Bioconjugate Chemistry最新文献

{"title":"Chelating [²²⁷Th]Th⁴⁺ for Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors.","authors":"Luke Wharton, Scott W McNeil, Harrison Meeres, Diduo Zhang, Aidan Ingham, Helen Merkens, Maryam Osooly, Cristina Rodríguez-Rodríguez, François Bénard, Hua Yang","doi":"10.1021/acs.bioconjchem.5c00129","DOIUrl":"10.1021/acs.bioconjchem.5c00129","url":null,"abstract":"<p><p>Targeted alpha therapy (TAT) has shown high promise for the effective treatment of advanced stage cancers. Of the proposed radionuclides for TAT, Thorium-227 represents an interesting candidate given its relatively long half-life, 18.7 days, and the cascade of short-lived, high-potency, alpha-emitting daughter progeny in its decay scheme. However, to date few chelators exist which can effectively and stably bind [²²⁷Th]Th⁴⁺ at molar activities high enough for TAT. To address this challenge, this study investigated various chelating ligands for coordination of [²²⁷Th]Th⁴⁺. H₄noneunpaX was identified as a promising chelator, demonstrating radiolabeling with [²²⁷Th]Th⁴⁺ at concentrations of 10^-6 M (A_m = 272 kBq/nmol). The coordination characteristics of [Th(noneunpaX)] have been investigated through ¹H NMR spectroscopy, mass spectrometry, and DFT calculations. In this study, we also investigate for the first time the pairing of Th-227 with a peptide-based bioconjugate and evaluate the <i>in vivo</i> biodistribution characteristics. [²²⁷Th]Th-nonenupaX-Ahx-Tyr³-TATE was prepared under mild conditions (ambient temperature, 30 min) and evaluated in NRG mice bearing AR42J xenografts as a model for pancreatic neuroendocrine tumors. The ²²⁷Th-labeled radiopeptide showed high uptake in tumors (25.8±6.2 %IA/g at 3 h p.i.) and low uptake in non-targeted organs. Although some release of Th-227 was noted in serum stability studies this was not observed <i>in vivo</i>. This ligand architecture serves as an interesting framework for future optimization, which will involve improvements to the overall stability by enhancing the rigidity of the backbone and assessing other pendent donor groups with a stronger affinity toward [²²⁷Th]Th⁴⁺. Overall, this study demonstrated for the first time the viability of using peptide-based targeting to effectively deliver Th-227 to tumor sites.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1273-1287"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of an Adamantane Phosphoramidite for Programmable and Automated Oligonucleotide-Functionalization.","authors":"Yuxiang Cong, Xiaoxing Chen, Thulasiram Bathini, Gang Chen, Da Han, Yangen Huang, Ruowen Wang","doi":"10.1021/acs.bioconjchem.5c00163","DOIUrl":"10.1021/acs.bioconjchem.5c00163","url":null,"abstract":"<p><p>Solid-phase synthesis has revolutionized the programmable preparation of oligonucleotides (ONs), enabling precise gene expression modulation and expanding their applications in therapeutic and material sciences. To further enhance ON functionality, this study introduces a novel adamantane-based phosphoramidite for oligonucleotide modification. Adamantane, known for its hydrophobicity and stability, was incorporated into nucleic acid aptamers using automated synthesis. Two aptamers─Sgc8 and AS1411─were functionalized with one or two adamantane units, and the products were purified and validated using high-performance liquid chromatography and mass spectrometry. The incorporation of adamantane significantly altered the aptamers' polarity and facilitated their self-assembly with poly-β-cyclodextrin, forming stable supramolecular complexes, as demonstrated by polyacrylamide gel electrophoresis. Additionally, adamantane-modified AS1411 exhibited enhanced degradation of its target protein, nucleolin, in MCF-7 cells, suggesting potential utility in targeted protein regulation. These findings establish a versatile platform for functionalizing ONs, broadening their potential for biomedical and nanotechnological applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1311-1318"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Light-Controllable PEG Hydrogel Cross-Linked by Reversibly Photodissociable Dimeric Green Fluorescent Protein pdDronpa for Drug Delivery.","authors":"Yen Thi Nguyen, Hyuck Jin Lee, Namdoo Kim","doi":"10.1021/acs.bioconjchem.5c00088","DOIUrl":"10.1021/acs.bioconjchem.5c00088","url":null,"abstract":"<p><p>Hydrogel