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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 chemotherapeutic efficacies.Notes: Nude mice harboring NuE (A, C) or WiDr (B, D) xenograft tumors were intravenously injected twice (0 and 5 days) with virosomes containing DOX (red squares), LP–DOX complexes (green circles), DOX (blue diamonds), DOXOVES (purple triangles), and control (black crosses) at a low DOX dose (2.3 mg/kg). Tumor volume (A, B) and body weight (C, D) of the mice were measured for 15 days. Error bars represent standard deviation (n=5). Black arrows indicate intravenous injections.Abbreviations: DOX, doxorubicin; LP, liposome.
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f7-ijn-10-4159: Evaluation of chemotherapeutic efficacies.Notes: Nude mice harboring NuE (A, C) or WiDr (B, D) xenograft tumors were intravenously injected twice (0 and 5 days) with virosomes containing DOX (red squares), LP–DOX complexes (green circles), DOX (blue diamonds), DOXOVES (purple triangles), and control (black crosses) at a low DOX dose (2.3 mg/kg). Tumor volume (A, B) and body weight (C, D) of the mice were measured for 15 days. Error bars represent standard deviation (n=5). Black arrows indicate intravenous injections.Abbreviations: DOX, doxorubicin; LP, liposome.

Mentions: The antitumor effect of virosomes containing DOX has been evaluated by in vivo tumor growth assays using a mouse xenograft model. Mice were intravenously injected with a low dose of DOX (2.3 mg/kg) twice (day 0 and day 5). Since virosomes alone showed no significant effect on tumor growth in comparison with control, we examined the chemotherapeutic efficacies of DOX, LP–DOX complexes, virosomes containing DOX, and DOXOVES. On day 15, in mice harboring NuE (target cell)-derived tumors, the average rates of tumor growth inhibition (T/C, treated versus control; %) of DOX, LP–DOX complexes, virosomes containing DOX, and DOXOVES were 90.9%, 81.6%, 54.1%, and 38.6%, respectively (Figure 7A). Meanwhile, in mice harboring WiDr (nontarget cell)-derived tumors on day 15, the T/C values (%) of DOX, LP–DOX complexes, virosomes containing DOX, and DOXOVES were 90.6%, 82.8%, 81.7%, and 74.9%, respectively (Figure 7B). None of the mice exhibited significant weight loss during the observations (Figure 7C and D). Compared with the LP–DOX complexes, the virosomes containing DOX, even at lower dose than the previous version (2.3 mg/kg as DOX, twice versus 6.0 mg/kg as DOX, every 4 days18), showed higher antitumor activity against NuE-derived tumors, indicating that the full fusion with BNCs successfully endowed LP–DOX complexes with the human hepatic cell-specific active targeting ability. However, their antitumor activities were lower than that of DOXOVES (driven by passive targeting machinery). If the virosomes containing DOX are more stabilized in the bloodstream, the complexes could exhibit higher antitumor activity than DOXOVES by taking advantage of the passive and active targeting abilities simultaneously. Generally, severe weight loss occurred because of high concentration of free DOX in serum.26 In the previous study,18 since free BNCs might attenuate the targeting ability of BNC–LP–DOX complexes in a competitive inhibition manner, we optimized the BNC–LP ratio for reducing the amount of free BNC as much as possible. Thus, we could lower free DOX concentration in serum and thereby repress the unexpected weight loss of mice. Other possible reasons for the repression of weight loss of mice are as follows: 1) the serum half-life of DDS nanocarrier may be extended by the shape change of virosomes (from rugged to smooth structure); 2) the smooth structure of virosomes may be more suitable for the in vivo targeting and/or the cellular uptake than the rugged structure.


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 chemotherapeutic efficacies.Notes: Nude mice harboring NuE (A, C) or WiDr (B, D) xenograft tumors were intravenously injected twice (0 and 5 days) with virosomes containing DOX (red squares), LP–DOX complexes (green circles), DOX (blue diamonds), DOXOVES (purple triangles), and control (black crosses) at a low DOX dose (2.3 mg/kg). Tumor volume (A, B) and body weight (C, D) of the mice were measured for 15 days. Error bars represent standard deviation (n=5). Black arrows indicate intravenous injections.Abbreviations: DOX, doxorubicin; LP, liposome.
© Copyright Policy
Related In: Results  -  Collection

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

f7-ijn-10-4159: Evaluation of chemotherapeutic efficacies.Notes: Nude mice harboring NuE (A, C) or WiDr (B, D) xenograft tumors were intravenously injected twice (0 and 5 days) with virosomes containing DOX (red squares), LP–DOX complexes (green circles), DOX (blue diamonds), DOXOVES (purple triangles), and control (black crosses) at a low DOX dose (2.3 mg/kg). Tumor volume (A, B) and body weight (C, D) of the mice were measured for 15 days. Error bars represent standard deviation (n=5). Black arrows indicate intravenous injections.Abbreviations: DOX, doxorubicin; LP, liposome.
Mentions: The antitumor effect of virosomes containing DOX has been evaluated by in vivo tumor growth assays using a mouse xenograft model. Mice were intravenously injected with a low dose of DOX (2.3 mg/kg) twice (day 0 and day 5). Since virosomes alone showed no significant effect on tumor growth in comparison with control, we examined the chemotherapeutic efficacies of DOX, LP–DOX complexes, virosomes containing DOX, and DOXOVES. On day 15, in mice harboring NuE (target cell)-derived tumors, the average rates of tumor growth inhibition (T/C, treated versus control; %) of DOX, LP–DOX complexes, virosomes containing DOX, and DOXOVES were 90.9%, 81.6%, 54.1%, and 38.6%, respectively (Figure 7A). Meanwhile, in mice harboring WiDr (nontarget cell)-derived tumors on day 15, the T/C values (%) of DOX, LP–DOX complexes, virosomes containing DOX, and DOXOVES were 90.6%, 82.8%, 81.7%, and 74.9%, respectively (Figure 7B). None of the mice exhibited significant weight loss during the observations (Figure 7C and D). Compared with the LP–DOX complexes, the virosomes containing DOX, even at lower dose than the previous version (2.3 mg/kg as DOX, twice versus 6.0 mg/kg as DOX, every 4 days18), showed higher antitumor activity against NuE-derived tumors, indicating that the full fusion with BNCs successfully endowed LP–DOX complexes with the human hepatic cell-specific active targeting ability. However, their antitumor activities were lower than that of DOXOVES (driven by passive targeting machinery). If the virosomes containing DOX are more stabilized in the bloodstream, the complexes could exhibit higher antitumor activity than DOXOVES by taking advantage of the passive and active targeting abilities simultaneously. Generally, severe weight loss occurred because of high concentration of free DOX in serum.26 In the previous study,18 since free BNCs might attenuate the targeting ability of BNC–LP–DOX complexes in a competitive inhibition manner, we optimized the BNC–LP ratio for reducing the amount of free BNC as much as possible. Thus, we could lower free DOX concentration in serum and thereby repress the unexpected weight loss of mice. Other possible reasons for the repression of weight loss of mice are as follows: 1) the serum half-life of DDS nanocarrier may be extended by the shape change of virosomes (from rugged to smooth structure); 2) the smooth structure of virosomes may be more suitable for the in vivo targeting and/or the cellular uptake than the rugged structure.

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