Frontiers in drug delivery最新文献

{"title":"Design of respirable sprayed microparticles of encapsulated bacteriophages","authors":"A. Baldelli, Mingtao Liang","doi":"10.3389/fddev.2023.1209534","DOIUrl":"https://doi.org/10.3389/fddev.2023.1209534","url":null,"abstract":"Antibiotic resistance is exponentially increasing, and the number of deaths caused by bacterial infections is expected to surge. When dealing with the respiratory system, inefficient antibiotics heighten the chance of death from bacterial infection. However, the alternatives to antibiotics are limited. Bacteriophages are a valid option since they can target a specific type of bacterium. Bacteriophages are highly specific and can avoid any side effects when delivered. However, their poor stability makes their use inefficient. Encapsulation is commonly used to protect any bioactive compound for different types of delivery. In the case of respiratory delivery, particle engineering is used to generate stable dry powders to target the nasal or lung areas. This review article provides a guideline for engineering a process of nasal dry powders of encapsulated bacteriophages.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41705974","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":"On a model-based approach to improve intranasal spray targeting for respiratory viral infections","authors":"Mohammad Mehedi Hasan Akash, Y. Lao, P. A. Balivada, P. Ato, Nogaye K. Ka, A. Mituniewicz, Z. Silfen, J. Suman, A. Chakravarty, D. Joseph-McCarthy, Saikat Basu","doi":"10.3389/fddev.2023.1164671","DOIUrl":"https://doi.org/10.3389/fddev.2023.1164671","url":null,"abstract":"The nasopharynx, at the back of the nose, constitutes the dominant initial viral infection trigger zone along the upper respiratory tract. However, as per the standard recommended usage protocol (“Current Use”, or CU) for intranasal sprays, the nozzle should enter the nose almost vertically, resulting in sub-optimal nasopharyngeal drug deposition. Through the Large Eddy Simulation technique, this study has replicated airflow under standard breathing conditions with 15 and 30 L/min inhalation rates, passing through medical scan-based anatomically accurate human airway cavities. The small-scale airflow fluctuations were resolved through use of a sub-grid scale Kinetic Energy Transport Model. Intranasally sprayed droplet trajectories for different spray axis placement and orientation conditions were subsequently tracked via Lagrangian-based inert discrete phase simulations against the ambient inhaled airflow field. Finally, this study verified the computational projections for the upper airway drug deposition trends against representative physical experiments on sprayed delivery performed in a 3D-printed anatomic replica. The model-based exercise has revealed a new “Improved Use” (or, IU) spray usage protocol for viral infections. It entails pointing the spray bottle at a shallower angle (with an almost horizontal placement at the nostril), aiming slightly toward the cheeks. From the conically injected spray droplet simulations, we have summarily derived the following inferences: (a) droplets sized between 7–17 μm are relatively more efficient at directly reaching the nasopharynx via inhaled transport; and (b) with realistic droplet size distributions, as found in current over-the-counter spray products, the targeted drug delivery through the IU protocol outperforms CU by a remarkable 2 orders-of-magnitude.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45625566","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":"Identification of transport systems involved in eflornithine delivery across the blood-brain barrier.","authors":"Christopher P Watson, Gayathri Nair Sekhar, Sarah A Thomas","doi":"10.3389/fddev.2023.1113493","DOIUrl":"10.3389/fddev.2023.1113493","url":null,"abstract":"<p><p>Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter (<i>Trypanosoma brucei</i> AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system-y⁺ and system-B^0,+. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an <i>in vitro</i> model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y⁺-system inhibitor, but not a B^0,+-system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y⁺-system protein, CAT1, and the B^0,+-system protein, ATB^0,+, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y⁺, and OCT to cross the BBB. This research highlights the potential of system-y⁺ to deliver drugs, including eflornithine, across the BBB to treat brain diseases.