PDGFR-Targeted Ruxolitinib Liposomes Modulate Fibroblast-Associated Colorectal Cancer-Stroma Interactions, Reducing...

Ruxolitinib (Rux) is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways and is clinically used for the treatment of myelofibrosis. In this study, a nanodelivery approach was developed to investigate the effects of Rux on fibroblast-associated tumor-stroma interactions in colorectal cancer. Platelet-derived growth factor receptor (PDGFR)-targeted, Rux-loaded liposomes (Lip/Rux/PDGFR) were prepared using a lipid thin-film hydration method and characterized by dynamic light scattering. The average hydrodynamic diameters of Lip/Rux and Lip/Rux/PDGFR were 186.2 ± 1.2 nm and 178.6 ± 2.0 nm, respectively, with slightly negative surface charges. Transmission electron microscopy confirmed the spherical morphology. Antiproliferative activity was evaluated in HT-29 colorectal cancer cells using MTT and three-dimensional tumor spheroid assays. Lip/Rux and Lip/Rux/PDGFR reduced HT-29 cell viability compared with free Rux and Lip/PDGFR controls. To assess stromal-associated effects, activated fibroblasts were treated and subsequently evaluated in coculture and 3D spheroid invasion models. Treatment of activated fibroblasts with Lip/Rux/PDGFR was associated with a greater reduction in HT-29 cell invasion than free Rux and Lip/PDGFR. Furthermore, pretreatment of activated fibroblasts with Lip/Rux/PDGFR was associated with improved 5-FU responsiveness in cocultured HT-29 spheroids, suggesting a reduction in fibroblast-associated chemoprotective effects. Taken together, these findings suggest that PDGFR-targeted liposomal delivery of Rux may affect fibroblast-associated tumor-stroma interactions, which could contribute to reduced colorectal cancer cell invasion and enhanced sensitivity to chemotherapy. Further studies are needed to clarify the underlying mechanisms and determine whether these effects are mediated through alterations in activated fibroblast functions.