Reactive oxygen species (ROS)-response nanomedicine through knocking down a novel therapeutic target NEDD8-conjugating enzyme UBC12 (UBE2M) in the treatment of liver cancer

Abstract

Knocking down the UBC12 with siRNA could significantly suppress the Neddylation pathway and result in an admirable anti-cancer effect. However, how to transport siRNA in vivo with low potential toxicity is an urgent problem to be solved. For enhancing bioavailability of siRNA, folic acid (FA)-modified PLGA (poly(lactic-co-glycolic acid))-TK (thioketal)-PEG (polyethylene glycol) nanomedicine was designed for siRNA delivery. The nano-vector possesses spherical morphology and admirable biocompatibility. After targeted endocytosis through the selective recognition between FA and its receptor in liver cancer cells, the genetic nanomedicine was triggered by high ROS level and released its cargo siRNA in tumor microenvironment. In vitro and In vivo results revealed that the genetic nanomedicine not only inhibits proliferation and promotes apoptosis of liver cancer cells, but also possesses excellent therapeutic efficacy by knowing down UBC12 and suppressing the Neddylation pathway as well as accumulating tumor-suppressive CRL substrates. Consequently, this work provides a novel approach to construct a biodegradable nanomedicine with targeted recognition and smart response. Moreover, it inhibits the viability of liver cancer cells with high efficiency and low potential toxicity. Importantly, the PLGA nanomedicine demonstrates the encouraging potential for multifunctional nano-system applicable for cancer therapy.

Keywords

• UBC12
• Neddylation
• siRNA-loaded nanomedicine
• Smart response
• Targeted delivery