Engineered Platforms for the Development of Electroporation-based Tumor Therapies

Abstract

Cancer is a complex and dynamic disease that is difficult to treat due to its heterogeneous nature at multiple scales. Standard therapies such as surgery, radiation, and chemotherapy often fail, therefore superior therapies must be developed. Electroporation-based therapies offer an alternative to standard treatments, utilizing pulsed electric fields to permeabilize cell membranes to either enhance drug delivery (electrochemotherapy) or induce cancer cell death (irreversible electroporation). Electroporation treatments show promise in the clinic, however, are limited in the size of tumors that they can safely treat without increasing the applied voltage to an extent that induces thermal damage or muscle contractions in patients. A method to increase ablation size safely is needed. To make this advancement and to advance other cancer treatments as well, better in vitro tumor models are needed. Heterogeneity not only makes cancer difficult to treat, but also difficult to recapitulate in vitro. This dissertation addresses the complementary need to develop both better cancer therapies and more physiologically relevant in vitro tumor models. My results demonstrate that by using a calcium adjuvant with irreversible electroporation treatment, ablation size can be increased without using a higher applied voltage. Additional mechanistic studies identified signaling pathways that were differentially dysregulated under calcium and no calcium conditions, impacting cell death. Finally, I have successfully encapsulated cells in fibrin microgels which may enable the creation of more physiologically relevant and complex 3D in vitro and ex-vivo platforms to investigate IRE as well as other tumor therapies.