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7615738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42002808","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":"Modified dipeptide based nanospheres as a potent adjuvating delivery system for recombinant vaccines","authors":"S. Biswas, N. Yadav, A. Somanathan, P. Mukherjee, V. Chauhan","doi":"10.3389/fddev.2023.1135209","DOIUrl":"https://doi.org/10.3389/fddev.2023.1135209","url":null,"abstract":"Recombinant protein vaccines offer an advantage without a safety risk in eliciting desired humoral and cell-mediated immune responses against infectious diseases. But one of their disadvantages is their low immunogenicity, thus requiring adjuvants that augment their immunogenicity. It is necessary to explore new technology that could provide a non-toxic, biodegradable, and biocompatible delivery system with adjuvant characteristics and nanotechnology provides an excellent platform for nanomaterial-based vaccine adjuvants. Here, we have synthesized a modified dipeptide, Arg-α, β-dehydrophenyalanine (RΔF) containing ΔF at its C-terminal, and characterized it using reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry techniques. RΔF upon its self-assembly to spherical nanoparticles (NPs) efficiently condensed a recombinant Plasmodium falciparum surface protein, histidine-tagged MSPFu24 (Fu24H). The morphological characteristics of the nanoparticle formulation was characterized using TEM. RΔF NPs and RΔF-Fu24H complex showed excellent in vitro biocompatibility toward two mammalian cell lines and human red blood cells (RBCs). Furthermore, mice treated with R∆F NPs showed histological and haematological properties similar to the untreated control group which indicated their very high in vivo biocompatibility. Mice treated with RΔF-Fu24H nanoformulation induced a high titers of anti-Fu24H specific antibodies and showed a mixed Th1 and Th2 profile, comparable to the FDA-approved adjuvant Alhydrogel®. The sera from immunized mice inhibited the erythrocyte invasion activity of P. falciparum’s laboratory line 3D7 in vitro which was comparable to that of Alhydrogel®. The present study suggests that the highly biocompatible dipeptide-based nanoparticle formulation can further be developed and used in clinic as a promising antigen delivery platform to elicit immune responses.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47337333","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":"Usefulness of direct intratumoral administration of doxorubicin hydrochloride with an electro-osmosis–assisted pump","authors":"Ayu Ito, S. Itakura, Yuya Hasegawa, Miyu Hashimoto, Akie Okada, Mamoru Hirafuji, H. Nakamura, K. Sugibayashi, H. Todo","doi":"10.3389/fddev.2023.1150894","DOIUrl":"https://doi.org/10.3389/fddev.2023.1150894","url":null,"abstract":"Patients receiving chemotherapy by intravenous (i.v.) or oral administration of anticancer drugs often experience side effects. In this study, an electro-osmotic flow (EO) pump was used for the direct administration of an anticancer drug with minimum side effects. Doxorubicin hydrochloride (DXR) was used as an anticancer drug, and its antitumor effect and toxicity were evaluated in comparison with i.v. administration. Balb/c female mice were subcutaneously transplanted with a breast cancer cell line (4T1/Luc) stably expressing luciferase, and 20 μL of DXR solution (1.0 mg/mL) was administered intratumorally (i.t.) at a slow rate (0.6 µL/min) using an EO pump or rapidly using a syringe. For comparison, 100 μL of DXR solution was injected through the tail vein at the same dose and a 5-times higher dose. A tumor growth inhibitory effect without significant weight loss was observed with direct i.t. administration of DXR using an EO pump. On the other hand, no suppressive tumor growth effect was observed with i.v. administration of DXR at the same dose. Although there was no significant difference in the suppression effect on tumor growth between i.t. administration with EO pump and syringe, the peripheral skin concentration of DXR were decreased after slow administration with EO pump compared with that after rapidly administration with a syringe. These results indicated that direct i.t. administration of DXR with lower dosing using an EO pump at slower administration rate may be useful for exhibiting antitumor effects and suppressing systemic side effects. In addition, the blood concentration and the peripheral skin concentration of DXR after administration at lower rate with EO pump were decreased compared with those after the rapidly administration with a syringe.