DNA-loaded nano-adjuvant formed with a vitamin E-scaffold intracellular environmentally-responsive lipid-like material for cancer immunotherapy |
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| Authors: | Minori Kawai Takashi Nakamura Naoya Miura Mio Maeta Hiroki Tanaka Keisuke Ueda Kenjirou Higashi Kunikazu Moribe Kota Tange Yuta Nakai Hiroki Yoshioka Hideyoshi Harashima Hidetaka Akita |
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| Affiliation: | 1. Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Hokkaido, Japan;2. DDS Research Laboratory NOF Corporation, Kawasaki-ku, Kawasaki, Kanagawa, Japan;3. Laboratory of Pharmacy and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba-Shi, Chiba, Japan;4. Laboratory of Pharmaceutical Technology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba-Shi, Chiba, Japan |
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| Abstract: | Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE). The pDNA-encapsulating LNP (ssPalmE-LNP) induced a high interferon-β production in Raw 264.7 cells. The subcutaneous injection of ssPalmE-LNP strongly enhanced antigen-specific cytotoxic T cell activity. The ssPalmE-LNP treatment efficiently induced antitumor effects against E.G7-OVA tumor and B16-F10 melanoma metastasis. Furthermore, when combined with an anti-programmed death 1 antibody, an extensive therapeutic antitumor effect was observed. Therefore, the ssPalmE-LNP is a promising carrier of adjuvants for cancer immunotherapy. |
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| Keywords: | Cancer immunotherapy DNA Adjuvant ssPalm Intracellular trafficking |
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