has been widely studied as a carrier model system for drug delivery. Efficient encapsulation of drug molecules and their controlled release are important factors in the design of hydrogels to control drug release at a desired time and location. In this study, we propose a photoresponsive hydrogel with tunable mechanical properties for drug delivery. The hydrogel was synthesized by cross-linking maleimide-functionalized 4-armed polyethylene glycol (4-armed PEG-Mal) with reversibly photodissociable green fluorescent protein pdDronpa. Transitions in the physical state and/or mechanical strength of the hydrogel occurred rapidly when the cross-linking agent pdDronpa was switched off and on between the monomer and dimer states using 500 and 400 nm illumination, respectively. Optically controlled release of fluorescently labeled insulin was investigated, demonstrating the ability of this hydrogel as a potent drug delivery system.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"1247-1256"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Marta Tuszynska*,&nbsp;Joanna Skopinska-Wisniewska,&nbsp;Mateusz Bartniak and Anna Bajek,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144355174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Santanu Sar,&nbsp;Shalini Gupta,&nbsp;Gourav Das,&nbsp;Swrajit Nath Sharma,&nbsp;Deepak K,&nbsp;Atanu Ghosh,&nbsp;Siddharam Shivappa Bagale,&nbsp;Sumit Gangopadhyay,&nbsp;Surajit Sinha* and Kiran R. Gore*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144429459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"4′-C-Cholesterol/Pyridyl-2′-O-Methyl Uridine-Functionalized siRNA Enhances Stability and Carrier-Free Gene Silencing","authors":"Santanu Sar,&nbsp;Shalini Gupta,&nbsp;Gourav Das,&nbsp;Swrajit Nath Sharma,&nbsp;Deepak K,&nbsp;Atanu Ghosh,&nbsp;Siddharam Shivappa Bagale,&nbsp;Sumit Gangopadhyay,&nbsp;Surajit Sinha* and Kiran R. Gore*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0007910.1021/acs.bioconjchem.5c00079","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00079https://doi.org/10.1021/acs.bioconjchem.5c00079","url":null,"abstract":"<p >Chemical modifications and targeted delivery through the conjugation of small molecules have transformed the potential of siRNA-based therapeutics. These advancements address key challenges, such as poor cellular uptake, low bioavailability, and limited metabolic stability, making siRNA delivery more efficient and clinically viable. Cholesterol-conjugated siRNA enables cellular uptake through lipoprotein pathways without transfection agents. In this study, we reported the synthesis of 4′-<i>C</i>-cholesterol-2′-<i>O</i>-methyl (4′-<i>C</i>-chol-2′-OMe) and 4′-<i>C</i>-methylpyridine-2′-<i>O</i>-methyl (4′-<i>C</i>-Mpy-2′-OMe) uridine conjugates via copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and their incorporation at the 3′-overhangs of the siRNA duplex. A single incorporation of 4′-<i>C</i>-chol-2′-OMe or 4′-<i>C</i>-Mpy-2′-OMe uridine marginally increased the stability of the siRNA duplex. In the nuclease resistance assay, 4′-<i>C</i>-Mpy-2′-OMe modification at the penultimate position of the 3′-end of poly dT₂₀ showed significant resistance against snake venom phosphodiesterase (SVPD), 3′-specific exonucleases. Gene silencing activity using anti-<i>Renilla</i> siRNA exhibited enhanced gene silencing activity when a single modification was incorporated at the 3′-overhang of the passenger strand. Similarly, 4′-<i>C</i>-Mpy-2′-OMe modification at the 3′-overhang of the passenger strand in anti-<i>Bcl</i>-2 siRNA showed compatibility to RISC assembly and exhibited effective gene silencing against the endogenous <i>Bcl-2</i> gene. A molecular modeling study illustrated that the 4′-<i>C</i>-Mpy-2′-OMe uridine at the 3′-overhang of the guide strand shows minimal interaction with the PAZ domain of the hAgo2 protein. The dual incorporation of cholesterol modifications at the 3′-overhang of both strands resulted in 68% and 93% reductions in <i>Renilla</i> luciferase expression at 1000 nM concentration after 48 and 96 h, respectively, in a carrier-free system. This study demonstrated that C4′-cholesterol conjugation provides effective cellular uptake, high nuclease resistance, and prolonged silencing activity in carrier-free mode.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"1234–1246 1234–1246"},"PeriodicalIF":4.