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

Abstract

In this study, we report the use of a multifunctional magnetic core-shell nanoparticle (MCNP), composed of a highly magnetic zinc-doped iron oxide (ZnFeO) 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.

New Advances in In Vivo Applications of Gated Mesoporous Silica as Drug Delivery Nanocarriers

“…Multifunctional magnetic core–shell MSNs able to deliver simultaneously let‐7a micro interfering RNA (miRNA), which has the ability to repress DNA repair mechanism and downregulate drug efflux pumps, and Dox in cancer cells were prepared by Lee and co‐workers ( Figure ) . Magnetic ZnFe 2 O 4 nanoparticles were coated with a mesoporous silica shell.…”

Functional Mesoporous Silica Nanocomposites: Biomedical Applications and Biosafety

“…To do so, the authors prepared negatively charged phosphonate IOMSNs, which were coated with PEI, (10 kDa) polymer. Then, onto it was deposited the miRNA and an RGD-modified PEI layer [62]. The resulting RGD-targeted cationic assembly provided enhanced internalization on MDA-MB-231 breast cancer cells.…”

“…One of the most acclaimed applications of MDDS is the possibility of achieving magnetic guidance, although for magnetic silica composites, it is difficult to find successful examples. One of those is the model reported by Lee, which profited from a facilitated in vitro magnetic transfection to increase the apoptotic effect induced by hyperthermia plus DOX and let-7a miRNA co-delivery into glioblastoma multiform cancer cells [62].…”

MicroRNAs and Metastasis

“…Liposomal nanoparticles loaded with miR-200c were demonstrated to sensitize metastatic lung cancer cells to radiotherapy in vivo [158]. In addition, multiple studies have been used combining miRNA modulators (mimics or anti-miRNAs) along with chemotherapy-most commonly, doxorubicin with miRNAs such as let-7a and miR-21 in breast cancer [159,160], miR-31 in cervical cancer [161] and miR-34a in prostate cancer [162]. Co-polymer nano-assemblies (PEG5K-VE4-DET20) were co-loaded with let-7b mimic and paclitaxel in NSCLC and demonstrated to potentiate the cytotoxicity of paclitaxel and induced apoptosis and inhibition of invasiveness in vivo [163].…”