Zinc-cystine bio-MOF coated with folic acid-modified chitosan nanogel for targeted pH/glutathione dual-responsive drug delivery

Abstract

Here, a zinc-cystine (Zn-cys) biological-metal-organic framework (bio-MOF) coated with folic acid-modified chitosan (FC) nanogel, was developed for pH/glutathione dual-responsive delivery of doxorubicin (DOX). In vitro drug release demonstrated a superior cumulative DOX release (83.5 %) at pH 5.8 and a high GSH concentration (10 mM). According to the MTT assay, the DOX-loaded Zn-cys bio-MOF/FC showed significant toxicity against MCF-7 cells (positive folate receptor) compared to HUVEC cells (low expressed level of folate receptor), by reducing cancer cell viability to 23.8 ± 0.34 % after 48 h incubation. The cellular uptake study confirmed that Zn-cys bio-MOF/FC could be readily internalized by MCF-7 cells via endocytosis. The results indicated an enhanced apoptosis rate of DOX@Zn-cys bio-MOF/FC (22.8 %) compared to free DOX (6.04 %). Fluorescence microscopy further confirmed higher cell death induced by the DOX@Zn-cys bio-MOF/FC nanocarrier in MCF-7 cells. Hemolysis analysis revealed that the nanocarrier was safe and exhibited no hemolytic activity. According to western blot analysis, DOX@Zn-cys bio-MOF/FC showed effective anti-cancer activity by up-regulating the expression level of Bax (a pro-apoptotic protein) and down-regulating the expression level of Bcl-2 (an anti-apoptotic protein). Therefore, the developed nanocarrier could be a promising candidate for targeted breast cancer therapy.

Keywords: Bio-MOFs; Chemotherapy; Chitosan; Doxorubicin; Nanogel; pH/GSH dual-responsive.