Abstract
Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. We performed PIT in a model of disseminated gastric cancer peritoneal carcinomatosis and monitored efficacy with in vivo GFP fluorescence imaging. In vitro and in vivo experiments were conducted with a HER2-expressing, GFP-expressing, gastric cancer cell line (N87-GFP). A conjugate comprised of a photosensitizer, IR-700, conjugated to trastuzumab (tra-IR700), followed by NIR light was used for PIT. In vitro PIT was evaluated by measuring cytotoxicity with dead staining and a decrease in GFP fluorescence. In vivo PIT was evaluated in a disseminated peritoneal carcinomatosis model and a flank xenograft using tumor volume measurements and GFP fluorescence intensity. In vivo anti-tumor effects of PIT were confirmed by significant reductions in tumor volume (at day 15, p<0.0001 vs. control) and GFP fluorescence intensity (flank model: at day 3, PIT treated vs. control p<0.01 and peritoneal disseminated model: at day 3 PIT treated vs. control, p<0.05). Cytotoxic effects in vitro were shown to be dependent on the light dose and caused necrotic cell rupture leading to GFP release and a decrease in fluorescence intensity in vitro. Thus, loss of GFP fluorescence served as a useful biomarker of cell necrosis after PIT.
Highlights
Gastric carcinoma causes more than 740,000 cancer-related deaths per year worldwide especially in Asia [1,2,3]
We examined the efficacy of PIT in a mouse model of disseminated peritoneal gastric cancer using in vivo GFP fluorescence imaging to monitor response
After 6 hr incubation with either pan-IR700 or tra-IR700, N87-GFP cells consistently showed higher brightness with tra-IR700 than pan-IR700 (Fig. 1A). These signals were almost entirely blocked by the addition of excess trastuzumab or panitumumab, suggesting specific binding and confirming the higher expression of HER2 than EGFR [21]. These data suggested that HER2 was the preferable target for PIT in N87-GFP cells due to its higher expression
Summary
Gastric carcinoma causes more than 740,000 cancer-related deaths per year worldwide especially in Asia [1,2,3]. The majority of gastric cancer patients present with locally advanced, recurrent or metastatic disease precluding curative surgery that is mostly managed by non-curative therapy [1]. Peritoneal carcinomatosis and liver metastasis are common life-threatening manifestations of advanced stage gastric cancer [1,4]. Peritoneal carcinomatosis occurs in ovarian, appendiceal, colon, pancreas and gastric cancers. Prognosis is universally poor and local treatments are invariably unsuccessful with high recurrence rates and morbidity associated with ascites and bowel obstruction. New methods of treating peritoneal carcinomatosis are needed
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