Co-delivery of SiRNA and a chemotherapeutic prodrug to trigger mitochondria-mediated cancer-cell apoptosis

Abstract

Triggering the mitochondrial apoptosis pathway to cause cancer-cell suicide is a potential option for cancer therapy. However, the therapeutic effects of drugs that act on mitochondria were not remarkable in clinical trials because the amount of the drugs that was delivered to the mitochondria was insufficient. Therefore, designing rational nanocarriers that would deliver mitochondriaacting drugs to mitochondria is urgent. In addition, the NPs must navigate from the injection site to the mitochondria through multiple physiological and biological barriers, involving transport via the blood to the extracellular matrix of the tumor, binding to the tumor-cell plasma membrane, internalization, and intracellular delivery to the mitochondria. Therefore, a well-designed mitochondria-targeted delivery system that possesses all of the abovementioned attributes for effective drug delivery in cancer therapy is rare and highly desirable. Herein, we synthesized and evaluated a novel mitochondria-targeted nanocarrier system that possessed the above-mentioned capabilities for the efficient co-delivery of a chemotherapeutic drug and siRNA. LND and the mitochondria targeting ligand TPP were linked to a biocompatible chitosangraft-polyethyleneimine copolymer (denoted as CP) via amide bonds to form the copolymer TPP-CP-LND (denoted as TCPL), and then the stealthy, pH-responsive detached and the tumor targeted copolymer poly (acrylic acid)-polyethylene glycol-folic acid (PPF) coated to rationally prepare a hierarchical mitochondria-targeted co-delivery system (denoted as TCPL/siBcl-2/PPF NPs) for cancer therapy. The unique structure of the TCPL/siBcl-2/PPF NPs endowed them with the capacities of prolonged blood circulation, simultaneously carrying siRNA and LND, and hierarchically targeting cancer cells and the intracellular site of action (mitochondria). TCPL/siBcl-2/PPF NPs could suppress the expression of antiapoptotic Bcl-2 and inhibit tumor growth remarkably better than LND and siBcl-2 alone through synergistically triggering mitochondria-mediated apoptosis pathway. The TCPL/siBcl-2/PPF NPs were characterized, and the mechanism through which they synergistically triggered mitochondriamediated apoptosis was investigated.