title: Virosomes of hepatitis B virus envelope L proteins containing doxorubicin: synergistic enhancement of human liver-specific antitumor growth activity by radiotherapy.
abstract: Bionanocapsules (BNCs) are hollow nanoparticles consisting of hepatitis B virus (HBV) envelope L proteins and have been shown to deliver drugs and genes specifically to human hepatic tissues by utilizing HBV-derived infection machinery. The complex of BNCs with liposomes (LPs), the BNC-LP complexes (a LP surrounded by BNCs in a rugged spherical form), could also become active targeting nanocarriers by the BNC function. In this study, under acidic conditions and high temperature, BNCs were found to fully fuse with LPs (smooth-surfaced spherical form), deploying L proteins with a membrane topology similar to that of BNCs (ie, virosomes displaying L proteins). Doxorubicin (DOX) was efficiently encapsulated via the remote loading method at 14.2%±1.0% of total lipid weight (mean ± SD, n=3), with a capsule size of 118.2±4.7 nm and a ζ-potential of -51.1±1.0 mV (mean ± SD, n=5). When mammalian cells were exposed to the virosomes, the virosomes showed strong cytotoxicity in human hepatic cells (target cells of BNCs), but not in human colon cancer cells (nontarget cells of BNCs), whereas LPs containing DOX and DOXOVES (structurally stabilized PEGylated LPs containing DOX) did not show strong cytotoxicity in either cell type. Furthermore, the virosomes preferentially delivered DOX to the nuclei of human hepatic cells. Xenograft mice harboring either target or nontarget cell-derived tumors were injected twice intravenously with the virosomes containing DOX at a low dose (2.3 mg/kg as DOX, 5 days interval). The growth of target cell-derived tumors was retarded effectively and specifically. Next, the combination of high dose (10.0 mg/kg as DOX, once) with tumor-specific radiotherapy (3 Gy, once after 2 hours) exhibited the most effective antitumor growth activity in mice harboring target cell-derived tumors. These results demonstrated that the HBV-based virosomes containing DOX could be an effective antitumor nanomedicine specific to human hepatic tissues, especially in combination with radiotherapy.
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute for Innovative Cancer Research, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea ; College of Pharmacy, Duksung Women's University, Seoul, Republic of Korea.
authors.forename: Joohee
authors.initials: J
authors.lastname: Jung
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan ; Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Somiya
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yoshimoto
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Niimi
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
authors.forename: Andrés D
authors.initials: AD
authors.lastname: Maturana
authors.affiliation: Institute for Innovative Cancer Research, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea ; ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seol Hwa
authors.initials: SH
authors.lastname: Shin
authors.affiliation: Institute for Innovative Cancer Research, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea ; ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Institute for Innovative Cancer Research, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea ; Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea ; Center for Development and Commercialization of Anti-Cancer Therapeutics, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.
authors.forename: Shun'ichi
authors.initials: S
authors.lastname: Kuroda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D011878:Radiotherapy / Q000379:methods; D014759:Viral Envelope Proteins / Q000737:chemistry*; D022701:Virosomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C096362:L protein, hepatitis B virus; D014759:Viral Envelope Proteins; D022701:Virosomes; D004317:Doxorubicin
keywords: bionanocapsule; chemoradiotherapy; doxorubicin; drug delivery system; liposomes; targeting