Wenhui Fu, Ephraim E. Parent, Justyna J. Gleba, Joshua A. Knight, Saad J. Kenderian, John A. Copland III* and Hancheng Cai*,
{"title":"PET Imaging of Thyroid-Stimulating Hormone Receptor (TSHR) in Oncocytic Thyroid Carcinoma for Monitoring TSHR CAR T-Cell Therapy Response","authors":"Wenhui Fu, Ephraim E. Parent, Justyna J. Gleba, Joshua A. Knight, Saad J. Kenderian, John A. Copland III* and Hancheng Cai*, ","doi":"10.1021/acs.bioconjchem.5c00235","DOIUrl":"10.1021/acs.bioconjchem.5c00235","url":null,"abstract":"<p >Oncocytic thyroid carcinoma (OTC) is often aggressive and refractory to radioiodine therapy, which is the current standard of care for metastatic thyroid cancer. The thyroid-stimulating hormone receptor (TSHR) regulates thyroid function and metabolism and is highly expressed in the thyroid gland and most thyroid tumors including OTC. Here, we report positron emission tomography (PET) imaging of radiolabeled TSHR antibody for detecting tumoral TSHR expression and monitoring TSHR chimeric antigen receptor (CAR) T-cell therapy response in an OTC mouse model. Radiotracer <sup>89</sup>Zr-DFO-TSHR-Ab was prepared as previously reported for PET imaging of TSHR expression. Tissue microarray analysis confirmed TSHR expression in both normal thyroid and OTC tumors. A human OTC xenograft model was established by subcutaneous injection of XTC.UC1 cells into NSG mice. PET imaging and biodistribution studies of TSHR expression were subsequently conducted in this model to assess TSHR-expression change before and after TSHR CAR T-cell therapy. TSHR-targeted CAR T-cells were administered intravenously, and longitudinal PET/CT imaging with <sup>89</sup>Zr-DFO-TSHR-Ab was performed at 24, 72, and 120 h postinjection to monitor tumor response. Eight weeks later, the same mice were rechallenged with XTC.UC1 cells in the contralateral flank to assess long-term therapeutic efficacy and immune memory through serial PET/CT imaging. PET imaging and biodistribution studies demonstrated that this radiotracer effectively detected TSHR-expressing OTC, with reasonable tumor uptake and imaging contrast. Following CAR T-cell therapy, TSHR PET showed significantly decreased tumor uptake, consistent with TSHR-targeted cell immunotherapy response with attenuated TSHR expression. These findings suggest <sup>89</sup>Zr-DFO-TSHR-Ab enables noninvasive identification of OTC tumors and real-time monitoring of response to TSHR-targeted CAR T-cell therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1744–1752"},"PeriodicalIF":3.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641232","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":"Exploring the Potentials of Antibody–siRNA Conjugates in Tumor Cell Gene Silencing without Cationic Assistance","authors":"Yahui Liu, Yanan Quan, Qi Mao, Ruolin Xu and Wanyi Tai*, ","doi":"10.1021/acs.bioconjchem.5c00212","DOIUrl":"10.1021/acs.bioconjchem.5c00212","url":null,"abstract":"<p >Antibody–siRNA conjugates (ARCs) are a type of promising drug modalities for cancer therapy. However, initial reports of ARCs present the gene knockdown effect only in limited tissues (e.g., muscles) or tumors of special targets (e.g., TenB2 and BCMA receptors). To expand the scope to more targets, herein we built structurally defined DAR2 ARCs and examined their effect on targeted gene silencing of tumor cells without cationic assistance. We first evaluated the impact of linker structures and Cys-engineered sites on conjugation efficiency, revealing that the ThioMab conjugation of siRNA is favored by the rigid sulfo-SMCC linker coupling at the HC-A118C site. With an additional anion exchange purification process, reactions of this condition can yield a homogeneous ARC product with DAR close to 2 (DAR: 1.9). We found that ARCs, despite a lack of endosome-disrupting ability, can induce effective gene silencing in multiple types of tumor cells by free uptake. The RNAi potency of ARCs is largely affected by siRNA stability and the time interval of uptake. The maximal mRNA knockdown (70–80%) can be achieved on the fourth day after the uptake of ARC bearing the fully modified siRNAs (Adv ESC mode). The delayed silencing activity, together with the restriction to the stable siRNA, indicates that ARC escape from endosomes is a slow and rate-limiting step, suggesting the importance of siRNA stability and resistance to endosomal degradation in ARC activity. In vivo, the anti-HER2 ARC displays a much-compromised circulatory half-life (<i>t</i><sub>1/2</sub> ∼ 8 h) in mice but can induce gene silencing in HCC1954 xenograft tumors and retard the tumor growth. This study demonstrates the potential of ARCs to treat cancers and other extrahepatic diseases.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1721–1732"},"PeriodicalIF":3.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606830","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}
