High therapeutic potential for systemic delivery of a liposome-conjugated herpes simplex virus.
OBJECTIVE
Oncolytic viral therapy is a newly developed modality to treat tumors. Many clinical trials worldwide have examined the efficacy of locally injected oncolytic viruses. However, systemic intravascular injections are limited by the humoral immune response, which dramatically decreases the level of infection. To overcome this limitation, we encapsulated the oncolytic virus in liposomes.


METHODS
The infectious properties of the herpes simplex virus type 1 (HSV-1) mutant, hrR3, with or without liposomes in the presence of neutralizing antibodies were evaluated using replication and cytotoxicity assays in vitro. To evaluate the efficacy of intravascular virus therapy with liposomes in the presence of neutralizing antibodies, immunized mice bearing multiple liver metastases were intraportally or peritoneally administered hrR3 or hrR3 complexed with liposomes.


RESULTS
Anti-HSV antibodies attenuated the infectiousness and cytotoxicity of hrR3, whereas hrR3/liposome complexes were not attenuated by these anti-HSV antibodies. Although the survival rate of non-immunized mice treated with hrR3 alone was similar to that of mice treated with the hrR3/liposome complexes, the survival rates of immunized mice treated with hrR3 alone were significantly reduced compared to mice treated with the hrR3/liposome complexes.


CONCLUSIONS
This systemic intravascular delivery of hrR3/liposome complexes in the presence of pre-existing neutralizing antibodies is effective to treat multiple liver metastases.
Department of Surgery II, Nagoya University Graduate School of Medicine, Tsuruma-cho, Showa-ku, Japan.
Toshio
T
Shikano
Hideki
H
Kasuya
Tevfik Tolga
TT
Sahin
Naohiro
N
Nomura
Akiyuki
A
Kanzaki
Makoto
M
Misawa
Yoko
Y
Nishikawa
Takashi
T
Shirota
Suguru
S
Yamada
Tsutomu
T
Fujii
Hiroyuki
H
Sugimoto
Naohito
N
Kanazumi
Shuji
S
Nomoto
Shin
S
Takeda
Akimasa
A
Nakao
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000276:immunology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology*; D018139:Simplexvirus / Q000276:immunology*
D057134:Antibodies, Neutralizing; D008081:Liposomes