Browsing by Subject "Irreversible Electroporation"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Advancing Focal Therapies for Cancer and Neural Targets
    (2023-04) Ranjbartehrani, Pegah
    Focal therapies (FT), including cryosurgery, thermal ablation and irreversible electroporation (IRE) have been widely used in the treatment of cancer and other diseases, with the aim to expose cells to extreme physical conditions, leading to cell death. The use of FT has increased recently due to advantages such as being minimally invasive and having lower costs, shorter recovery periods, and lower morbidity. The advent of imaging tools has also helped FT gain more attention among surgeons. However, limited understanding of the energy field around the FT probes might cause undertreatments, which would lead to recurrence of the disease, or overtreatment, which would lead to damages to the surrounding sensitive organs such as nerves and create severe side effects. Moreover, choosing the most suitable FT modality for treating a special organ target is essential.Our first objective for a successful focal therapy treatment is to have a clear understanding of the energy field distribution around the probes, both in clinical and preclinical applications. In preclinical cancer research, syngeneic tumors and xenograft tumors in rodent models are often used to define pre-clinical thresholds and outcomes for focal therapy modalities alone and with adjuvant approaches. Nevertheless, application of clinical-sized focal therapy probes in rodent tumor models can be difficult to control or characterize for this purpose. This, in turn, affects our understanding of the energy dose necessary to destroy diseased tissue. The fact that tumors in small animals come in different sizes and shapes and have thermal properties raises the need for a computational model capable of visualizing the temperature and electric field distribution within the tumor during the process of focal ablation. Understanding the interaction between the energy field and the tissue affects our understanding of the actual role of those ablation modalities in creating the tissue damage and enables us to predict and optimize the outcome of the procedure. Our second objective for a successful focal therapy treatment is to propose methods for preventing the damage to the surrounding organs, especially neural targets that are in close proximity to the treated area. In this work, we focus on preventing neural damage during prostate cancer cryosurgery. One major complication associated with prostate cancer cryosurgery is erectile dysfunction, caused by cryoinjury to the cavernous nerve in the neurovascular bundle, which is in close proximity to the prostate and is therefore directly exposed to freezing temperatures during cryosurgery. The use of cryoprotective agents (CPAs) to protect nerves against freezing temperatures is a method that has been used in nerve cryopreservation. While existing literature has established the idea of using CPAs to prevent nerve damage, there is still a lack of experimental data and quantitative models to study the effect of CPAs in preventing nerve cryoinjury during prostate cryosurgery. Moreover, no comprehensive study has assessed both the toxicity and the cryoprotective effectiveness of CPA exposure to the nerve within a repeatable and relevant biological model. Choosing a suitable FT modality is also crucial for a successful FT treatment. Certain modalities have better outcomes for specific organ targets than others. In this work, we propose a novel approach for renal denervation using Iron-oxide nanoparticle heating for treating hypertension. The most common ablation technique currently used in clinic for renal denervation is radiofrequency. However, this approach suffers from several disadvantages due to heating from inside of the renal artery which would result in damage to the artery wall, limited nerve ablation depth and inconsistent and unpredictable denervation. The use of iron-oxide nanoparticles, however, will alleviate some of the disadvantages mentioned by providing a repeatable treatment that can be used in combination with alcohol or other neurolytic agents as well. Using iron-oxide nanoparticles can also benefit from image guidance. This work will advance the application of FT by helping to better understand the energy field around the probe and helping to prevent unwanted damage to surrounding organs such as nerves.