Anne de Dreu, Koen de Bruin, Ayla M. Hokke, David P. Schrijver, Danyel N. H. Beelen, Lars M. Verhalle, Maria C. Clavijo Perez, Tom Anbergen, Iris Versteeg, Rianne Maas, Robby C. Zwolsman, Cristina Grao-Roldán, Branca Bartelet, Mirre M. Trines, Daniek Hoorn, Gijs Ros, Yohana C. Toner, Ewelina Kluza, Thijs Beldman, Carlos Pérez-Medina, Mihai G. Netea, Maarten Merkx, Roy van der Meel and Willem J. M. Mulder*,
{"title":"Engineering Fusion Proteins for Nanomedicine-Based Cytokine Therapy","authors":"Anne de Dreu, Koen de Bruin, Ayla M. Hokke, David P. Schrijver, Danyel N. H. Beelen, Lars M. Verhalle, Maria C. Clavijo Perez, Tom Anbergen, Iris Versteeg, Rianne Maas, Robby C. Zwolsman, Cristina Grao-Roldán, Branca Bartelet, Mirre M. Trines, Daniek Hoorn, Gijs Ros, Yohana C. Toner, Ewelina Kluza, Thijs Beldman, Carlos Pérez-Medina, Mihai G. Netea, Maarten Merkx, Roy van der Meel and Willem J. M. Mulder*, ","doi":"10.1021/acs.bioconjchem.5c00182","DOIUrl":"10.1021/acs.bioconjchem.5c00182","url":null,"abstract":"<p >Cytokines play a crucial role in cell communication and immunity, making them interesting potential therapeutics for immune-mediated conditions. However, cytokine therapeutics’ clinical translation is hampered by their short blood half-lives and unfavorable biodistribution, resulting in toxicity and poor pharmacokinetics. In this study, we present a strategy to improve cytokines’ pharmacokinetic profile by engineering fusions of apolipoproteins and cytokines, which are formulated into apolipoprotein-based nanoparticles (cytokine-aNPs). After establishing chemical and recombinant fusion approaches, we created a small library of diverse proteins, comprising fusions between apolipoprotein A1 or apolipoprotein E with either interleukin 1β, interleukin 2, or interleukin 4. Although chemical conjugation successfully generated biologically active fusion proteins, their yield and purity were insufficient for cytokine-aNP formulation. Using the recombinant method, we expressed and purified the fusion proteins and then incorporated them into cytokine-aNPs. In addition, we show that all cytokine-aNPs remain stable over at least 10 days and are of similar size and shape. We found that the fusion protein’s cytokine component remains biologically active after purification and after formulation into cytokine-aNPs. In mice, using zirconium-89 radiolabeling to enable <i>in vivo</i> positron emission tomography imaging, we found that the pharmacokinetic profile of the cytokines incorporated into aNPs changed considerably. As compared to the native cytokines, we found the cytokine-aNPs to predominantly accumulate in the spleen, bone marrow, lymph nodes, and liver. Together, our results demonstrate that we can improve cytokines’ <i>in vivo</i> properties using our fusion protein technology and aNP platform, opening up a translational avenue for nanomedicine-based cytokine therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1698–1708"},"PeriodicalIF":3.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612040","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}
Christopher J. LaSalle, David V. Morrissey and Theresa M. Reineke*,
{"title":"Clickable and Degradable Polycarbonate Vehicles for mRNA Delivery","authors":"Christopher J. LaSalle, David V. Morrissey and Theresa M. Reineke*, ","doi":"10.1021/acs.bioconjchem.5c00073","DOIUrl":"10.1021/acs.bioconjchem.5c00073","url":null,"abstract":"<p >The development of nucleic acid therapies has enabled access to treatments for several diseases previously thought untreatable, yet effective and safe delivery remains a hurdle. The benefit of synthetic vehicles lies in their modularity in optimizing performance and safety. Herein, we present a novel biodegradable polycarbonate alternative to the nondegradable synthetic and viral vectors often utilized in commercial gene therapies. This PC system leverages ring-opening polymerization of a cyclic carbonate to produce polymers (∼20 kDa) with pendant allyl groups compatible with thiol–ene click post-polymerization modification. The derivatization of the parent polymer enables a direct comparison of the pendant groups without molecular weight and dispersity variables. These pendants include 2-(dimethylamino)ethanethiol hydrochloride (DMA) as the cation and one of three hydrophilic modifiers: mercaptopropanol (OH), thioglycolic acid (COOH), and methoxy polyethylene glycol thiol (PEG), which modulate cellular membrane interaction, charge density, and sheathing properties. This family of vehicles forms stable polymer-mRNA complexes (polyplexes), confirmed via dynamic light scattering and gel electrophoresis. <i>In vitro</i> screening assays showed minimal cytotoxic effects with HEK293T (human embryonic kidney) and A549 (human lung cancer) cells, resulting in a statistically significant viability improvement over the polymer control, JetPEI. Coupling the viability with expression values of EGFP-encoded (enhanced green fluorescent protein) mRNA, <i>in vitro</i> delivery efficiency shows the polycarbonate performance on par with JetPEI in nearly all cases while offering degradation via hydrolysis. Overall, this modular polycarbonate scaffold improves cell viability and maintains performance similar to that of positive controls while featuring modularity and degradability.