Development of pH-Responsive Hyaluronic Acid-Based Antigen Carriers for Induction of Antigen-Specific Cellular Immune ResponsesClick to copy article linkArticle link copied!
- Maiko MiyazakiMaiko MiyazakiDepartment of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, JapanMore by Maiko Miyazaki
- Eiji Yuba*Eiji Yuba*Email: [email protected]. Tel: +81-72-254-9330. Fax: +81-72-254-9330 (E.Y.).Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, JapanMore by Eiji Yuba
- Hiroshi HayashiHiroshi HayashiSciencelin, 1-1-35, Nishiawaji, Higashiyodogawa-ku, Osaka, Osaka 533-0031, JapanMore by Hiroshi Hayashi
- Atsushi Harada*Atsushi Harada*Email: [email protected] (A.H.).Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, JapanMore by Atsushi Harada
- Kenji KonoKenji KonoDepartment of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, JapanMore by Kenji Kono
Abstract

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.
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