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49460071","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":"CRISPR-mediated optogene expression from a cell-specific endogenous promoter in retinal ON-bipolar cells to restore vision","authors":"A. Maddalena, S. Kleinlogel","doi":"10.3389/fddev.2023.934394","DOIUrl":"https://doi.org/10.3389/fddev.2023.934394","url":null,"abstract":"Retinitis pigmentosa, an inherited form of retinal degeneration, is characterized by a progressive loss of rods and subsequent degeneration of cones, leading to blindness. However, the remaining neural portion of the retina (bipolar and ganglion cells) remains anatomically and functionally intact for an extended time. A possible treatment to restore the light sensitivity of the retina consists of rendering the remaining retinal cells photosensitive using optogenetic tools like, for example, Opto-mGluR6, a light-sensitive mGluR6 receptor. We have previously demonstrated that AAV vector-mediated expression of Opto-mGluR6 in ON-bipolar cells restores visual function in otherwise blind mice. However, classical gene supplementation therapy still suffers from high off-target expression rates and uncontrollable target gene expression levels that may lead to either cytotoxicity or lack of functional restoration. To address these issues and achieve cell-specific and endogenously controlled Opto-mGluR6 expression, we employed the CRISPR/Cas technology—in particular, homology-independent targeted integration (HITI) and microhomology-dependent targeted integration (MITI)—to knock-in the Opto-mGluR6 gene behind the ON-bipolar cell-specific GRM6 promoter. We compared four Cas systems in vitro and show that SpCas9 for HITI and LbCpf1 for MITI are well suited to promoting knock-in. As AAV2-mediated ON-bipolar cell transduction resulted in inefficiency, we evaluated Exo-AAVs as delivery vehicles and found Exo-AAV1 efficient for targeting ON-bipolar cells. We demonstrate that intravitreal injection of Exo-AAV1 carrying vectors that promote MITI significantly improved visual acuity in otherwise blind rd1 mice. We conclude by confirming and providing a qualitative evaluation of the MITI-mediated knock-in in the correct genomic locus.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49159478","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":"Roles of biomaterials in modulating the innate immune response in ocular therapy","authors":"Mehrnoosh Rafiei, Jin Teng Chung, Y. Chau","doi":"10.3389/fddev.2023.1077253","DOIUrl":"https://doi.org/10.3389/fddev.2023.1077253","url":null,"abstract":"The eye is a hard-to-treat organ due to its poor regenerative capacity and susceptibility to inflammation; as a result, it has an immune privilege mechanism. In the case of ocular degenerative disorders, chronic and uncontrolled ocular inflammations can overcome this immune response to initiate and exacerbate tissue degeneration, ultimately leading to blindness. Recent landmark discoveries on the key roles of the ocular innate immune system in regulating acute and chronic inflammations as well as tissue fibrosis and homeostasis have shed light on the value of novel treatment interventions in modulating ocular immune responses at the molecular, cellular, and tissue levels. This strategy can be attained by using therapeutics to target resident phagocytes and antigen-presenting cells, namely, microglia and dendritic cells, as well as infiltrating neutrophils and macrophages. Biomaterials are foreign materials to the host and interact with innate immune cells. To leverage such intrinsic immunomodulatory properties, biomaterials such as implants, injectable depots, and nano/micro particles can be used alone as a treatment or with different payloads as carriers in immune-related ocular disorders. This article discusses how physicochemical properties such as biodegradability, size, shape, and charge affect biomaterials’ interaction with the eye’s innate immune system, therefore influencing outcomes towards pro- or anti-inflammatory responses. Knowledge about the eye’s immunological response is required for designing tolerogenic biomaterials including intraocular lenses, cellular scaffolds, therapeutic molecule depots, or carriers of gene therapies. The discussion presented in this review will shed light on the potential use of biomaterials to direct immune responses toward favorable treatment outcomes.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42234731","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":"Molecular distribution in intradermal injection for transfer and delivery of therapeutics","authors":"E. Lallow, Kishankumar J. Busha, Sarah H. Park, Maria Atzampou, N. C. Jhumur, Yasir Demiryurek, C. Roberts, J. Shan, J. Zahn, D. Shreiber, Young K Park, J. Singer, J. Maslow, Hao Lin","doi":"10.3389/fddev.2023.1095181","DOIUrl":"https://doi.org/10.3389/fddev.2023.1095181","url":null,"abstract":"Intradermal (ID) injection is a technique widely used in laboratorial and clinical applications. The boundary of the dome-like bleb formed during injection is assumed to represent the lateral extent of the injected