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimeric Conjugates Using Engineered Peptide Scaffolds for Efficient siRNA Delivery","authors":"Quentin Vicentini,&nbsp;Dennis Hekman,&nbsp;Deepak Bhatt,&nbsp;Rouven Stulz,&nbsp;Mahya Dezfouli,&nbsp;Peter Gennemark,&nbsp;Nicola Guzzi,&nbsp;Naoko Toki,&nbsp;Bojana Lazovic,&nbsp;Carolina Tängemo,&nbsp;Shalini Andersson,&nbsp;Samir EL Andaloussi* and Anders Dahlén*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0015610.1021/acs.bioconjchem.5c00156","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00156https://doi.org/10.1021/acs.bioconjchem.5c00156","url":null,"abstract":"<p >Oligonucleotide therapeutics (ONT) traditionally involve a single targeting moiety per oligonucleotide when conjugated for organ delivery. Multimerization represents a novel approach by connecting multiple ONTs to a single scaffold, thereby influencing the drug’s activity and biophysical properties <i>in vivo</i>. Recently, others have demonstrated the efficacy of this strategy, showing enhanced tissue retention and extended silencing with the capability to target multiple genes simultaneously. The investigation of diverse multimeric designs is thus an exciting opportunity to explore the delivery of the ONT. In this study, we engineered a versatile peptide branching unit able to link up to four small interfering RNAs together. We conjugated a GalNAc targeting moiety to these scaffolds for liver hepatocyte delivery and assessed their silencing activity. Our approach was further expanded to explore different peptide architectures (linear versus cyclized) and additional functionalities, including endosomal escape domains and dual target silencing. We then evaluated the constructs via subcutaneous and intravenous (i.v.) administration in mice. Notably, the intravenous administration of multimeric siRNA GalNAc demonstrated potent silencing in the liver and significantly affected liver-to-kidney biodistribution. Our findings suggest that peptides as branching units offer a promising pathway for ONT multimerization, advancing the challenges of drug delivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"1299–1310 1299–1310"},"PeriodicalIF":4.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.5c00156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiprotein Silencing Using WRAP-Based Nanoparticles: A Proof of Concept","authors":"Karidia Konate,&nbsp;Irène Pezzati,&nbsp;Karima Redjatti,&nbsp;Estelle Agnel,&nbsp;Eric Vivès,&nbsp;Sandrine Faure,&nbsp;Pascal de Santa Barbara,&nbsp;Prisca Boisguérin* and Sébastien Deshayes*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0006910.1021/acs.bioconjchem.5c00069","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00069https://doi.org/10.1021/acs.bioconjchem.5c00069","url":null,"abstract":"<p >Cancer remains the leading cause of death, with chemotherapy, radiotherapy, and surgical resection being the primary treatment methods. However, chemotherapy’s side effects, surgical limitations, and drug resistance present significant challenges. Small interfering RNA (siRNA) has emerged as a promising tool in cancer therapy due to its ability to silence disease-related genes selectively. Recent advancements in nonviral delivery systems, particularly cell-penetrating peptides (CPPs), have enhanced the efficacy of siRNA delivery. The use of siRNA as a therapeutic tool in cancer treatment has been reported in the literature. However, silencing only one target protein has only a minor effect on tumor cell proliferation, as previously shown for WRAP-based nanoparticles targeting cyclin-dependent kinase 4 (CDK4) in human U87 glioblastoma cells. Here, we designed a more sophisticated approach to enhance therapeutic efficacy, encapsulating multiple siRNAs targeting CDK4, cyclin D1 (CD1), and MCL-1 proteins. The siRNA cocktail, delivered via WRAP5 nanoparticles, effectively silenced these targets and reduced cell proliferation in human U87 glioblastoma cells. Furthermore, the nanoparticles also demonstrated potential therapeutic impact in gastrointestinal stromal tumors (GIST), a rare cancer characterized by its tendency to resist standard treatments. This study highlights the versatility of WRAP5 nanoparticles as a platform for personalized cancer therapy, suggesting that siRNA delivery systems may be tailored to specific cancer types for more effective treatment strategies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"1218–1233 1218–1233"},"PeriodicalIF":4.