Overcoming Chemoresistance in Cancer via Combined MicroRNA Therapeutics with Anticancer Drugs Using Multifunctional Magnetic Core-Shell Nanoparticles.

In this study, we report the use of a multifunctional magnetic core-shell nanoparticle (MCNP), composed of a highly magnetic zinc-doped iron oxide (ZnFe2O4) core nanoparticle and a biocompatible mesoporous silica (mSi) shell, for the simultaneous delivery of let-7a microRNA (miRNA) and anticancer drugs (e.g., doxorubicin) to overcome chemoresistance in breast cancer. Owing to the ability of let-7a to repress DNA repair mechanisms (e.g., BRCA1 and BRCA2) and downregulate drug efflux pumps (e.g., ABCG2), delivery of let-7a could sensitize chemoresistant breast cancer cells (MDA-MB-231) to subsequent doxorubicin chemotherapy both in vitro and in vivo. Moreover, the multifunctionality of our MCNPs allows for the monitoring of in vivo delivery via magnetic resonance imaging. In short, we have developed a multifunctional MCNP-based therapeutic approach to provide an attractive method with which to enhance our ability not only to deliver combined miRNA therapeutics with small-molecule drugs in both selective and effective manner but also to sensitize cancer cells for the enhanced treatment via the combination of miRNA replacement therapy using a single nanoplatform.

Stem cell-based gene therapy activated using magnetic hyperthermia to enhance the treatment of cancer.

Stem cell-based gene therapies, wherein stem cells are genetically engineered to express therapeutic molecules, have shown tremendous potential for cancer applications owing to their innate ability to home to tumors. However, traditional stem cell-based gene therapies are hampered by our current inability to control when the therapeutic genes are actually turned on, thereby resulting in detrimental side effects. Here, we report the novel application of magnetic core-shell nanoparticles for the dual purpose of delivering and activating a heat-inducible gene vector that encodes TNF-related apoptosis-inducing ligand (TRAIL) in adipose-derived mesenchymal stem cells (AD-MSCs). By combining the tumor tropism of the AD-MSCs with the spatiotemporal MCNP-based delivery and activation of TRAIL expression, this platform provides an attractive means with which to enhance our control over the activation of stem cell-based gene therapies. In particular, we found that these engineered AD-MSCs retained their innate ability to proliferate, differentiate, and, most importantly, home to tumors, making them ideal cellular carriers. Moreover, exposure of the engineered AD-MSCS to mild magnetic hyperthermia resulted in the selective expression of TRAIL from the engineered AD-MSCs and, as a result, induced significant ovarian cancer cell death in vitro and in vivo.