material. This work systematically characterizes cargo molecule distribution (puddle) as a function of injection volume and molecular/particle size in rat skin post ID injection. In general, results indicate that the puddle forms a subdomain laterally contained within the bleb, with an area inversely correlating to the molecular size of the injected material. For 50 μL and 100 µL injections, the average area of the bleb was 40.97 ± 6.30 mm2 and 55.64 ± 8.20 mm2, respectively, regardless of the molecular/particle size. On the other hand, the area of the puddle was dependent on the molecular size and ranged between 45.38 ± 8.29 mm2 and 6.14 ± 4.50 mm2 for 50 µL injections, and 66.64 ± 11.22 mm2 and 11.50 ± 9.67 mm2 for 100 µL injections. The lateral distribution appears to have no time-dependency up to 10 min post injection. The trend in the depth of cargo penetration is also similar, with smaller particles extending deeper into the dermis and subcutaneous fat layers. Because the area of puddle can be significantly less than that of the bleb, establishing base characterization is essential to understand cellular interactions with the injected biological substances.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48693504","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":"SorLA in astrocytes regulates blood-brain barrier integrity","authors":"A. Tóth, Adrián Klepe, Dora V. Lipka, C. Goldeman, B. Brodin, M. Nielsen","doi":"10.3389/fddev.2022.1082689","DOIUrl":"https://doi.org/10.3389/fddev.2022.1082689","url":null,"abstract":"The brain`s homeostasis depends heavily on the integrity of the blood-brain barrier (BBB). Astrocytes are an essential part of the BBB in modulating and maintaining the barrier properties of the brain endothelial cells (BECs). Despite decades of research, the elements of glial regulation are not fully elucidated. SorLA/SorL1/LR11, a multifunctional receptor, is the most composite member of the Vps10p domain receptor family. In this study, we characterize the expression and function of SorLA in the cells of the BBB. The applied in vitro approaches describe BBB functions in primary cells isolated from wild-type and Sorl1 −/− knock-out rats. Here, we present that Sorl1 gene is highly expressed in wild-type astrocytes but not in BECs and pericytes. Furthermore, we show that SorLA in astrocytes is an important regulator of the BBB’s tightness. The primary rat BBB models where astrocytes lack SorLA protein proved leaky, which correlated well with the decrease in claudin-5 tight junction protein in BECs. Meanwhile, other junctional proteins, i.e., occludin and zonula occludens-1 are unaffected. Collectively, these data suggest that the absence of SorLA in astrocytes affects the tight junctions of BECs, thereby disturbing the BBB. Our results add another layer to understanding astrocyte-endothelial interactions in the healthy and diseased BBB.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46942899","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":"Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier.","authors":"William M Pardridge","doi":"10.3389/fddev.2023.1227816","DOIUrl":"https://doi.org/10.3389/fddev.2023.1227816","url":null,"abstract":"<p><p>Therapeutic antibody drug development is a rapidly growing sector of the pharmaceutical industry. However, antibody drug development for the brain is a technical challenge, and therapeutic antibodies for the central nervous system account for ~3% of all such agents. The principal obstacle to antibody drug development for brain or spinal cord is the lack of transport of large molecule biologics across the blood-brain barrier (BBB). Therapeutic antibodies can be made transportable through the blood-brain barrier by the re-engineering of the therapeutic antibody as a BBB-penetrating bispecific antibody (BSA). One arm of the BSA is the therapeutic antibody and the other arm of the BSA is a transporting antibody. The transporting antibody targets an exofacial epitope on a BBB receptor, and this enables receptor-mediated transcytosis (RMT) of the BSA across the BBB. Following BBB transport, the therapeutic antibody then engages the target receptor in brain. RMT systems at the BBB that are potential conduits to the brain include the insulin receptor (IR), the transferrin receptor (TfR), the insulin-like growth factor receptor (IGFR) and the leptin receptor. Therapeutic antibodies have been re-engineered as BSAs that target the insulin receptor, TfR, or IGFR RMT systems at the BBB for the treatment of Alzheimer's disease and Parkinson's disease.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10426772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10022062","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}