EIC Pathfinder #101099963

Introduction: Many chemotherapeutic treatments for cancer exhibit limited effectiveness due to issues related to drug delivery efficiency and systemic toxicity. We aim for difficult-to-treat types of cancer, particularly Pancreatic Adenocarcinoma (PAAD). The tumor frequently resides in close proximity to vital anatomical structures responsible for blood supply. As a result, the feasibility of surgical resection is compromised until the tumor attains a manageable dimension. Consequently, reducing the tumor's dimensions emerges as a promising strategy to render inoperable PAAD patients suitable for surgical intervention.

Aim: This study proposes a solution employing iontronic devices for accurate and timed molecule delivery of a specific trigger molecule into a hydrogel which contains a covalently bound chemotherapeutic drug (a drug-loaded hydrogel). Within this hydrogel, the trigger molecule sets off a "click-to-release" (C2R) reaction, facilitating the direct release of the drug at the tumor site. Through the localized implementation of the bioSWITCH concept, our objective is to position highly potent pharmaceutical agents in direct vicinity of the tumor. This approach aims to effectively optimize the anti-cancer impact of the released medications by precisely targeting the tumor site.

Methods: The C2R system components underwent testing across various cancer cell lines to determine IC₅₀ concentrations and toxicity levels. In parallel, iontronically-mediated trigger molecule delivery rates were determined with two ion exchange membranes (anionic hyperbranched polyglycerols and polyAMPSA). Subsequently, the iontronic-controlled C2R of potent chemotherapy drugs, as well as hydrogel prototypes, were tested in two cancer models: a 2D cell culture setup and a 3D in vivo tumor model involving the chick chorioallantoic membrane (CAM).

Results: The study successfully devised a C2R mechanism using iontronic devices to trigger controlled release of a potent prodrug. Initial proof-of-concept experiments were conducted in vitro on tumor cells. The prodrug demonstrated biocompatibility while bound, but the introduction of the trigger molecule through iontronics prompted an interaction between the compounds, leading to drug release. Notably, precise control over system activation and deactivation was achieved, effectively modulating cancer cell death. These outcomes highlight the considerable potential of this approach and lay the foundation for pre-clinical investigations towards a novel PAAD therapy strategy.