Pulse timing during irreversible electroporation achieves enhanced destruction in a hindlimb model of cancer

The use of irreversible electroporation (IRE) for cancer treatment has increased during the past decade due to many advantages over other focal therapies. However, despite early success in pre-clinical and clinical IRE trials, in vivo studies have shown that IRE suffers from an inability to destroy large volumes of cancer tissue without repeating treatment and/or increasing the applied electrical dose to dangerous levels. The present work demonstrates a simple method whereby treatment volumes can be enhanced by changing pulse timing (delivering pulsing in three trains, 30 s apart), without changing the electrical dose (51 pulses at pulse strengths of 600 V, durations of 50 µs, and repetition rates of 10 Hz), during IRE in a 3D hindlimb tumor model. Results show that 3 weeks of tumor growth delay was achieved with pulse timing compared to 1 week in baseline IRE (200% increase). Furthermore, the pulse timing approach does not introduce any foreign molecules into the body and can easily be integrated into existing treatment or enhancement protocols of IRE. The enhanced injury may correlate to longer pore exposures, or time during which pores exist on the membrane during pulse timing. This in turn increases the likelihood of membrane failure, and/or death from secondary injury such as loss of critical ions, proteins and other cellular components. In summary this work demonstrates a simple translational approach to increase 3D IRE treatment volumes in vivo by using pulse timing.