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Near infrared photoimmunotherapy in the treatment of pleural disseminated NSCLC: preclinical experience.

Sato K, Nagaya T, Choyke PL, Kobayashi H - Theranostics (2015)

Bottom Line: In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs.Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180).Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1088.

ABSTRACT
Pleural metastases are common in patients with advanced thoracic cancers and are a cause of considerable morbidity and mortality yet is difficult to treat. Near Infrared Photoimmunotherapy (NIR-PIT) is a cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of pleural disseminated non-small cell lung carcinoma (NSCLC). In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing NSCLC cell line (Calu3-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in mice with tumors implanted intrathoracic cavity or in the flank, and assessed by tumor volume and/or bioluminescence and fluorescence thoracoscopy. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs. APC) and luciferase activity (p = 0.0004 vs. APC) in a flank model, and prolonged survival (p < 0.0001). Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180). Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease. In conclusion, NIR-PIT has the ability to effectively treat pleural metastases caused by NSCLC in mice. Thus, NIR-PIT is a promising therapy for pleural disseminated tumors.

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Evaluation of NIR-PIT effects on pleural disseminated NSCLC model by bioluminescence. (A) The regimen of NIR-PIT is shown. Images were obtained as indicated. (B) In vivo BLI and fluorescence imaging of the pleural disseminated model. Prior to treatment mice exhibiting approximately the same luciferase activity in the chest were selected. (C) Quantitative RLU in the pleural disseminated model showed a significant decrease after NIR-PIT (n = 7 mice in each group)(*p = 0.0180 < 0.05, PIT vs. APC, Tukey's test with ANOVA). (D) BW ratio of tumor bearing mice in response to NIR-PIT demonstrates no significant difference among the groups (n = 7).
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Figure 4: Evaluation of NIR-PIT effects on pleural disseminated NSCLC model by bioluminescence. (A) The regimen of NIR-PIT is shown. Images were obtained as indicated. (B) In vivo BLI and fluorescence imaging of the pleural disseminated model. Prior to treatment mice exhibiting approximately the same luciferase activity in the chest were selected. (C) Quantitative RLU in the pleural disseminated model showed a significant decrease after NIR-PIT (n = 7 mice in each group)(*p = 0.0180 < 0.05, PIT vs. APC, Tukey's test with ANOVA). (D) BW ratio of tumor bearing mice in response to NIR-PIT demonstrates no significant difference among the groups (n = 7).

Mentions: After treatment with NIR-PIT pleural disseminated tumors decreased in bioluminescence and fluorescence (Fig. 4A and 4B and Additional File 1: Fig. S3B). While the RLU decreased in the NIR-PIT treated tumors, RLU of tumor in other groups showed a gradual increase due to tumor growth. In contrast, luciferase activity decreased 1 day after repeated NIR-PIT (*p = 0.0180 < 0.05, PIT vs. APC, Tukey's test with ANOVA)(Fig. 4C). The BW ratio showed no change (ns, PIT vs. APC, light, control, Tukey's test with ANOVA) (Fig. 4D). Taken together, these data suggest that NIR-PIT caused significant tumor reduction in vivo pleural disseminated model.


Near infrared photoimmunotherapy in the treatment of pleural disseminated NSCLC: preclinical experience.

Sato K, Nagaya T, Choyke PL, Kobayashi H - Theranostics (2015)

Evaluation of NIR-PIT effects on pleural disseminated NSCLC model by bioluminescence. (A) The regimen of NIR-PIT is shown. Images were obtained as indicated. (B) In vivo BLI and fluorescence imaging of the pleural disseminated model. Prior to treatment mice exhibiting approximately the same luciferase activity in the chest were selected. (C) Quantitative RLU in the pleural disseminated model showed a significant decrease after NIR-PIT (n = 7 mice in each group)(*p = 0.0180 < 0.05, PIT vs. APC, Tukey's test with ANOVA). (D) BW ratio of tumor bearing mice in response to NIR-PIT demonstrates no significant difference among the groups (n = 7).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4402494&req=5

Figure 4: Evaluation of NIR-PIT effects on pleural disseminated NSCLC model by bioluminescence. (A) The regimen of NIR-PIT is shown. Images were obtained as indicated. (B) In vivo BLI and fluorescence imaging of the pleural disseminated model. Prior to treatment mice exhibiting approximately the same luciferase activity in the chest were selected. (C) Quantitative RLU in the pleural disseminated model showed a significant decrease after NIR-PIT (n = 7 mice in each group)(*p = 0.0180 < 0.05, PIT vs. APC, Tukey's test with ANOVA). (D) BW ratio of tumor bearing mice in response to NIR-PIT demonstrates no significant difference among the groups (n = 7).
Mentions: After treatment with NIR-PIT pleural disseminated tumors decreased in bioluminescence and fluorescence (Fig. 4A and 4B and Additional File 1: Fig. S3B). While the RLU decreased in the NIR-PIT treated tumors, RLU of tumor in other groups showed a gradual increase due to tumor growth. In contrast, luciferase activity decreased 1 day after repeated NIR-PIT (*p = 0.0180 < 0.05, PIT vs. APC, Tukey's test with ANOVA)(Fig. 4C). The BW ratio showed no change (ns, PIT vs. APC, light, control, Tukey's test with ANOVA) (Fig. 4D). Taken together, these data suggest that NIR-PIT caused significant tumor reduction in vivo pleural disseminated model.

Bottom Line: In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs.Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180).Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1088.

ABSTRACT
Pleural metastases are common in patients with advanced thoracic cancers and are a cause of considerable morbidity and mortality yet is difficult to treat. Near Infrared Photoimmunotherapy (NIR-PIT) is a cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of pleural disseminated non-small cell lung carcinoma (NSCLC). In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing NSCLC cell line (Calu3-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in mice with tumors implanted intrathoracic cavity or in the flank, and assessed by tumor volume and/or bioluminescence and fluorescence thoracoscopy. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs. APC) and luciferase activity (p = 0.0004 vs. APC) in a flank model, and prolonged survival (p < 0.0001). Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180). Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease. In conclusion, NIR-PIT has the ability to effectively treat pleural metastases caused by NSCLC in mice. Thus, NIR-PIT is a promising therapy for pleural disseminated tumors.

Show MeSH
Related in: MedlinePlus