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Light-Controllable PEG Hydrogel Cross-Linked by Reversibly Photodissociable Dimeric Green Fluorescent Protein pdDronpa for Drug Delivery","authors":"Yen Thi Nguyen,&nbsp;Hyuck Jin Lee* and Namdoo Kim*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0008810.1021/acs.bioconjchem.5c00088","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00088https://doi.org/10.1021/acs.bioconjchem.5c00088","url":null,"abstract":"<p >Hydrogel has been widely studied as a carrier model system for drug delivery. Efficient encapsulation of drug molecules and their controlled release are important factors in the design of hydrogels to control drug release at a desired time and location. In this study, we propose a photoresponsive hydrogel with tunable mechanical properties for drug delivery. The hydrogel was synthesized by cross-linking maleimide-functionalized 4-armed polyethylene glycol (4-armed PEG-Mal) with reversibly photodissociable green fluorescent protein pdDronpa. Transitions in the physical state and/or mechanical strength of the hydrogel occurred rapidly when the cross-linking agent pdDronpa was switched off and on between the monomer and dimer states using 500 and 400 nm illumination, respectively. Optically controlled release of fluorescently labeled insulin was investigated, demonstrating the ability of this hydrogel as a potent drug delivery system.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"1247–1256 1247–1256"},"PeriodicalIF":4.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing and Characterizing the Tumor-Targeting Efficiency of an Anti-EphA2-CD11b Bispecific Antibody","authors":"Peggy A. Birikorang,&nbsp;Dominic M. Menendez,&nbsp;Robert Edinger,&nbsp;Gary Kohanbash* and W. Barry Edwards*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0007010.1021/acs.bioconjchem.5c00070","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00070https://doi.org/10.1021/acs.bioconjchem.5c00070","url":null,"abstract":"<p >Targeting molecules, such as antibodies and peptides, play a key role in the precise delivery of cytotoxic payloads to tumor sites by binding to specific tumor-associated antigens or other proteins within the tumor microenvironment. This investigation evaluates the potential therapeutic application of a bispecific antibody (BsAb), which simultaneously targets EphA2, a tumor-associated antigen, and CD11b, a protein expressed by tumor-associated macrophages and myeloid-derived suppressor cells (TAMCs). Recombinantly produced anti-EphA2-CD11b-BsAb was conjugated to a bifunctional chelator, NOTA-SCN, and then radiolabeled with copper-64 (⁶⁴Cu). The [⁶⁴Cu]Cu-NOTA-anti-EphA2-CD11b-BsAb radioimmunoconjugate was subsequently administered to HT1080-fibrosarcoma-bearing nude mice via tail vein injection. Positron Emission Tomography (PET) and ex vivo biodistribution analyses were performed to determine tumor uptake and pharmacokinetic localization. At 4, 24, and 48 h postinjection (p.i.), the percent injected dose per gram (%ID/g) of [⁶⁴Cu]Cu-NOTA-anti-EphA2-CD11b-BsAb in HT1080 xenografts were 5.35 ± 2.24, 4.44 ± 1.90, and 4.10 ± 0.60, respectively. There was high uptake in the liver as well as in CD11b-expressing organs, including the spleen, bone marrow, and lung. Binding in these CD11b-rich organs was significantly reduced by coadministering the dose with nonradiolabeled anti-CD11b-IgG and anti-EphA2-CD11b-BsAb, with a concurrent increase in tumor uptake compared to nonblocked mice (8.39 ± 1.37%ID/g for blocked and 4.44 ± 1.90%ID/g for nonblocked at 24 h p.i., <i>p</i> = 0.0175). Further optimization studies showed that at lower molar activity (3.7 MBq/nmol, 100 μCi/nmol), there were significantly higher tumor accumulations and reduced uptake in CD11b-expressing organs compared to higher molar activity (22.2 MBq/nmol, 600 μCi/nmol). Anti-EphA2-CD11b-BsAb is a functional targeting molecule and would require optimization through molar activity or blocking with nonradiolabeled antibody to maximize tumor targeting.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 6","pages":"1208–1217 1208–1217"},"PeriodicalIF":4.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}