Radiolabeled liposome imaging determines an indication for liposomal anticancer agent in ovarian cancer mouse xenograft models.
Liposomal anticancer agents can effectively deliver drugs to tumor lesions, but their therapeutic effects are enhanced in only limited number of patients. Appropriate biomarkers to identify responder patients to these liposomal agents will improve their treatment efficacies. We carried out pharmacological and histopathological analyses of mouse xenograft models bearing human ovarian cancers (Caov-3, SK-OV-3, KURAMOCHI, and TOV-112D) to correlate the therapeutic effects of doxorubicin-encapsulated liposome (Doxil(®) ) and histological characteristics linked to the enhanced permeability and retention effect. We next generated (111) In-encapsulated liposomes to examine their capacities to determine indications for Doxil(®) treatment by single-photon emission computed tomography (SPECT)/CT imaging. Antitumor activities of Doxil(®) were drastically enhanced in Caov-3, moderately in SK-OV-3, and minimally in KURAMOCHI and TOV-112D when compared to doxorubicin. Microvessel density and vascular perfusion were high in Caov-3 and SK-OV-3, indicating a close relation with the enhanced antitumor effects. Next, (111) In-encapsulated liposomes were given i.v. to the animals. Their tumor accumulation and area under the curve values over 72 h were high in Caov-3, relatively high in SK-OV-3, and low in two other tumors. Importantly, as both Doxil(®) effects and liposomal accumulation varied in the SK-OV-3 group, we individually obtained SPECT/CT images of SK-OV-3-bearing mouse (n = 11) before Doxil(®) treatment. Clear correlation between liposomal tumor accumulation and effects of Doxil(®) was confirmed (R(2) = 0.73). Taken together, our experiments definitely verified that enhanced therapeutic effects through liposomal formulations of anticancer agents depend on tumor accumulation of liposomes. Tumor accumulation of the radiolabeled liposomes evaluated by SPECT/CT imaging is applicable to appropriately determine indications for liposomal antitumor agents.
Halichondrin Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.|Division of Functional Imaging, National Cancer Center, Kashiwa, Japan.
Ken
K
Ito
Division of Functional Imaging, National Cancer Center, Kashiwa, Japan.
Shusei
S
Hamamichi
Oncology Product Creation Unit, Eisai Co., Ltd., Tsukuba, Japan.
Makoto
M
Asano
Division of Functional Imaging, National Cancer Center, Kashiwa, Japan.|Oncology Product Creation Unit, Eisai Co., Ltd., Tsukuba, Japan.
Yusaku
Y
Hori
Oncology Product Creation Unit, Eisai Co., Ltd., Tsukuba, Japan.
Junji
J
Matsui
Oncology Product Creation Unit, Eisai Co., Ltd., Tsukuba, Japan.
Masao
M
Iwata
Biomarkers and Personalized Medicine Core Function Unit, Eisai Inc., Andover, Massachusetts, USA.
Yasuhiro
Y
Funahashi
Division of Functional Imaging, National Cancer Center, Kashiwa, Japan.
Izumi O
IO
Umeda
Division of Functional Imaging, National Cancer Center, Kashiwa, Japan.
Hirofumi
H
Fujii
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D007205:Indium Radioisotopes; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
Doxil; ovarian cancer; radiolabeled liposomes; single-photon emission computed tomography/computed tomography imaging; theranostics