  • Thumbnail Image
    Item
    Membrane-Targeting Approaches for Enhanced Cell Destruction with Irreversible Electroporation
    (2014-05) Jiang, Chunlan
    Irreversible Electroporation (IRE) has gained increasing popularity in the cancer treatment field during the past decade due to many advantages over other focal therapies. 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. There are approaches to expand the treatment volume by IRE with the addition of chemotherapeutic or cytotoxic agents. While these studies demonstrated improved cell killing, the focus was on enhancing the ability of chemotherapeutic drugs or cytotoxic agents to enter and kill the cancer cells rather than enhancing the efficacy of IRE itself. Therefore, the aim of this work is to investigate the ability to increase the destructive capability of IRE without relying on cytotoxic drugs. Specifically, mechanisms that directly modify membrane properties should reduce the voltage threshold for lethal permeabilization and therefore increase the efficacy of cell killing and therefore the volume treated after a given IRE level. Two methods to achieve these changes are proposed in this study: 1) addition of surfactant (e.g. Dimethyl sulfoxide, or DMSO) to directly interact with membrane lipids thereby changing membrane line tension and surface tension, and 2) use of pulse timing (i.e. introduction and persistence of defects in the membrane between pulses). Here then we began by Investigation of IRE enhancement in vitro to understand the impacts of our proposed mechanisms and their ideal working parameters. We found that the best enhancement effect was achieved with addition of 5% v/v DMSO, which resulted in a significant increase of 75% more cell destruction compared to baseline IRE. Similarly with pulse timing, when dividing the pulses into three trains with 30s delays in between, an enhancement of 67% more cell destruction was achieved compared to baseline IRE. Next we tested our IRE enhancement approaches in an in vivo dorsal skin fold chamber (DSFC) model of prostate cancer with optimal parameters selected from our in vitro experiments. The results reproducibly showed that more than 120% and 101% enhancement in the treatment volume were achieved by the addition of DMSO and pulse timing, respectively, with two independent injury assessment methods (histological and perfusion defect). Finally, we translated one of the enhancement approaches (pulse timing) to an in vivo hind limb model of prostate cancer and demonstrated that more than 33% additional tumor destruction and 2 weeks longer tumor growth delay could be achieved compared to baseline IRE treatment without relying on any cytotoxic drugs or agents. Because DMSO is commercially available and regularly used at low concentrations (<10% v/v) in clinic, this approach could easily be integrated into current IRE procedures to increase the treatment efficacy. In addition, introducing pulse timing delays in IRE also increases the destructive potential of IRE without the introduction of any foreign agents into the body. Further opportunities exist in improving the adjuvant delivery methods, optimizing the pulse timing delivery approach and understanding the fundamental mechanisms of IRE. Nevertheless, we suggest that the simple and safe nature of our proposed approaches compared with cytotoxic drugs may help to translate IRE into the clinic.
  • Thumbnail Image
    Item
    The Role of Protein Change (Cellular Protein Loss and Denaturation) in Determining Outcomes of Heating, Cryotherapy and Irreversible Electroporation
    (2018-04) Liu, Feng
    Atrial fibrillation currently affects millions of people in the US alone. Focal therapy is an increasingly attractive treatment for atrial fibrillation that avoids the debilitating effects of drugs for disease control. Perhaps the most widely used focal therapy for atrial fibrillation (AF) is heat-based radiofrequency (heating), although cryotherapy (cryo) is rapidly replacing it due to a reduction in side effects and positive clinical outcomes. A third focal therapy, irreversible electroporation (IRE), is also being considered in some settings. This study was designed to help guide treatment thresholds and compare mechanism of action across heating, cryo, and IRE. Testing was undertaken on HL-1 cells, a well-established cardiomyocyte cell line, to assess injury thresholds for each treatment method. Cell viability, as assessed by Hoechst and PI staining, was found to be minimal after exposure to temperatures ≤-40 °C (cryo), ≥60 °C (heating), and when field strengths ≥1500 V/cm (IRE) were used. Viability was then correlated to protein denaturation fraction (PDF) as assessed by Fourier Transform Infrared (FTIR) spectroscopy, and protein loss fraction (PLF) as assessed by Bicinchoninic Acid (BCA) assay after the three treatments. These protein changes were assessed both in the supernatant and the pellet of cell suspensions post treatment. We found that dramatic viability loss (≥50%) correlated strongly with ≥12% protein change (PLF, PDF or a combination of the two) in every focal treatment. These studies help in defining both cellular thresholds and protein-based mechanisms of action that can be used to improve focal therapy application for atrial fibrillation.