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Abstract
BackgroundPhotoimmunotherapy (PIT) is a novel type of molecular optical imaging-guided cancer phototherapy based on a monoclonal antibody conjugated to a photosensitizer, IR700, in combination with near-infrared (NIR) light. PIT rapidly causes target-specific cell death by inducing cell membrane damages and appears to be highly effective; however, we have previously demonstrated that tumor recurrences were eventually seen in PIT-treated mice, likely owing to inhomogeneous mAb-IR700 conjugate distribution in the tumor, thus limiting the effectiveness of PIT as a monotherapy. Here, we examined the effects of human epidermal growth factor-2 (HER2)-targeted PIT in combination with 5-fluorouracil (5-FU) compared to PIT alone for HER2-expressing human gastric cancer cells.MethodsNCI-N87 cells, HER2-positive human gastric cancer cells, were used for the experiments. Trastuzumab, a monoclonal antibody directed against HER2, was conjugated to IR700. To assess the short-term cytotoxicity and examine the apoptotic effects upon addition of 5-FU in vitro, we performed LIVE/DEAD and caspase-3 activity assays. Additionally, to explore the effects on long-term growth inhibition, trypan blue dye exclusion assay was performed. NCI-N87 tumor xenograft models were prepared for in vivo treatment studies and the tumor-bearing mice were randomized into various treatment groups.ResultsCompared to PIT alone, the combination of HER2-targeted PIT and 5-FU rapidly induced significant cytotoxicity in both the short-term and long-term cytotoxicity assays. While both 5-FU and/or trastuzumab-IR700 conjugate treatment induced an increase in caspase-3 activity, there was no additional increase in caspase-3 activity upon NIR light irradiation after incubation with 5-FU and/or trastuzumab-IR700. The combination of HER2-targeted PIT and 5-FU resulted in greater and longer tumor growth inhibition than PIT monotherapy in vivo. This combined effect of PIT and 5-FU is likely owing to their different mechanisms of inducing tumor cell death, namely necrotic membrane damage by PIT and apoptotic cell death by 5-FU and trastuzumab.ConclusionsPIT in combination with 5-FU resulted in enhanced antitumor effects compared to PIT alone for HER2-expressing human gastric cancer in vitro and in vivo. This combination photoimmunochemotherapy represents a practical method for treating human gastric cancer and should be investigated further in the clinical setting.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2072-0) contains supplementary material, which is available to authorized users.
Highlights
Photoimmunotherapy (PIT) is a novel type of molecular optical imaging-guided cancer phototherapy based on a monoclonal antibody conjugated to a photosensitizer, IR700, in combination with near-infrared (NIR) light
When pre-incubated with 100 μg of unconjugated trastuzumab to block the human epidermal growth factor-2 (HER2) molecules, the signal from Tra-IR700 was completely blocked in both the NCI-N87 and MKN-45 cells (Fig. 1a, b); the ratios of the mean fluorescence intensity (MFI) compared to the isotype control in the NCIN87 and MKN-45 cells were 7.4 ± 2.7 and 1.9 ± 0.3, respectively (n = 3 each)
IR700 fluorescence was detected on the surface and cytoplasmic vesicles in HER2-expressing NCI-N87 cells after 3 h incubation with Tra-IR700, while MKN-45 cells did not show detectable IR700 fluorescence under the same image acquisition conditions (Fig. 1c, e)
Summary
Photoimmunotherapy (PIT) is a novel type of molecular optical imaging-guided cancer phototherapy based on a monoclonal antibody conjugated to a photosensitizer, IR700, in combination with near-infrared (NIR) light. PIT rapidly causes target-specific cell death by inducing cell membrane damages and appears to be highly effective; we have previously demonstrated that tumor recurrences were eventually seen in PIT-treated mice, likely owing to inhomogeneous mAb-IR700 conjugate distribution in the tumor, limiting the effectiveness of PIT as a monotherapy. Gastric cancer is associated with a poor prognosis [1,2,3] Conventional cancer therapies, such as surgery, radiation, and chemotherapy, can cause damage or toxicity to both the adjacent and distant normal tissues, which in turn limits the effectiveness of these therapies [4, 5]. To achieve more effective cancer control, as well as to minimize the side effects associated with conventional cancer therapies, molecular targeted cancer therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have been developed in recent years [4, 6]. Trastuzumab, a humanized mAb directed against HER2, has been demonstrated to induce antitumor effects in HER2-positive gastric cancer, both alone and in combination with various chemotherapeutic agents [9, 11]
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