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Objective: To study the safety and efficacy of algorithmically controlled electroporation (ACE) against spontaneous equine melanoma., Methods: A custom temperature sensing coaxial electrode was paired with a high voltage pulse generation system with integrated temperature feedback controls. Computational modeling and ex vivo studies were conducted to evaluate the system's ability to achieve and maintain target temperatures. Twenty-five equine melanoma tumors were treated with a 2000 V protocol consisting of a 2-5-2 waveform, 45 °C temperature set point, and integrated energized times of 0.005 s, 0.01 s, or 0.02 s (2500x, 5000x, and 10000x 2 μs pulses, respectively). Patients returned 20-50 days post treatment to determine the efficacy of the treatment., Results: ACE temperature control algorithms successfully achieved and maintained target temperatures in a diverse population of spontaneous tumors with significant variation in tissue impedance. All treatments were completed successfully without and without adverse events. Complete response rates greater than 93% were achieved in all treatment groups., Conclusion: ACE is a safe and effective treatment for spontaneous equine melanoma. The temperature control algorithm enabled rapid delivery of electroporation treatments without prior knowledge of tissue electrical or thermal properties and could adjust to real time changes in tissue properties., Significance: Real time temperature control in electroporation procedures enables treatments near critical structures where thermal damage is contraindicated. Unlike standard approaches, ACE protocols do not require extensive pretreatment planning or knowledge of tissue properties to determine an optimal energy delivery rate and they can account for changes in tissue state (e.g., perfusion) in real time to simultaneously minimize treatment time and potential for thermal damage.

Objective: This study sought to investigate a novel strategy using temperature-controlled delivery of nanosecond pulsed electric fields as an alternative to the 50-100 microsecond pulses used for irreversible electroporation., Methods: INSPIRE treatments were carried out at two temperatures in 3D tumor models using doses between 0.001 s and 0.1 s. The resulting treatment zones were quantified using viability staining and lethal electric field intensities were determined numerically. Computational modeling was then used to determine parameters necessary for INSPIRE treatments to achieve equivalent treatment zones to clinical electroporation treatments and evaluate the potential for these treatments to induce deleterious thermal damage., Results: Lethal thresholds between 1109 and 709 V/cm were found for nominal 0.01 s treatments with pulses between 350 ns and 2000 ns at physiological temperatures. Further increases in dose resulted in significant decreases in lethal thresholds. Given these experimental results, treatment zones comparable to clinical electroporation are possible by increasing the dose and voltage used with nanosecond duration pulses. Temperature-controlled simulations indicate minimal thermal cell death while achieving equivalent treatment volumes to clinical electroporation., Conclusion: Nanosecond electrical pulses can achieve comparable outcomes to traditional electroporation provided sufficient electrical doses or voltages are applied. The use of temperature-controlled delivery may minimize thermal damage during treatment., Significance: Intense muscle stimulation and the need for cardiac gating have limited irreversible electroporation. Nanosecond pulses can alleviate these challenges, but traditionally have produced significantly smaller treatment zones. This study suggests that larger ablation volumes may be possible with the INSPIRE approach and that future in vivo studies are warranted.

Expanding the volume of an irreversible electroporation treatment typically necessitates an increase in pulse voltage, number, duration, or repetition. This study investigates the addition of polyethylenimine nanoparticles (PEI-NP) to pulsed electric field treatments, determining their combined effect on ablation size and voltages. U118 cells in an in vitro 3D cell culture model were treated with one of three pulse parameters (with and without PEI-NPs) which are representative of irreversible electroporation (IRE), high frequency irreversible electroporation (H-FIRE), or nanosecond pulsed electric fields (nsPEF). The size of the ablations were compared and mapped onto an electric field model to describe the electric field required to induce cell death. Analysis was conducted to determine the role of PEI-NPs in altering media conductivity, the potential for PEI-NP degradation following pulsed electric field treatment, and PEI-NP uptake. Results show there was a statistically significant increase in ablation diameter for IRE and H-FIRE pulses with PEI-NPs. There was no increase in ablation size for nsPEF with PEI-NPs. This all occurs with no change in cell media conductivity, no observable degradation of PEI-NPs, and moderate particle uptake. These results demonstrate the synergy of a combined cationic polymer nanoparticle and pulsed electric field treatment for the ablation of cancer cells. These results set the foundation for polymer nanoparticles engineered specifically for irreversible electroporation.