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

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• 作者：Gaofeng Zhao ; MD ; PhD ; Yong-Ming Yu ; MD ; PhD ; Timothy M. Shoup ; PhD ; David R. Elmaleh ; PhD ; Ali A. Bonab ; PhD ; Ronald G. Tompkins ; MD ; Alan J. Fischman ; MD ; PhD ; ^{aajjff@gmail.com" class="auth_mail}
• 关键词：18F-TPP ; Mitochondria ; Membrane potential ; Apoptosis
• 刊名：Journal of Surgical Research
• 出版年：15 May, 2014
• 年：2014
• 卷：188
• 期：2
• 页码：473-479
• 全文大小：995 K

文摘

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: ¹⁸F-triphenylphosphonium (¹⁸F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis.

Methods

Studies were conducted in both ex聽vivo cell lines and in聽vivo using a burned animal model. Uptake of ¹⁸F-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 ¹⁸F-TPP uptake by biodistribution.

Results

We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in ¹⁸F-TPP uptake, with a slope of 0.62聽卤聽0.08 and a correlation coefficient of 0.936聽卤聽0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of ¹⁸F-TPP. Staurosporine significantly decreased the uptake of ¹⁸F-TPP in PC-3 cells from 14.2聽卤聽3.8% to 5.6聽卤聽1.3% (P聽<聽0.001). Burn-induced significant apoptosis (sham: 4.4聽卤聽1.8% versus burn: 24.6聽卤聽6.7 %; P聽<聽0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13聽卤聽0.24% versus sham: 3.28聽卤聽0.67%; P聽<聽0.005). Biodistribution studies demonstrated that burn-induced significant reduction in ¹⁸F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis.

Conclusions

¹⁸F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.