Fluorescent probes for detection of copper
Patent Number: US8865914
Executive Summary:
General Description:
Copper is biologically important. It has been demonstrated that copper is involved in the development and progression of many diseases, including Menkes disease, Wilson's disease, neurodegenerative diseases, anemia, heart disease, and cancer. Furthermore, copper is a well-known metal cofactor in many enzymes and is necessary for proper cellular function. This patent details small molecules that can act as sensors that can detect copper in living cells and animals. It is uncertain whether tumors or premalignant lesions harbor abnormal levels of copper, and the ability of these molecular sensors to detect copper in cancer cells has not yet been determined.
Strengths:
Weaknesses:
Patent Status:
Publications:
Recognition- and reactivity-based fluorescent probes for studying transition metal signaling in living systems. Aron AT, Ramos-Torres KM, Cotruvo JA Jr, Chang CJ. Acc Chem Res. 2015 Aug 18;48(8):2434-42. doi: 10.1021/acs.accounts.5b00221. Epub 2015 Jul 28.
PMID: 26215055
Synthetic fluorescent probes for studying copper in biological systems. Cotruvo JA Jr, Aron AT, Ramos-Torres KM, Chang CJ. Chem Soc Rev. 2015 Jul 7;44(13):4400-14. doi: 10.1039/c4cs00346b. Epub 2015 Feb 18. Review. PMID: 25692243
Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model. Hirayama T, Van de Bittner GC, Gray LW, Lutsenko S, Chang CJ. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2228-33. doi: 10.1073/pnas.1113729109. Epub 2012 Jan 30.
PMID: 22308360
A targetable fluorescent sensor reveals that copper-deficient SCO1 and SCO2 patient cells prioritize mitochondrial copper homeostasis.
Dodani SC, Leary SC, Cobine PA, Winge DR, Chang CJ. J Am Chem Soc. 2011 Jun 8;133(22):8606-16. doi: 10.1021/ja2004158. Epub 2011 May 12. PMID: 21563821
Calcium-dependent copper redistributions in neuronal cells revealed by a fluorescent copper sensor and X-ray fluorescence microscopy.
Dodani SC, Domaille DW, Nam CI, Miller EW, Finney LA, Vogt S, Chang CJ. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):5980-5. doi: 10.1073/pnas.1009932108. Epub 2011 Mar 28. PMID: 21444780
Visualizing ascorbate-triggered release of labile copper within living cells using a ratiometric fluorescent sensor. Domaille DW, Zeng L, Chang CJ. J Am Chem Soc. 2010 Feb 3;132(4):1194-5. doi: 10.1021/ja907778b. PMID: 20052977
Preparation and use of Coppersensor-1, a synthetic fluorophore for live-cell copper imaging. Miller EW, Zeng L, Domaille DW, Chang CJ. Nat Protoc. 2006;1(2):824-7. PMID: 17406313
A selective turn-on fluorescent sensor for imaging copper in living cells. Zeng L, Miller EW, Pralle A, Isacoff EY, Chang CJ. J Am Chem Soc. 2006 Jan 11;128(1):10-1. PMID: 16390096
Inventor Bio: Christopher J. Chang
http://chemistry.berkeley.edu/faculty/chem/chris-chang
Executive Summary:
- Invention Type: Diagnostic
- Patent Status: Patent granted
- Patent Link: https://www.google.com/patents/US8865914/
- Research Institute: University of California, Berkeley
- Disease Focus: No specific cancer type, general method for detecting copper in living cells and organisms using fluorescent probes
- Basis of Invention: Multiple molecular sensors for the detection of copper, which are based on fluorescent scaffolds
- How it works: In the absence of copper, these fluorescent sensors have little to no fluorescent signal following excitation by a light source. However, in the presence of copper, these fluorescent sensors have an increase in fluorescent signal following excitation by a light source
- Lead Challenge Inventor: Christopher J. Chang
- Inventors: Christopher J. Chang, Genevieve C. van de Bittner, Tasuku Hirayama, Jefferson Chan
- Development Stage: Pre-clinical, in vivo assay data available
- Novelty:
- The method would allow study of copper in biological context in real time
- Many research tools require destroying samples for analysis (e.g. mass spectrometry), but using fluorescent probes to track copper could allow for non-destructive studies of copper
- Some of the developed fluorescent copper sensors emit light in the near-infrared region (NIR) of the electromagnetic spectrum, making them ideal for in vivo imaging because they circumvent issues of autofluorescence and signal attenuation by tissue. In fact, two of these fluorescent copper sensors, Copper Sensor 788 (CS788) and Copper Sensor 790C Acetoxy Methyl Ester (CS790AM), have been used to detect changes in the level of copper in healthy mice. Use of these NIR fluorescent sensors is the first example of the use of turn-on fluorescent sensors for the detection of a metal ion in living mice
- Clinical Applications:
- These molecular probes could potentially be used to detect copper in living cells in humans
- Copper detection may have prognostic/diagnostic value in patients
General Description:
Copper is biologically important. It has been demonstrated that copper is involved in the development and progression of many diseases, including Menkes disease, Wilson's disease, neurodegenerative diseases, anemia, heart disease, and cancer. Furthermore, copper is a well-known metal cofactor in many enzymes and is necessary for proper cellular function. This patent details small molecules that can act as sensors that can detect copper in living cells and animals. It is uncertain whether tumors or premalignant lesions harbor abnormal levels of copper, and the ability of these molecular sensors to detect copper in cancer cells has not yet been determined.
