title: Membrane potential-dependent uptake of 18F-triphenylphosphonium--a new voltage sensor as an imaging agent for detecting burn-induced apoptosis.
abstract: BACKGROUND
  Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: (18)F-triphenylphosphonium ((18)F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis.
  
  
  METHODS
  Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of (18)F-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extracellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone and staurosporine. Apoptosis was studied in a burn animal model using terminal deoxynucleotidyl transferase dUTP nick end labeling staining and simultaneous assessment of (18)F-TPP uptake by biodistribution.
  
  
  RESULTS
  We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in (18)F-TPP uptake, with a slope of 0.62 ± 0.08 and a correlation coefficient of 0.936 ± 0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of (18)F-TPP. Staurosporine significantly decreased the uptake of (18)F-TPP in PC-3 cells from 14.2 ± 3.8% to 5.6 ± 1.3% (P < 0.001). Burn-induced significant apoptosis (sham: 4.4 ± 1.8% versus burn: 24.6 ± 6.7 %; P < 0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13 ± 0.24% versus sham: 3.28 ± 0.67%; P < 0.005). Biodistribution studies demonstrated that burn-induced significant reduction in (18)F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis.
  
  
  CONCLUSIONS
  (18)F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yu
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shoup
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts.
authors.forename: David R
authors.initials: DR
authors.lastname: Elmaleh
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Bonab
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts. Electronic address: aajjff@gmail.com.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D000818:Animals; D017209:Apoptosis; D002056:Burns / Q000000981:diagnostic imaging*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005462:Fluorine Radioisotopes; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011188:Potassium; D013154:Spleen / Q000000981:diagnostic imaging; D019311:Staurosporine; D014634:Valinomycin
chemical_list: D005462:Fluorine Radioisotopes; D009943:Organophosphorus Compounds; D014634:Valinomycin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D019311:Staurosporine; D011188:Potassium
keywords: (18)F-TPP; Apoptosis; Membrane potential; Mitochondria