title: Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo.
abstract: BACKGROUND
  pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer.
  
  
  METHODS
  A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model.
  
  
  RESULTS
  In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7-750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7-750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging.
  
  
  CONCLUSIONS
  Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer.
authors.affiliation: The Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, Kentucky.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Kimbrough
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Anil
authors.initials: A
authors.lastname: Khanal
authors.affiliation: The Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, Kentucky.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zeiderman
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Bigya R
authors.initials: BR
authors.lastname: Khanal
authors.affiliation: iThera Medical, Munich, Germany.
authors.forename: Neal C
authors.initials: NC
authors.lastname: Burton
authors.affiliation: The Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, Kentucky.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McMasters
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky. Lacey_McNally@hotmail.com.
authors.forename: Lacey R
authors.initials: LR
authors.lastname: McNally
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005453:Fluorescence; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D061088:Photoacoustic Techniques / Q000379:methods; D014054:Tomography / Q000379:methods
chemical_list: D008565:Membrane Proteins; C533201:pHLIP protein