Development of vismodegib-loaded PLGA nanoparticles for the treatment of pancreatic cancer: Formulation and in vitro assessment in co-culture monolayers and spheroids

Abstract

The desmoplastic tumour microenvironment (TME) is a defining feature of pancreatic cancer and presents as a major barrier to drug delivery and efficacy. Vismodegib is a clinically approved drug that targets the Hedgehog pathway via its receptor, Smoothened. This pathway is activated in cancer-associated fibroblasts (CAFs), one of the main cell types in the TME. In this study, vismodegib was loaded into PLGA nanoparticles to improve its solubility and enhance the efficacy of the chemotherapeutic drug, gemcitabine. Vismodegib-loaded PLGA nanoparticles (Vis-PLGA NPs) were prepared and optimised based on the PLGA polymer, drug to polymer ratio and formulation method. Vis-PLGA NPs formulated by single emulsion method improved the encapsulation efficiency from 36% to 86% when compared to nanoprecipitation. More importantly, the drug release profile demonstrated a slower burst release, with sustained release for the single emulsion method at 35% vs 86% for nanoprecipitation after 48 h. In pancreatic stellate cells, Vis-PLGA NPs treatment selectively inhibited 2D co-cultured induced Hh pathway activation via the effector glioma-associated protein 1 (Gli1), when compared to free vismodegib. More importantly, Vis-PLGA NPs enhanced gemcitabine efficacy as a sequential treatment by prolonging spheroid growth inhibition, combined with higher apoptotic cell population compared to gemcitabine single treatment (10.3% vs 7.5%). This higher apoptosis was not observed with free vismodegib pre-treatment compared to gemcitabine alone. These promising results provide a platform for further in vitro characterisation and in vivo studies of Vis-PGLA NPs for pancreatic cancer treatment.