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      A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery

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          Abstract

          Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.

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          Most cited references82

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          Analysis of nanoparticle delivery to tumours

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            Principles of nanoparticle design for overcoming biological barriers to drug delivery.

            Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
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              Tumor-associated macrophages: from mechanisms to therapy.

              The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate that these macrophages generally play a protumoral role. In the primary tumor, macrophages can stimulate angiogenesis and enhance tumor cell invasion, motility, and intravasation. During monocytes and/or metastasis, macrophages prime the premetastatic site and promote tumor cell extravasation, survival, and persistent growth. Macrophages are also immunosuppressive, preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immunotherapy. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                wolfram.joy@mayo.edu
                mferrari@houstonmethodist.org
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                23 October 2017
                23 October 2017
                2017
                : 7
                : 13738
                Affiliations
                [1 ]ISNI 0000 0004 0445 0041, GRID grid.63368.38, Department of Nanomedicine, Houston Methodist Research Institute, ; Houston, TX 77030 USA
                [2 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Transplantation, Mayo Clinic, ; Jacksonville, FL 32224 USA
                [3 ]ISNI 0000 0004 1936 8278, GRID grid.21940.3e, Applied Physics Graduate Program, Rice University, ; Houston, TX 77005 USA
                [4 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Cell and Developmental Biology, Weill Cornell Medicine, ; New York, NY 10065 USA
                [5 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Medicine, Weill Cornell Medicine, Weill Cornell Medicine, ; New York, NY 10065 USA
                Article
                14221
                10.1038/s41598-017-14221-2
                5653759
                29062065
                928dd27d-5bf0-4344-8191-499de4cefea0
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 May 2017
                : 6 October 2017
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