Abstract B138: Biocompatible, injectable, and thermoresponsive nanoparticle-loaded hydrogel for the controlled release of FGFR irreversible inhibitor-1 of pancreatic perineural invasion

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive microenvironment and a pronounced tendency for perineural invasion (PI), which worsens prognosis and contributes to pain and local recurrence [1]. Local controlled drug delivery may improve therapeutic outcomes while reducing systemic toxicity [2]. To address this aim, this study presents an injectable nanoparticle-loaded hydrogel as a local biocompatible therapeutic delivery platform for the controlled release of FGFR irreversible inhibitor-1 (FIIN-1) to limit the perineural invasion in PDAC. FIIN-1 inhibitor has been encapsulated within poly(maleic anhydride-alt-1-octadecene) (PMAO) nanoparticles (NPs), which were subsequently incorporated into a previously developed and characterized Chitosan–Pectin hydrogel, a semi-interpenetrating polymer network (semi-IPN), to create a hybrid delivery system that combines nanoparticle drug-loading with the sustained-release properties of a polymeric matrix. Release studies were performed comparing FIIN-1 release from nanoparticles alone and from nanoparticles embedded within the hydrogel. The hydrogel-NPs formulation showed a more controlled release profile, suggesting that the hydrogel matrix can modulate FIIN-1 diffusion and prolong its local availability. Physicochemical characterization of the hydrogel displayed its injectability, thermo-responsiveness, and biocompatibility, supporting its use as a platform for FIIN-1 delivery. Stability studies further showed that the hydrogel preserves its structural integrity under physiological conditions, supporting its suitability for local injection. Biological characterization also demonstrated good biocompatibility of the hydrogel–NPs system with both PDAC cells and primary rat Schwann cells (SCs) at different concentrations of the inhibitor. In conclusion, these results support the chitosan–pectin thermoresponsive hydrogel loaded with NPs containing the FIIN-1 inhibitor as a promising local delivery strategy to modulate perineural invasion in PDAC. This hydrogel-based delivery system may represent a promising platform for future preclinical applications, supporting investigations of drug response and the development of localized therapeutic strategies. References:[1] Sun, Y., Jiang, W., Liao, X., & Wang, D. (2024). Hallmarks of perineural invasion in pancreatic ductal adenocarcinoma: new biological dimensions. Frontiers in Oncology, 14, 1421067. [2] Minaei, E., Ranson, M., Aghmesheh, M., Sluyter, R., & Vine, K. L. (2024). Enhancing pancreatic cancer immunotherapy: Leveraging localized delivery strategies through the use of implantable devices and scaffolds. Journal of Controlled Release, 373, 145-160.