Programmable Enzymatic Logic Circuits for the Spatiotemporal Management of Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is still a highly aggressive form of cancer with a high chance of spreading early on, dense fibrous tissue and large metabolic differences among the cells that make it up. Traditional methods of determining if a person has this type of cancer and providing treatment rely on one marker (such as the KRAS mutation) and fixed treatment plans, do not consider the dynamic nature of the tumor microenvironment (TME) of PDAC. In this review, we examine the development of programmable based enzyme logic (PEL) technologies as potential novel treatments for the management of PDAC. By using complex biochemical processes (i.e., intracellular enzymatic cascades) as logical gates (AND, OR, NOT & XOR), the PEL systems will allow clinicians to use very clear metabolic rates associated with KRAS, specific proteases (MMP's & UPA) and fluctuations in pH as biochemical signals to produce diagnostic value and the ability to autonomously release therapies with high specificity. We will outline the biochemical device architecture, how these devices are incorporated into multifunctional delivery vehicles and their potential application in overcoming the antigenic "dark matter" associated with PDAC. The PEL approach provides an innovative progression from reacting to proactively based decisions by using logic for future precision cancer care ultimately addressing the unique issues presented by metastatic pancreatic cancer.