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ORIGINAL RESEARCH ARTICLE

Time and Dose Dependence of Pluronic Bioactivity in Hyperthermia-Induced Tumor Cell Death

Tianyi M. Krupka^*,, David Dremann and Agata A. Exner^*,,1

^* Department of Radiology and Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106

To whom requests for reprints should be addressed at ¹ Department of Radiology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5056. E-mail: agata.exner{at}case.edu

Pluronic block copolymers have been shown to sensitize cancer cells resulting in an increased activity of antineoplastic agents. In the current study we examined a new application of Pluronic bioactivity in potentiating hyperthermia-induced cancer cell injury. DHD/K12/TRb rat adenocarcinoma cells were exposed to low-grade hyperthermia at 43°C with or without Pluronic P85 or Pluronic L61. A range of Pluronic doses, pre-exposure and heat exposure durations were investigated, and the test conditions were optimized. Treatment efficacy was assessed by measurement of intracellular ATP and mitochondrial dehydrogenase activity. Both P85 and L61 in synergy with heat reduced cell viability appreciably compared to either heat or Pluronic alone. Under optimal conditions, P85 (10 mg/ml, 240 mins) combined with 15 mins heat reduced intracellular ATP to 60.1 ± 3.5% of control, while heat alone and P85 without heat caused a negligible decrease in ATP of 1.2% and 3.8%, respectively. Similarly, cells receiving 120 mins pre-exposure of L61 (0.3 mg/ml) showed reduction in intracellular ATP to 14.1 ± 2.1% of control. Again, heat or L61 pre-exposure alone caused a minor decrease in levels of intracellular ATP (1.5% and 4.4%, respectively). Comparable results were observed when viability was assessed by mitochondrial enzyme activity. Survival studies confirmed that the loss of viability translates to a long-term reduction in proliferative activity, particularly for L61 treated cells. Based on these results, we conclude that Pluronic is effective in improving hyperthermic cancer treatment in vitro by potentiating heat-induced cytotoxicity in a concentration and time dependent manner.

Key Words: hyperthermia • Pluronic P85 • Pluronic L61 • thermosensitizer • tumor thermal ablation