerated in SGF. However, negligible drug release was observed in SGF at room temperature (below the glass transition temperature of the nanoparticles). Enzymatic proteins in the media did not significantly influence the release rates. The advanced AF4 analyses of the drug distribution and release profiles affirmed negligible drug–protein interactions in the media and provided evidence that accelerated release in SGF was attributed to enhanced radial diffusion rates of entrapped drug through the nanoparticles, rather than particle erosion or shrinking. DFT modeling further demonstrated that changes in the charge state of the enrofloxacin and carboxylated PLGA result in diminished drug–polymer interactions upon SGF intrusion into the nanoparticles. Altogether, this study demonstrates the benefits of integrated experimental and modeling analyses to understand drug release mechanisms.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 5","pages":" 994-1007"},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00175c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Pharmaceutical salts of azole anti-fungal drugs: physicochemical behaviour and activity studies","authors":"Hafsa Qadri, Asif A. Malik, Aadil A. Ahangar, Manzoor Ahmad Mir, Aijaz A. Dar and Abdul Haseeb Shah","doi":"10.1039/D4PM90015D","DOIUrl":"https://doi.org/10.1039/D4PM90015D","url":null,"abstract":"<p >Correction for ‘Pharmaceutical salts of azole anti-fungal drugs: physicochemical behaviour and activity studies’ by Hafsa Qadri <em>et al.</em>, <em>RSC Pharm.</em>, 2024, https://doi.org/10.1039/d4pm00003j.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 4","pages":" 854-854"},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm90015d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmable protein delivery from microgel/hydrogel composites (MHCs) via discrete combinations of multi-state protein-loaded unit ingredients†","authors":"Longfei Chen and Saif A. Khan","doi":"10.1039/D4PM00080C","DOIUrl":"https://doi.org/10.1039/D4PM00080C","url":null,"abstract":"<p >Therapeutic proteins have drawn increasing attention in the development of advanced drugs and biomedical devices, yet there are outstanding challenges for the delivery of multiple-protein therapies with customized release profiles. Hydrogel-based drug delivery systems (DDS) have been widely investigated, primarily <em>via</em> highly specific chemical modification routes, for programmable topical, injectable, and depot-based protein delivery. In this paper, we propose a microgel/hydrogel composite (MHC) DDS for tunable and programmable multi-protein delivery, which leverages different <em>physical states</em> of proteins (freely dissolved or coacervated) and completely avoids bespoke chemical modifications on the hydrogels. We load model proteins in distinct physical states into dextran-based hydrogel microparticles (microgels) fabricated using microfluidics, after which simple discrete combinations of these microgel ‘unit ingredients’ are packaged into poly(ethylene glycol) hydrogel matrices to formulate the MHC DDS. With discrete combinations of unit ingredients, we demonstrate how these MHC DDSs can achieve both <em>tunable</em> release for a single low-molecular-weight model protein (and ideally, highly similar proteins) and a counterintuitive <em>rate-reversed</em> release of two model proteins that are vastly different in size. Moreover, we show that these MHCs follow Korsmeyer-Peppas kinetic behavior as a function of the discrete combinations packaged, thus highlighting the quantitative tunability of release behaviors. We envision the use of these MHC DDSs as topically applied wound dressings or implantable protein-releasing depots that allow scheduled and programmable multi-protein delivery in biomedical and clinical applications.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 4","pages":" 689-704"},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/pm/d4pm00080c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}