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      Uricase alkaline enzymosomes with enhanced stabilities and anti-hyperuricemia effects induced by favorable microenvironmental changes

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          Abstract

          Enzyme therapy is an effective strategy to treat diseases. Three strategies were pursued to provide the favorable microenvironments for uricase (UCU) to eventually improve its features: using the right type of buffer to constitute the liquid media where catalyze reactions take place; entrapping UCU inside the selectively permeable lipid vesicle membranes; and entrapping catalase together with UCU inside the membranes. The nanosized alkaline enzymosomes containing UCU/(UCU and catalase) (ESU/ESUC) in bicine buffer had better thermal, hypothermal, acid-base and proteolytic stabilities, in vitro and in vivo kinetic characteristics, and uric acid lowering effects. The favorable microenvironments were conducive to the establishment of the enzymosomes with superior properties. It was the first time that two therapeutic enzymes were simultaneously entrapped into one enzymosome having the right type of buffer to achieve added treatment efficacy. The development of ESU/ESUC in bicine buffer provides valuable tactics in hypouricemic therapy and enzymosomal application.

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          Most cited references 46

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          Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy.

          The tumor microenvironment is being increasingly recognized as an important determinant of tumor progression as well as of therapeutic response. We investigated oncolytic virus (OV) therapy-induced changes in tumor blood vessels and the impact of modulating tumor vasculature on the efficacy of oncolytic virus therapy. Rat glioma cells (D74/HveC) were implanted intracranially in immune-competent rats. Seven days later, the rats (groups of 3-7 rats) were treated with oncolytic virus (hrR3), and, 3 days later, brains were harvested for evaluation. Some rats were treated with angiostatic cRGD peptide 4 days before oncolytic virus treatment. Some rats were treated with cyclophosphamide (CPA), an immunosuppressant, 2 days before oncolytic virus treatment. Changes in tumor vascular perfusion were evaluated by magnetic resonance imaging of live rats and by fluorescence microscopy of tumor sections from rats perfused with Texas red-conjugated lectin immediately before euthanasia. Leukocyte infiltration in tumors was evaluated by anti-CD45 immunohistochemistry, and the presence of oncolytic virus in tumors was evaluated by viral titration. Changes in cytokine gene expression in tumors were measured by quantitative real-time polymerase chain reaction-based microarrays. Survival was analyzed by the Kaplan-Meier method. All statistical tests were two-sided. Oncolytic virus treatment of experimental rat gliomas increased tumor vascular permeability, host leukocyte infiltration into tumors, and intratumoral expression of inflammatory cytokine genes, including interferon gamma (IFN-gamma). The increase in vascular permeability was suppressed in rats pretreated with cyclophosphamide. Compared with rats treated with hrR3 alone, rats pretreated with a single dose of cRGD peptide before hrR3 treatment had reduced tumor vascular permeability, leukocyte infiltration, and IFN-gamma protein levels (mean IFN-gamma level for hrR3 versus hrR3 + cRGD = 203 versus 65.6 microg/mg, difference = 137 microg/mg, 95% confidence interval = 72.7 to 202.9 microg/mg, P = .006); increased viral titers in tumor tissue; and longer median survival (21 days versus 17 days, P<.001). A single dose of angiostatic cRGD peptide treatment before oncolytic virus treatment enhanced the antitumor efficacy of oncolytic virus.
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            Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002.

            Chronic kidney disease (CKD) and hyperuricemia often coexist, and both conditions are increasing in prevalence in the United States. However, their shared role in cardiovascular risk remains highly debated.
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              Co-delivery of Cisplatin and Rapamycin for Enhanced Anticancer Therapy through Synergistic Effects and Microenvironment Modulation

              The tumor microenvironment plays an important role in the tumor’s progression and metastasis. Therefore, successful alteration of this delicate setting against the tumor’s favor can open a window for therapeutic efficacy. We have developed a modality to bring about treatment-induced alterations in the tumor microenvironment by employing the synergistic effects between two drugs. Co-delivery of rapamycin (RAPA), an mTOR inhibitor that may offer notable therapy through antiangiogenic activity, alongside cisplatin can foster significant potency as RAPA sensitizes A375 melanoma cells to cisplatin therapy through microenvironment modulation. However, encapsulation of these drugs into poly(lactic-co-glycolic acid) (PLGA) NPs was inefficient due to the incompatibility between the two free drugs and the polymer matrix. Here, we show cisplatin can be made hydrophobic by coating a nanoprecipitate (cores) of the drug with dioleoylphosphatidic acid (DOPA). These DOPA coated cisplatin cores are compatible with PLGA and can be coencapsulated in PLGA NPs alongside RAPA at a molar ratio to promote synergistic antitumor activity. The presence of the cisplatin cores significantly improved the encapsulation of RAPA into PLGA NPs. Furthermore, PLGA NPs containing both cisplatin cores and RAPA induced significant apoptosis on A375-luc human melanoma cells in vitro. Additionally, they inhibited the growth of A375-luc melanoma in a xenograft tumor model through modulation of the tumor vasculature and permitted enhanced penetration of NPs into the tumor.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                29 January 2016
                2016
                : 7
                Affiliations
                [1 ]Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Yixueyuan Road, Yuzhong District , Chongqing 400016, China
                [2 ]West China School of Pharmacy, Sichuan University , Chengdu 610041, China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep20136
                10.1038/srep20136
                4731772
                26823332
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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