Synergistic cytotoxicity of irinotecan combined with polysaccharide-based nanoparticles for colorectal carcinoma

Abstract

Functional polymeric nanoparticles (NPs) with antitumor potential were combined with the topoisomerase I inhibitor, irinotecan (IRT), to enhance cytotoxicity against colorectal cancers. The negatively charged γ-polyglutamic acid (γ-PGA) or fucoidan (FCD) was complexed with the positively charged chitosan (CS) to encapsulate IRT. The size of the γ-PGA/CS/IRT NPs and FCD/CS/IRT NPs were 146.0 ± 8.0 nm and 230.8 ± 2.5 nm, respectively, with polydispersity index ≤0.3. The cellular uptake ability of FCD/CS-FITC NPs was better than that of γ-PGA/CS-FITC NPs, especially in p-selectin positive HCT116 colorectal cancer cells (4.8 ± 0.8 μg/mL vs 11.4 ± 2.2 μg/mL). The IC50 of FCD/CS/IRT NPs was 2.4 times lower than that of γ-PGA/CS/IRT NPs in HCT116 cells (4.8 ± 0.8 μg/mL vs 11.4 ± 2.2 μg/mL), indicating its superior antitumor potential. The combination of irinotecan and fucoidan-based NPs exhibited a synergistic effect (CI <1), resulting in better anticancer activity of FCD/CS/IRT NPs than irinotecan alone. The apoptosis-related proteins, caspase 3, caspase 9, and poly(ADP-ribose) polymerase (PARP), were prominently increased in FCD/CS/IRT NPs-treated HCT116 cells by 2.3 folds, 3.5 folds, and 6.3 folds, respectively. All results support that fucoidan-based irinotecan-loaded nanoparticles possess the ability to effectively enhance cellular uptake and induce synergistic apoptosis of colorectal cancer cells.