Engineering and In Vitro Evaluation of Acid Labile Cholesterol Tethered MG132 Nanoparticle for Targeting Ubiquitin‐Proteasome System in Cancer

Abstract

In recent years, proteasome has evolved as one of the important alternative targets in cancer chemotherapy. However, selective targeting of proteasome system in cancer cells still remains a major challenge. To address this, a potent peptide based proteasome inhibitor MG132 was chemically conjugated with biocompatible‐biodegradable cholesterol by acid cleavable hydrazone linkage. Spherical nanoparticles (MG132‐NPs) were engineered from cholesterol‐MG132 conjugate. Increased amount of free MG132 was released from these nanoparticles in acidic environment compared to physiological milieu in a slow and controlled manner. These MG132‐NPs were taken up by breast cancer MCF7 cells into lysosomes within 6 h. Proteasome system was inhibited by these MG132‐NPs leading to stabilization of β‐catenin, cyclin A and cyclin B in HEK‐293T cells. Interestingly, MG132‐NPs induced much improved cell death in drug resistant MDA‐MB‐231 cells with insignificant toxicity in healthy cells (HEK293 and L929) even in higher concentration.