Mitochondrial delivery of microRNA mimic let-7b to NSCLC cells by PAMAM-based nanoparticles

Abstract

Many biological mechanisms including cellular metabolism and cell death are regulated by mitochondria known as powerhouse of the cell. Recently, let-7b, a tumour-suppressor microRNA has been detected in mitochondria of human cells targeting several mitochondrial-encoded respiratory chain genes. Triphenylphosphonium cation (TPP) is one of the major classes of mitochondriotropics that possess the ability of specifically targeting the mitochondria. PAMAM dendrimers are one of the most available agents in gene delivery due to their well-defined and beneficial features such as large density of surface functional groups. Hyaluronic acid (HA), a natural polysaccharide has been demonstrated to have the abilities such as good biocompatibility and targeting CD44 overexpressed receptors on non-small cell lung cancer (NSCLC) cells. In this research, let-7b-PAMAM (G5)-TPP and let-7b-PAMAM (G5)-TPP-HA nano-carriers were designed to deliver let-7b miRNA mimic to NSCLC cells’ mitochondria as a novel way of cancer cells inhibition. Nano-carriers were capable of being successfully taken up by A549 cells and localised in mitochondria environment. Let-7b loaded nanoparticles reduced cell viability and induced apoptosis significantly. Expression of genes involved in mitochondrial oxidative function was decreased resulting in nanoparticles effect on mitochondria. Application of mitochondria targeted-miRNA delivery systems could regulate cellular functions to inhibit lung cancer.

Keywords:

• PAMAM (G5) dendrimers
• microRNA let-7b
• triphenylphosphonium
• hyaluronic acid
• mitochondria

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was financially supported by a grant from Tehran University of Medical Sciences. (Contract research Grant no. 96-02-33-35072). Thanks to Dr Abbas Beh-Pajooh for his collaboration in Quantitative real time-PCR experiments.