Advancing Focal Therapies for Cancer and Neural Targets

Abstract

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.