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      Arming Filamentous Bacteriophage, a Nature-Made Nanoparticle, for New Vaccine and Immunotherapeutic Strategies

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          Abstract

          The pharmaceutical use of bacteriophages as safe and inexpensive therapeutic tools is collecting renewed interest. The use of lytic phages to fight antibiotic-resistant bacterial strains is pursued in academic and industrial projects and is the object of several clinical trials. On the other hand, filamentous bacteriophages used for the phage display technology can also have diagnostic and therapeutic applications. Filamentous bacteriophages are nature-made nanoparticles useful for their size, the capability to enter blood vessels, and the capacity of high-density antigen expression. In the last decades, our laboratory focused its efforts in the study of antigen delivery strategies based on the filamentous bacteriophage ‘fd’, able to trigger all arms of the immune response, with particular emphasis on the ability of the MHC class I restricted antigenic determinants displayed on phages to induce strong and protective cytotoxic responses. We showed that fd bacteriophages, engineered to target mouse dendritic cells (DCs), activate innate and adaptive responses without the need of exogenous adjuvants, and more recently, we described the display of immunologically active lipids. In this review, we will provide an overview of the reported applications of the bacteriophage carriers and describe the advantages of exploiting this technology for delivery strategies.

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          Organ targeting in vivo using phage display peptide libraries.

          Preferential homing of tumour cells and leukocytes to specific organs indicates that tissues carry unique marker molecules accessible to circulating cells. Organ-selective address molecules on endothelial surfaces have been identified for lymphocyte homing to various lymphoid organs and to tissues undergoing inflammation, and an endothelial marker responsible for tumour homing to the lungs has also been identified. Here we report a new approach to studying organ-selective targeting based on in vivo screening of random peptide sequences. Peptides capable of mediating selective localization of phage to brain and kidney blood vessels were identified, and showed up to 13-fold selectivity for these organs. One of the peptides displayed by the brain-localizing phage was synthesized and shown to specifically inhibit the localization of the homologous phage into the brain. When coated onto glutaraldehyde-fixed red blood cells, the peptide caused selective localization of intravenously injected cells into the brain. These peptide sequences represent the first step towards identifying selective endothelial markers, which may be useful in targeting cells, drugs and genes into selected tissues.
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            The inflammasomes: mechanisms of activation and function.

            Eicke Latz (2010)
            In response to injurious or infectious agents caspase-1 activating multiprotein complexes, termed inflammasomes, assemble in the cytoplasm of cells. Activated caspase-1 cleaves the proforms of the interleukin-1 cytokine family members leading to their activation and secretion. The IL-1 family cytokines have multiple proinflammatory activities implicating them in the pathogenesis of many inflammatory diseases. While defined ligands have been identified for the NLRP1, IPAF, and AIM2 inflammasomes, little is known about the activation mechanisms of the NLRP3 inflammasome. Numerous different molecular entities, such as various crystals, pore-forming toxins, or extracellular ATP can trigger the NLRP3 inflammasome. Recent work proposes that NLRP3 is activated indirectly by host factors that are generated in response to NLRP3 triggers. Copyright 2009 Elsevier Ltd. All rights reserved.
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              Stepwise dismantling of adenovirus 2 during entry into cells.

              Adenoviruses enter their host cells by receptor-mediated endocytosis and acid-activated penetration from endosomes into the cytosol and deliver their DNA genome into the nucleus. Our results show that incoming adenovirus type 2 particles undergo a stepwise disassembly program necessary to allow progress of the virus in the entry pathway and release of the genome into the nucleus. The fibers are released, the penton base structures dissociated, the proteins connecting the DNA to the inside surface of the capsid degraded or shed, and the capsid-stabilizing minor proteins eliminated. The uncoating process starts immediately upon endocytic uptake with the loss of fibers and ends with the uptake of dissociated hexon proteins and DNA into the nucleus.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                01 September 2019
                September 2019
                : 11
                : 9
                : 437
                Affiliations
                [1 ]Institute of Biochemistry and Cell Biology (IBBC), 80131 CNR Naples, Italy
                [2 ]Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), 80131 CNR Naples, Italy
                Author notes
                [* ]Correspondence: luciana.dapice@ 123456cnr.it ; Tel.: +39-081-613-2584
                Author information
                https://orcid.org/0000-0003-0153-9377
                https://orcid.org/0000-0002-6513-2237
                https://orcid.org/0000-0001-8061-0068
                Article
                pharmaceutics-11-00437
                10.3390/pharmaceutics11090437
                6781307
                31480551
                f9e05d02-5d06-46c9-9648-fd25f2b438da
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 June 2019
                : 22 August 2019
                Categories
                Review

                filamentous bacteriophage,vaccine,nanoparticle,targeting,phage display,antigen delivery

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