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1628–1638"},"PeriodicalIF":3.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598902","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":"Synthetic Redox-Responsive Nanocomplexes Facilitate Spatially Controlled mRNA Release and Tumor-Selective Expression","authors":"Sheng Lin, Xia Cheng, Xiyi Chen, Jinxuan He*, Wenxiu An, Qiufang Bai, Qixian Chen, Lie Ma, Jianhua Hu, Yue Wang* and Xiabin Lan*, ","doi":"10.1021/acs.bioconjchem.5c00264","DOIUrl":"10.1021/acs.bioconjchem.5c00264","url":null,"abstract":"<p >The refinement of dynamic molecular mechanisms regulating mRNA release kinetics represents a critical frontier in advancing the synthetic mRNA delivery systems. This study details the synthesis of an intriguing ROS-responsive cationic block copolymer (pM-pBD) via reversible addition−fragmentation chain transfer (RAFT) polymerization, employing biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC) and charge-reversible (2-acryloyl)ethyl(boronic acid benzyl)diethylammonium bromide (BD) as monomeric precursors. The synthesized copolymer facilitates electrostatic-driven self-assembly with anionic mRNA. Mechanistically, the pBD block exhibits ROS-mediated charge transition, enabling stimulus-dependent molecular decomposition and promoting mRNA payload liberation, thereby establishing spatial regulation of translational activity. Furthermore, intracellular ROS modulation experiments revealed that systemic ascorbic acid administration selectively enriches reactive oxygen species within tumor microenvironments. This redox microenvironment significantly amplifies pM-pBD nanocomplex-mediated mRNA expression by an order of magnitude across multiple carcinogenic cell lines, validating the ROS-responsive characteristics of our rationally designed delivery platform. In vivo studies demonstrated the highest mRNA expression levels in tumors when aided by ascorbic acid adjuvants, despite lower tumor accumulation of mRNA compared to renal and hepatic sequestration post intravenous administration of the pM-pBD nanocomplex. This spatial expression pattern correlates with ascorbic acid-mediated intratumoral ROS accumulation, which promotes cargo release and subsequent protein synthesis of approximately 6.4-fold enhancement. Our approach, integrating redox-responsive polymer design with organ-specific pharmacological modulation, signifies a transformative advancement in targeted nucleic acid delivery. By merging stimulus-responsive materials science with tumor microenvironment biology, this methodology provides a foundation for spatially controlled mRNA expression, presenting an innovative strategy for precision oncology applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1775–1785"},"PeriodicalIF":3.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598903","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}
Gyung A Kim, Seungyoon Kang, Myo Naing Win, Min Su Han
{"title":"Simple and High-Throughput Fluorescence Assay Method for DNA Damage Analysis in Single-Stranded DNA-Encoded Library Synthesis.","authors":"Gyung A Kim, Seungyoon Kang, Myo Naing Win, Min Su Han","doi":"10.1021/acs.bioconjchem.5c00219","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00219","url":null,"abstract":"<p><p>The fluorescent dye-based simple and high-throughput DNA damage assay method was developed for the single-stranded DNA-encoded library (ssDEL) synthesis. The extent of DNA hybridization between single-stranded DNA (ssDNA) and its complementary DNA is influenced by the damage ratio of ssDNA. This damage can be quantified by measuring the change in the fluorescence of PicoGreen, providing valuable insights into the overall ssDNA integrity and facilitating the screening of DNA-compatible conditions for ssDEL synthesis. The assay performance under various conditions, such as pH, temperature, metal ions, and solvents commonly used in ssDEL synthesis, was evaluated, and the results were cross-checked using high-performance liquid chromatography. While certain conditions have been identified as compatible with double-stranded DNA-encoded library synthesis using headpiece DNA, they may still cause considerable DNA damage during ssDEL synthesis due to the low chemical stability of ssDNA. Given its simplicity and speed, this assay can facilitate high-throughput screening of multiple reaction conditions during the early stages of ssDEL synthesis.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590051","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}
Qi Cao, Xiao Wu, Juan Tan, Hanying Xu, Ying Zhang, Yang Hu, Yuxi Chen, Shiyong Zhang and Tian Tang*,
