Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a highly cell-selective cancer therapy based on an armed antibody conjugated with a phthalocyanine-based photo-absorber, IRDye700DX (IR700). NIR-PIT can quickly kill target cells that express specific proteins on the cellular membrane but only when the antibody-IR700 conjugate binds to the cell membrane and is then exposed to NIR light. NIR-PIT is highly selective based on the specificity of the antibody. Galactosyl serum albumin (GSA) is composed of albumin decorated with galactose molecules conjugated to the carboxyl groups of albumin. GSA binds to beta-D-galactose receptors, a surface lectin, which are overexpressed on the cell surface of many cancers, including ovarian cancers and is quickly internalized after binding. Here, we demonstrate the feasibility of NIR-PIT in a model of disseminated peritoneal ovarian cancer (SHIN3 cells) using GSA-IR700 that binds to beta-D-galactose receptors. GSA-IR700 bound quickly to SHIN3 cells, then accumulated in the endo-lysosomes. Cell-specific killing was observed in vitro, yet a relatively large dose of NIR light exposure was required for cell killing compared to antibody-IR700 conjugates. To evaluate in vivo therapeutic effects of GSA-IR700 NIR-PIT, peritoneal disseminated SHIN3 tumor-bearing mice were separated into four groups: no treatment; NIR light only; GSA-IR700 only; and GSA-IR700 NIR-PIT. Repeated NIR-PIT showed significant suppression of tumor based on bioluminescence compared to the other groups (p < 0.05). Thus, repeated NIR-PIT using GSA-IR700 can achieve efficient antitumor effects, although GSA-IR700 NIR-PIT was less effective than antibody-IR700 NIR-PIT conjugates likely due to the rapid internalization of GSA-IR700.
Highlights
Epithelial ovarian carcinoma (EOC) is the leading cause of death among patients with gynecologic malignancies. 85% of women with EOC present with advanced stage III or IV disease, leading to high morbidity and mortality
At 3 and 6 h post-incubation, Galactosyl serum albumin (GSA)-IR700 bound to SHIN3 cells could be identified as small fluorescent dots in the cytoplasm that is typical of uptake within endo-lysosomes, but surface binding was minimal
The fluorescence intensity of GSA-IR700 bound to SHIN3 cells increased in a concentration dependent manner (Figure 1B)
Summary
Epithelial ovarian carcinoma (EOC) is the leading cause of death among patients with gynecologic malignancies. 85% of women with EOC present with advanced stage III or IV disease, leading to high morbidity and mortality. Epithelial ovarian carcinoma (EOC) is the leading cause of death among patients with gynecologic malignancies. 85% of women with EOC present with advanced stage III or IV disease, leading to high morbidity and mortality. Cytoreductive surgery followed by systemic chemotherapy is the standard therapy for advanced-stage ovarian cancer. Overall five-year survival (OFS) rate of all ovarian cancer patients has been improved by 2.0 % each year from 2003 to 2012, reaching 46 % in 2015. The OFS rate of patients with advanced ovarian cancer remains at only 28 % [1, 2]. Poorly differentiated ovarian cancers often lead to diffuse peritoneal dissemination consisting of a large number of sub-millimeter lesions which are unresectable. Even after cyto-reductive surgery, recurrence of disease is likely
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