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Pancreas-targeted NIR fluorophores for dual-channel image-guided abdominal surgery.

Wada H, Hyun H, Vargas C, Gravier J, Park G, Gioux S, Frangioni JV, Henary M, Choi HS - Theranostics (2015)

Bottom Line: Three different 800 nm NIR fluorophores were employed for dual-channel FLARE™ imaging in pigs: 2 μmol of ZW800-1 for vessels and kidney, 1 μmol of ZW800-3C for lymph nodes, and 2 μmol of ESNF31 for adrenal glands.In pigs, T700-F produced an SBR≥2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection.Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real-time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries.

View Article: PubMed Central - PubMed

Affiliation: 1. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215. ; 2. Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.

ABSTRACT

Objective: Pancreas-related complications are some of the most serious ones in abdominal surgery. The goal of this study was to develop and validate novel near-infrared (NIR) fluorophores that would enable real-time pancreas imaging to avoid the intraoperative pancreatic injury.

Design: After initial screening of a large NIR fluorophore library, the performance of 3 selected pancreas-targeted 700 nm NIR fluorophores, T700-H, T700-F, and MB, were quantified in mice, rats, and pigs. Dose ranging using 25 and 100 nmol, and 2.5 µmol of T700-F, and its imaging kinetics over a 4 h period were tested in each species. Three different 800 nm NIR fluorophores were employed for dual-channel FLARE™ imaging in pigs: 2 μmol of ZW800-1 for vessels and kidney, 1 μmol of ZW800-3C for lymph nodes, and 2 μmol of ESNF31 for adrenal glands.

Results: T700-F demonstrated the highest signal to background ratio (SBR), with peak SBR at 4 h postinjection in mice. In pigs, T700-F produced an SBR≥2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection. The combination of T700-F with each 800 nm NIR fluorophore provided simultaneous dual-channel intraoperative imaging of pancreas with surrounding organs in real time.

Conclusion: Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real-time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries.

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Quantitative Evaluation of NIR Fluorophore Uptake in Mouse Pancreas: a) SBR (mean ± SD) of pancreas against liver, spleen, and duodenum was compared using various NIR fluorophores. b) Quantitative time-course assessment: 25 nmol of T700-F was injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at different time points (T = 0, 1, 2, 4, 8, and 24 h). c) Dose-response curve: 0, 10, 25, 50 and 100 nmol of T700-F were injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at 4 h post-injection. d) Real-time intraoperative imaging of pancreas in different time and doses. Controls were injected with D5W alone, and at least 3 animals were used for each data point. Scale bars = 0.5 cm. *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations used are: Du, duodenum; Li, liver; Pa, pancreas (arrow); Sp, spleen; St, stomach; Pa/Li, pancreas-to-liver ratio; Pa/Sp, pancreas-to-spleen ratio; Pa/Du, pancreas-to-duodenum ratio. All NIR fluorescence images have identical exposure times and normalizations.
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Figure 2: Quantitative Evaluation of NIR Fluorophore Uptake in Mouse Pancreas: a) SBR (mean ± SD) of pancreas against liver, spleen, and duodenum was compared using various NIR fluorophores. b) Quantitative time-course assessment: 25 nmol of T700-F was injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at different time points (T = 0, 1, 2, 4, 8, and 24 h). c) Dose-response curve: 0, 10, 25, 50 and 100 nmol of T700-F were injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at 4 h post-injection. d) Real-time intraoperative imaging of pancreas in different time and doses. Controls were injected with D5W alone, and at least 3 animals were used for each data point. Scale bars = 0.5 cm. *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations used are: Du, duodenum; Li, liver; Pa, pancreas (arrow); Sp, spleen; St, stomach; Pa/Li, pancreas-to-liver ratio; Pa/Sp, pancreas-to-spleen ratio; Pa/Du, pancreas-to-duodenum ratio. All NIR fluorescence images have identical exposure times and normalizations.

Mentions: Initial in vivo screening in mice. Our NIR fluorophore library consists of over 300 novel compounds. Initial screening in mice revealed 2 pentamethine indocyanine fluorophores, T700-H and T700-F, with unusually high uptake in pancreas (Supplementary Material: Figure S1). T700-F showed a stronger pancreas signal and higher contrast to surrounding organs, such as duodenum, spleen, and liver. Both, however, also had strong kidney signal due to renal elimination. We then compared these two NIR fluorophores to clinically available MB in mice and re-measured SBR. As shown Figure 2A, T700-F showed the highest uptake in pancreas compared to others, and a significant improvement in SBR was found when compared with MB, which was injected at a 4-fold higher dose and exhibited a 10-fold shorter retention time 11. Because T700-F demonstrated the highest SBR, we explored its dose optimization and kinetics, and expanded the study to 2 additional species, rats and pigs.


Pancreas-targeted NIR fluorophores for dual-channel image-guided abdominal surgery.