Strengths:
- First described method of imaging copper in living animals (mice)
- Small molecules used as probes are easy to commercialize into research and diagnostic tools
Weaknesses:
- The importance of copper detection in cancer patients requires further study.
- Competing technologies exist: Zeng, L.; Miller, E. W.; Pralle, A.; Isacoff, E. Y.; Chang, C. J. “A Selective Turn-On Fluorescent Sensor for Imaging Copper in Living Cells”, J. Am. Chem. Soc., 2006, 128, 10-11. Miller, E. W.; Zeng, L.; Domaille, D. W.; Chang, C. J. “Preparation and Use of Coppersensor-1, a Synthetic Fluorophore for Live-Cell Copper Imaging”, Nature Protocols, 2006, 1, 824-827. Domaille, D. W.; Zeng, L.; Chang, C. J. “Visualizing Ascorbate-Triggered Release of Labile Copper within Living Cells using a Ratiometric Fluorescent Sensor”, J. Am. Chem. Soc., 2010, 132, 1194-1195. Riefke, B.; Licha, K.; Semmler, W.; Nolte, D.; Ebert, B.; Rinneberg, H., In vivo characterization of cyanine dyes as contrast agents for near-infrared imaging, Proceedings of SPIE—The International Society for Optical Engineering (1996), 2927 (Optical and Imaging Techniques for Biomonitoring II), 199-208; Rajopadhye, Milind; Groves, Kevin. “Biocompatible cyanine fluorescent imaging agents and method of in vivo optical imaging”, WO 2007028163 A1; Peterson, Jeffrey D.; Rajopadhye, Milind. “Viable near-infrared fluorochrome labeled cells, methods of making labeled cells and in vivo imaging methods for tracking, locating or detg. quantity of viable cells”, WO 2008109832 A2; Kojima, H, “Development of near-infrared fluorescent probes for in vivo imaging”, Yakugaku Zasshi, 2008, 128(11): 1653-1663.
Patent Status:
- Publication date Oct 21, 2014
- Filing date Mar 14, 2013
- Priority date May 21, 2012
Publications:
Recognition- and reactivity-based fluorescent probes for studying transition metal signaling in living systems. Aron AT, Ramos-Torres KM, Cotruvo JA Jr, Chang CJ. Acc Chem Res. 2015 Aug 18;48(8):2434-42. doi: 10.1021/acs.accounts.5b00221. Epub 2015 Jul 28.
PMID: 26215055
Synthetic fluorescent probes for studying copper in biological systems. Cotruvo JA Jr, Aron AT, Ramos-Torres KM, Chang CJ. Chem Soc Rev. 2015 Jul 7;44(13):4400-14. doi: 10.1039/c4cs00346b. Epub 2015 Feb 18. Review. PMID: 25692243
Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model. Hirayama T, Van de Bittner GC, Gray LW, Lutsenko S, Chang CJ. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2228-33. doi: 10.1073/pnas.1113729109. Epub 2012 Jan 30.
PMID: 22308360
A targetable fluorescent sensor reveals that copper-deficient SCO1 and SCO2 patient cells prioritize mitochondrial copper homeostasis.
Dodani SC, Leary SC, Cobine PA, Winge DR, Chang CJ. J Am Chem Soc. 2011 Jun 8;133(22):8606-16. doi: 10.1021/ja2004158. Epub 2011 May 12. PMID: 21563821
Calcium-dependent copper redistributions in neuronal cells revealed by a fluorescent copper sensor and X-ray fluorescence microscopy.
Dodani SC, Domaille DW, Nam CI, Miller EW, Finney LA, Vogt S, Chang CJ. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):5980-5. doi: 10.1073/pnas.1009932108. Epub 2011 Mar 28. PMID: 21444780
Visualizing ascorbate-triggered release of labile copper within living cells using a ratiometric fluorescent sensor. Domaille DW, Zeng L, Chang CJ. J Am Chem Soc. 2010 Feb 3;132(4):1194-5. doi: 10.1021/ja907778b. PMID: 20052977
Preparation and use of Coppersensor-1, a synthetic fluorophore for live-cell copper imaging. Miller EW, Zeng L, Domaille DW, Chang CJ. Nat Protoc. 2006;1(2):824-7. PMID: 17406313
A selective turn-on fluorescent sensor for imaging copper in living cells. Zeng L, Miller EW, Pralle A, Isacoff EY, Chang CJ. J Am Chem Soc. 2006 Jan 11;128(1):10-1. PMID: 16390096
Inventor Bio: Christopher J. Chang
http://chemistry.berkeley.edu/faculty/chem/chris-chang