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Development of pH-Responsive Hyaluronic Acid-Based Antigen Carriers for Induction of Antigen-Specific Cellular Immune Responses
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    Development of pH-Responsive Hyaluronic Acid-Based Antigen Carriers for Induction of Antigen-Specific Cellular Immune Responses
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    • Maiko Miyazaki
      Maiko Miyazaki
      Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
    • Eiji Yuba*
      Eiji Yuba
      Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
      *Email: [email protected]. Tel: +81-72-254-9330. Fax: +81-72-254-9330 (E.Y.).
      More by Eiji Yuba
    • Hiroshi Hayashi
      Hiroshi Hayashi
      Sciencelin, 1-1-35, Nishiawaji, Higashiyodogawa-ku, Osaka, Osaka 533-0031, Japan
    • Atsushi Harada*
      Atsushi Harada
      Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
      *Email: [email protected] (A.H.).
    • Kenji Kono
      Kenji Kono
      Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
      More by Kenji Kono
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    ACS Biomaterials Science & Engineering

    Cite this: ACS Biomater. Sci. Eng. 2019, 5, 11, 5790–5797
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    https://doi.org/10.1021/acsbiomaterials.9b01278
    Published October 15, 2019
    Copyright © 2019 American Chemical Society

    Abstract

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    Cancer immunotherapy has gained much attention because of the recent success of immune checkpoint inhibitors. Nevertheless, clinical therapeutic effects of immune checkpoint inhibitors remain limited, probably because most patients have other immune checkpoint molecules or because they lack cancer-specific cytotoxic T lymphocytes. Induction of cancer-specific cytotoxic T lymphocytes requires efficient antigen delivery systems that can convey cancer antigens specifically to antigen presenting cells, promote the endosomal escape of antigen into cytosol, and activate immune cells. Earlier, we reported cytoplasmic delivery systems of antigen using pH-sensitive polymer-modified liposomes. Adjuvant molecules were further incorporated into these liposomes to provide activation properties of cellular immune responses. This study further introduced cell specificity to these liposomal systems using hyaluronic acid-based pH-sensitive polymers, which are recognized by CD44 expressing on antigen presenting cells. pH-Sensitive hyaluronic acid derivative-modified liposomes showed much higher cellular association to antigen presenting cells than to fibroblasts with less CD44 expression. These liposomes achieved the delivery of model antigenic proteins into cytosol of dendritic cells and promoted Th1 cytokine production from the cells. Subcutaneous administration of these liposomes to mice induced antigen-specific cellular immune response in the spleen, leading to tumor regression in tumor-bearing mice. The results show that pH-sensitive hyaluronic acid derivative-modified liposomes are promising as multifunctional antigen carriers having cell-specificity, cytoplasmic antigen delivery performance, and adjuvant property to induce antigen-specific cellular immunity.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsbiomaterials.9b01278.

    • Synthesis and characterization of HA derivatives (Tables S1 and S2); HA derivative contents in liposomes (Table S3); OVA retention in liposomes after incubation at pH 7.4 or 4.5 (Figure S1); relative CD44 mRNA expression in APCs after siRNA transfection (Figure S2); effect of CD44 knockdown on cellular association of liposomes (Figure S3); intracellular distribution of DiI-labeled liposomes containing FITC-OVA in DC2.4 cells (Figure S4); evaluation of Th1 response in spleen of mice immunized with liposomes (Figure S5); change in body weight of mice in Figure 4 (Figure S6); and effect of conventional adjuvant inclusion into liposomes on therapeutic effect of tumor-bearing mice (Figure S7) (PDF)

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    ACS Biomaterials Science & Engineering

    Cite this: ACS Biomater. Sci. Eng. 2019, 5, 11, 5790–5797
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsbiomaterials.9b01278
    Published October 15, 2019
    Copyright © 2019 American Chemical Society

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