title: Enhancement of the anti-tumor effect of DNA vaccination using an ultrasound-responsive mannose-modified gene carrier in combination with doxorubicin-encapsulated PEGylated liposomes.
abstract: A method involving the use of doxorubicin-loaded polyethylene-glycol-modified liposomes and transfection using mannose-modified bubble lipoplexes in combination with ultrasound irradiation may be a promising approach to cancer treatment; it could not only suppress early-stage tumor growth but also enhance transfection efficacy in antigen-presenting cells, thus enhancing the therapeutic potential of a DNA vaccine. However, to date only limited research has been carried out regarding this combination DNA vaccination method for use in cancer therapy. In this study, we examined the anti-tumor effect of DNA vaccination using an ultrasound-responsive mannose-modified gene carrier combined with doxorubicin-encapsulated polyethylene-glycol-modified liposomes. Doxorubicin-encapsulated PEGylated liposomes activated transcriptional factors, such as nuclear factor-κB and AP-1 in the spleen; subsequently pUb-M, ubiquitylated melanoma-related antigen encoding plasmid DNA expression in splenic cells was significantly enhanced. Moreover, effective cytotoxic T-lymphocyte activities were stimulated by DNA vaccination combined with the administration of doxorubicin-encapsulated polyethylene-glycol-modified liposomes. Furthermore, potent DNA vaccine effects against established solid tumor and metastatic tumor derived from B16BL6 melanoma were observed. These results suggest that the combined use of DNA vaccination with doxorubicin-encapsulated polyethylene-glycol-modified liposomes could be an effective method for the treatment of melanoma using immunotherapy.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Division of Analytical Research for Pharmacoinformatics, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: y-kono@fc.ritsumei.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kono
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Un
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: Department of Biopharmaceutics, School of Pharmaceutical Science, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8302, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008358:Mannose / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D010957:Plasmids; D011092:Polyethylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000276:immunology; D014162:Transfection; D014464:Ultrasonic Therapy / Q000379:methods*; D019444:Vaccines, DNA / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019444:Vaccines, DNA; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D008358:Mannose
keywords: Bubble lipoplexes,; DNA vaccination; Doxorubicin; Melanoma treatment; Transcriptional activation