PLGA‑PEG nanoparticles loaded with the Cdc42 inhibitor CASIN suppress migration and invasion of colorectal cancer cells in Vitro

Vollständiger Abstract

Worum geht es in dieser Arbeit?

Introduction. Colorectal cancer remains one of the most lethal malignant tumours, and the deterioration in prognosis is largely due to the development of metastases. Cdc42, a small Rho GTPase, regulates the actin cytoskeleton, cellular polarity, and invasively metastatic phenotype, making it an attractive cancer therapy target. The low molecular weight Cdc42 inhibitor CASIN has antitumor activity, but its use is limited by unfavourable physico-chemical properties. We previously developed PLGA-PEG nanoparticles loaded with CASIN, demonstrating hemocompatibility and antiproliferative effect in vitro. Here, for the first time, we investigated their effect on migration and invasion of colorectal cancer cells. Objective. To evaluate the effect of PLGA-PEG nanoparticles loaded with the Cdc42 inhibitor CASIN on migration and invasion of human colorectal cancer cell lines in vitro. Methods. PLGA-PEG nanoparticles loaded with CASIN were prepared by single-stage nanoprecipitation. The HCT116, SW620, and HT 29 cell lines were studied. Migration was assessed by scratch assay (wound gap closure dynamics) and invasion by Transwell assay with matrigel-coated membranes. Cells were incubated with PLGA-PEG-CASIN at IC50 concentrations; untreated cells served as controls. Results. PLGA-PEG-CASIN at concentrations close to IC50 significantly suppressed migration and invasion in all three colorectal cancer lines. In scratch assay, nanoparticle treatment slowed down the closure of the wound defect: in HT 29, the gap area after 24 and 72 hours was 91% and 86% versus 85% and 60% in the control; in SW620, 88% and 82% versus 72% and 52%; in HCT116, 90% and 85% versus 81% and 64%, respectively. In the Transwell assay, invasive activity decreased approximately 3.6-fold in HT-29, 5.3-fold in SW620, and 4.3-fold in HCT116 compared with controls. Conclusions. PLGA-PEG nanoparticles loaded with the Cdc42 inhibitor CASIN effectively reduce migration and invasion of colorectal cancer cells in vitro, supporting their potential as a candidate for preclinical development of targeted therapy for metastatic colorectal cancer. Keywords: colorectal cancer, targeted therapy, Cdc42, PLGA-PEG nanoparticles.