Wada H, Hyun H, Vargas C, Gravier J, Park G, Gioux S, Frangioni JV, Henary M, Choi HS - Theranostics (2015)

Quantitative Evaluation of NIR Fluorophore Uptake in Mouse Pancreas: a) SBR (mean ± SD) of pancreas against liver, spleen, and duodenum was compared using various NIR fluorophores. b) Quantitative time-course assessment: 25 nmol of T700-F was injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at different time points (T = 0, 1, 2, 4, 8, and 24 h). c) Dose-response curve: 0, 10, 25, 50 and 100 nmol of T700-F were injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at 4 h post-injection. d) Real-time intraoperative imaging of pancreas in different time and doses. Controls were injected with D5W alone, and at least 3 animals were used for each data point. Scale bars = 0.5 cm. *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations used are: Du, duodenum; Li, liver; Pa, pancreas (arrow); Sp, spleen; St, stomach; Pa/Li, pancreas-to-liver ratio; Pa/Sp, pancreas-to-spleen ratio; Pa/Du, pancreas-to-duodenum ratio. All NIR fluorescence images have identical exposure times and normalizations.
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Related In: Results  -  Collection

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Figure 2: Quantitative Evaluation of NIR Fluorophore Uptake in Mouse Pancreas: a) SBR (mean ± SD) of pancreas against liver, spleen, and duodenum was compared using various NIR fluorophores. b) Quantitative time-course assessment: 25 nmol of T700-F was injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at different time points (T = 0, 1, 2, 4, 8, and 24 h). c) Dose-response curve: 0, 10, 25, 50 and 100 nmol of T700-F were injected intravenously into CD-1 mice, and SBR (Pa/Li), SBR (Pa/Sp) and SBR (Pa/Du) were measured at 4 h post-injection. d) Real-time intraoperative imaging of pancreas in different time and doses. Controls were injected with D5W alone, and at least 3 animals were used for each data point. Scale bars = 0.5 cm. *P < 0.05, **P < 0.01, and ***P < 0.001. Abbreviations used are: Du, duodenum; Li, liver; Pa, pancreas (arrow); Sp, spleen; St, stomach; Pa/Li, pancreas-to-liver ratio; Pa/Sp, pancreas-to-spleen ratio; Pa/Du, pancreas-to-duodenum ratio. All NIR fluorescence images have identical exposure times and normalizations.
Mentions: Initial in vivo screening in mice. Our NIR fluorophore library consists of over 300 novel compounds. Initial screening in mice revealed 2 pentamethine indocyanine fluorophores, T700-H and T700-F, with unusually high uptake in pancreas (Supplementary Material: Figure S1). T700-F showed a stronger pancreas signal and higher contrast to surrounding organs, such as duodenum, spleen, and liver. Both, however, also had strong kidney signal due to renal elimination. We then compared these two NIR fluorophores to clinically available MB in mice and re-measured SBR. As shown Figure 2A, T700-F showed the highest uptake in pancreas compared to others, and a significant improvement in SBR was found when compared with MB, which was injected at a 4-fold higher dose and exhibited a 10-fold shorter retention time 11. Because T700-F demonstrated the highest SBR, we explored its dose optimization and kinetics, and expanded the study to 2 additional species, rats and pigs.

Bottom Line: Three different 800 nm NIR fluorophores were employed for dual-channel FLARE™ imaging in pigs: 2 μmol of ZW800-1 for vessels and kidney, 1 μmol of ZW800-3C for lymph nodes, and 2 μmol of ESNF31 for adrenal glands.In pigs, T700-F produced an SBR≥2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection.Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real-time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries.

View Article: PubMed Central - PubMed

Affiliation: 1. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215. ; 2. Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.

ABSTRACT

Objective: Pancreas-related complications are some of the most serious ones in abdominal surgery. The goal of this study was to develop and validate novel near-infrared (NIR) fluorophores that would enable real-time pancreas imaging to avoid the intraoperative pancreatic injury.

Design: After initial screening of a large NIR fluorophore library, the performance of 3 selected pancreas-targeted 700 nm NIR fluorophores, T700-H, T700-F, and MB, were quantified in mice, rats, and pigs. Dose ranging using 25 and 100 nmol, and 2.5 µmol of T700-F, and its imaging kinetics over a 4 h period were tested in each species. Three different 800 nm NIR fluorophores were employed for dual-channel FLARE™ imaging in pigs: 2 μmol of ZW800-1 for vessels and kidney, 1 μmol of ZW800-3C for lymph nodes, and 2 μmol of ESNF31 for adrenal glands.

Results: T700-F demonstrated the highest signal to background ratio (SBR), with peak SBR at 4 h postinjection in mice. In pigs, T700-F produced an SBR≥2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection. The combination of T700-F with each 800 nm NIR fluorophore provided simultaneous dual-channel intraoperative imaging of pancreas with surrounding organs in real time.

Conclusion: Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real-time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries.

Show MeSH
Related in: MedlinePlus