Assessment and optimization of electroporation-assisted tumoral nanoparticle uptake in a nude mouse model of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal form of cancer. In 2012, the incidence of PDAC was 43,920. Five-year survival for patients with PDAC is around 6%, regardless of staging, making PDAC one of the deadliest forms of cancer. One reason for this dismal prognosis is chemoresistance to the current first-line therapy, gemcitabine. There are multiple factors that contribute to the chemoresistance observed in pancreatic cancer. Among them, desmoplasia has been increasingly seen as a significant contributor to chemoresistance. To overcome desmoplastic chemoresistance, several novel methods of treatment have been developed. Electroporation is one such novel treatment. High electrical fields are applied to cells to create pores that increase cell permeability. It has been previously demonstrated that electroporation enhances the therapeutic efficacy of anticancer drugs in pancreatic tumor models. Nanoparticle-based drug delivery systems constitute a second novel method to overcome desmoplastic chemoresistance. Due to their intrinsic design advantages, nanoparticles have been shown to increase the effectiveness of chemotherapeutic agents, while further reducing or even eliminating side effects. To date, there have been no studies evaluating the cumulative effect of combining both nanoparticle and electroporation strategies to overcome chemoresistance in PDAC. Our preliminary studies assessed the in vitro and in vivo uptake of doxorubicin-loaded iron oxide nanoparticles as a function of electroporation voltage and timing of administration in pancreatic adenocarcinoma cells. Our studies demonstrated that addition of electroporation to administration of nanoparticles significantly increased the amount of intracellular iron oxide nanoparticle uptake by a PANC-1 cell line in an athymic nude mouse model of PDAC. Further, electroporation-assisted nanoparticle uptake could be significantly altered by changing the timing of application of electroporation.

Antitumor efficacy of liposome-encapsulated NVP-BEZ 235 in combination with irreversible electroporation

“…However, the combination of L-BEZ with electroporation significantly increased cytotoxicity. Literature suggests that the timing of electroporation and cell exposure to nanoparticles resulted in different levels of the cellular uptake of iron nanoparticles (West et al., 2013 ). Our in vitro result of IRE + L-BEZ suggests similar cytotoxicity regardless of timing.…”

Reversible Electroporation–Mediated Liposomal Doxorubicin Delivery to Tumors Can Be Monitored With 89Zr-Labeled Reporter Nanoparticles

“…Membrane permeabilization has been considered the primary route for RE-mediated nanoparticle delivery into tumors. This assumption led to studies that closely timed the delivery of nanoparticles and electroporation 12 and used selective intra-arterial administration of nanoparticles to maximize the uptake following electroporation. 11,13 The results of our study identify that RE-related changes in vascular permeability could be another mode for delivery nanoparticles (DOX and 89 Zr-NRep) into tumors.…”

Nanocomposite Polymer Scaffolds Responding under External Stimuli for Drug Delivery and Tissue Engineering Applications

“…It needs surgery to locate the electrodes close to the tumor and the EP presents risks for the surrounding healthy tissues. The EP is usually reached for a potential of 400 V and the time varies from 3 to 12 min before NPs delivery …”