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Virosomes of hepatitis B virus envelope L proteins containing doxorubicin: synergistic enhancement of human liver-specific antitumor growth activity by radiotherapy.

Liu Q, Jung J, Somiya M, Iijima M, Yoshimoto N, Niimi T, Maturana AD, Shin SH, Jeong SY, Choi EK, Kuroda S - Int J Nanomedicine (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Evaluation of cardiotoxicity.Notes: Mice were intravenously injected with DOX, LP–DOX complexes, and virosomes containing DOX (as DOX 5 mg/kg) two times per week for 3 weeks. Myocardial samples were isolated from the left ventricle. Mitochondria (M) and myofibril (My) structures were shown in myocardium electron micrographs. Scale bars represent 1 μm.Abbreviations: DOX, doxorubicin; LP, liposome.
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f8-ijn-10-4159: Evaluation of cardiotoxicity.Notes: Mice were intravenously injected with DOX, LP–DOX complexes, and virosomes containing DOX (as DOX 5 mg/kg) two times per week for 3 weeks. Myocardial samples were isolated from the left ventricle. Mitochondria (M) and myofibril (My) structures were shown in myocardium electron micrographs. Scale bars represent 1 μm.Abbreviations: DOX, doxorubicin; LP, liposome.

Mentions: As for the in vivo cytotoxicity of virosomes containing DOX, since BNC possesses a HBV-derived infection system, there have been concerns that the virosomes containing DOX (the complex of BNCs and LP–DOX) could induce the immune system into attacking healthy liver cells. However, BNC (targeting molecule of virosomes) has already been shown as a safe biomaterial in humans.30,31 And, the LP–DOX complexes (ie, Doxil, DOXOVES) have also been confirmed safe in human.26 It was therefore considered that the virosomes containing DOX are not cytotoxic in vivo. Furthermore, we examined the in vivo cytotoxicity of the drug in mice. Because the virosomes can target human liver only (not mouse liver) and DOX shows strong cytotoxicity in heart,26 we examined the cardiotoxicity by observation under TEM. As shown in Figure 8, the DOX-treated mice displayed more extensive mitochondrial degeneration in association with marked swelling, cristae disorganization, and myofibril degeneration compared with nontreated mice. Mice treated with LP–DOX complexes and those with virosomes containing DOX exhibited no significant change from nontreated mice, indicating that both drugs have no cardiotoxicity. As for liver injury, the virosomes containing DOX did not increase AST and ALT levels in mouse serum compared with the levels in control mice (40±3 U/L and 22±2 U/L, respectively; n=5). Based upon the safety data in human, the cardiotoxicity, and the serum data, it was strongly suggested that the virosomes containing DOX are not cytotoxic in vivo.


Virosomes of hepatitis B virus envelope L proteins containing doxorubicin: synergistic enhancement of human liver-specific antitumor growth activity by radiotherapy.

Liu Q, Jung J, Somiya M, Iijima M, Yoshimoto N, Niimi T, Maturana AD, Shin SH, Jeong SY, Choi EK, Kuroda S - Int J Nanomedicine (2015)

Evaluation of cardiotoxicity.Notes: Mice were intravenously injected with DOX, LP–DOX complexes, and virosomes containing DOX (as DOX 5 mg/kg) two times per week for 3 weeks. Myocardial samples were isolated from the left ventricle. Mitochondria (M) and myofibril (My) structures were shown in myocardium electron micrographs. Scale bars represent 1 μm.Abbreviations: DOX, doxorubicin; LP, liposome.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487236&req=5

f8-ijn-10-4159: Evaluation of cardiotoxicity.Notes: Mice were intravenously injected with DOX, LP–DOX complexes, and virosomes containing DOX (as DOX 5 mg/kg) two times per week for 3 weeks. Myocardial samples were isolated from the left ventricle. Mitochondria (M) and myofibril (My) structures were shown in myocardium electron micrographs. Scale bars represent 1 μm.Abbreviations: DOX, doxorubicin; LP, liposome.
Mentions: As for the in vivo cytotoxicity of virosomes containing DOX, since BNC possesses a HBV-derived infection system, there have been concerns that the virosomes containing DOX (the complex of BNCs and LP–DOX) could induce the immune system into attacking healthy liver cells. However, BNC (targeting molecule of virosomes) has already been shown as a safe biomaterial in humans.30,31 And, the LP–DOX complexes (ie, Doxil, DOXOVES) have also been confirmed safe in human.26 It was therefore considered that the virosomes containing DOX are not cytotoxic in vivo. Furthermore, we examined the in vivo cytotoxicity of the drug in mice. Because the virosomes can target human liver only (not mouse liver) and DOX shows strong cytotoxicity in heart,26 we examined the cardiotoxicity by observation under TEM. As shown in Figure 8, the DOX-treated mice displayed more extensive mitochondrial degeneration in association with marked swelling, cristae disorganization, and myofibril degeneration compared with nontreated mice. Mice treated with LP–DOX complexes and those with virosomes containing DOX exhibited no significant change from nontreated mice, indicating that both drugs have no cardiotoxicity. As for liver injury, the virosomes containing DOX did not increase AST and ALT levels in mouse serum compared with the levels in control mice (40±3 U/L and 22±2 U/L, respectively; n=5). Based upon the safety data in human, the cardiotoxicity, and the serum data, it was strongly suggested that the virosomes containing DOX are not cytotoxic in vivo.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan ; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.

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.

No MeSH data available.


Related in: MedlinePlus