{"title":"Targeting GPX4-Dependent Ferroptosis via a Dihydroartemisinin-Conjugated Cross-Linked Lipoic Acid Nanodrug for Endometrial Carcinoma Therapy","authors":"Qi Cao, Xiao Wu, Juan Tan, Hanying Xu, Ying Zhang, Yang Hu, Yuxi Chen, Shiyong Zhang and Tian Tang*, ","doi":"10.1021/acs.bioconjchem.5c00256","DOIUrl":"10.1021/acs.bioconjchem.5c00256","url":null,"abstract":"<p >Endometrial cancer (EC) is a significant global cause of cancer-related mortality. Chemoresistance is a major challenge in treating advanced or recurrent EC, necessitating the search for new anti-EC drugs. Dihydroartemisinin (DHA)-induced ferroptosis shows promise as a therapy for EC, but its poor solubility and insufficient antitumor potency hinder its clinical use. A novel nanodrug delivery system, DHA@cLAVs, was developed using cross-linked lipoic acid to enhance DHA solubility and antitumor efficacy. Benefiting from the pro-oxidant effects of lipoic acid on tumor cells and its improved water solubility, DHA@cLAVs outperformed DHA alone, showing promising ferroptosis-based antitumor effects via the c-jun/c-fos-GPX4 pathway in both in vitro and in vivo experiments, offering promising prospects for endometrial carcinoma treatment.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1541–1552"},"PeriodicalIF":3.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558423","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}
Ritam Das, Jewel Medeiros, Jithu Krishna, Sriya Munugoti, Ranit Dutta, Anirudh Devarajan, Arpan Ghosh and S. Thayumanavan*,
{"title":"Multicheckpoint Cellular Targeting of siRNAs Using Antibody-Directed Lipid-Polymer Hybrid Nanoparticles","authors":"Ritam Das, Jewel Medeiros, Jithu Krishna, Sriya Munugoti, Ranit Dutta, Anirudh Devarajan, Arpan Ghosh and S. Thayumanavan*, ","doi":"10.1021/acs.bioconjchem.5c00205","DOIUrl":"10.1021/acs.bioconjchem.5c00205","url":null,"abstract":"<p >Despite advancements in tissue-specific gene therapy, current technologies struggle to target organs beyond the liver, spleen, and lungs. Passive approaches such as selective organ targeting (SORT) lipids show potential but require time-intensive optimization. Active targeting, exemplified by antibody-drug conjugates (ADCs), offers a modular and effective alternative. Building on this, we developed antibody-functionalized hybrid lipid-polymer nanoparticles for siRNA delivery, targeting cancer-overexpressed receptors such as EGFR and TROP2, prevalent in aggressive cancers like triple-negative breast cancer (TNBC). In addition, to enhance therapeutic safety and efficacy, we integrated multi-siRNA delivery into a multicheckpoint targeting strategy, minimizing reliance on single antigens and reducing off-target risks. Using TNBC cells as a model, this platform demonstrates potential for developing a robust and safe therapeutic approach. In this article, we present our findings that lay the foundation for developing a multicheckpoint strategy to enhance target selectivity in nanomedicine.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1527–1540"},"PeriodicalIF":3.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558422","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":"Addition of Oligoarginine to a Membrane Permeabilizing Peptide M-Lycotoxin Facilitates Intracellular Antibody Infusion from Microcondensate","authors":"Junya Michibata, Yoshimasa Kawaguchi, Yusei Furuyama, Yoshihiro Sasaki, Kazunari Akiyoshi and Shiroh Futaki*, ","doi":"10.1021/acs.bioconjchem.5c00176","DOIUrl":"10.1021/acs.bioconjchem.5c00176","url":null,"abstract":"<p >Coacervate-based intracellular delivery of biomacromolecules has attracted our attention due to the feasibility of easy condensation of the biomacromolecules and their controllable release. Our laboratory has developed a unique, coacervate-based delivery system that uses the conjugate of the polysaccharide pullulan with membrane-permeabilizing peptides, including L17E and M-lycotoxin. This system enables immunoglobulin G (IgG) antibodies labeled with the negatively charged fluorophore Alexa Fluor 488 to enter the cytosol directly through the plasma membrane. Cyotosolic IgG distribution is complete within a few minutes after infusion initiation, and infusion can be achieved in serum-containing medium. The purpose of this study was to refine this system to reduce the amount of antibody required while maintaining satisfactory delivery efficiencies. Therefore, pullulan conjugates with M-lytocoxin bearing two to eight arginine residues were designed to enhance the interaction of M-lycotoxin with the cell membrane. The conjugates were able to form microcondensates with Alexa Fluor 488 labeled IgGs. The addition of arginine residues improved the efficiency of cytosolic infusion and successfully reduced the amounts of both antibodies and pullulan-peptide conjugates required for the delivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"1494–1503"},"PeriodicalIF":3.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537396","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}