Membrane potential-dependent uptake of 18F-triphenylphosphonium--a new voltage sensor as an imaging agent for detecting burn-induced apoptosis

J Surg Res. 2014 May 15;188(2):473-9. doi: 10.1016/j.jss.2014.01.011. Epub 2014 Jan 11.

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.

Keywords: (18)F-TPP; Apoptosis; Membrane potential; Mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Burns / diagnostic imaging*
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Fluorine Radioisotopes*
  • Humans
  • Membrane Potential, Mitochondrial*
  • Mice
  • Mice, Inbred C57BL
  • Organophosphorus Compounds / therapeutic use*
  • Positron-Emission Tomography
  • Potassium
  • Spleen / diagnostic imaging
  • Staurosporine
  • Valinomycin

Substances

  • Fluorine Radioisotopes
  • Organophosphorus Compounds
  • Valinomycin
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Staurosporine
  • Potassium