Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles

Abstract

Over the past decade, RNA interference (RNAi) has been ubiquitously utilized to study biological function in vitro; however, limitations were associated with its utility in vivo More recently, small interfering RNA (siRNA) nanoparticles with improved biocompatibility have gained prevalence as a potential therapeutic option for the treatment of various diseases. The adaptability of siRNA nanoparticles enables the delivery of virtually any siRNA, which is especially advantageous for therapeutic applications in heterogeneous diseases that lack unifying molecular features, such as triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of breast cancer that is stratified by the lack of estrogen receptor/progesterone receptor expression and HER2 amplification. There are currently no FDA-approved targeted therapies for the treatment of TNBCs, making cytotoxic chemotherapy the only treatment option available to these patients. In this review, we outline the current status of siRNA nanoparticles in clinical trials for cancer treatment and discuss the promising preclinical approaches that have utilized siRNA nanoparticles for TNBC treatment. Next, we address TNBC subtype-specific therapeutic interventions and highlight where and how siRNA nanoparticles fit into these strategies. Lastly, we point out ongoing challenges in the field of siRNA nanoparticle research that, if addressed, would significantly improve the efficacy of siRNA nanoparticles as a therapeutic option for cancer treatment.

Keywords: siRNA nanoparticles; therapeutic strategy; triple-negative breast cancer.

Figure 1

The siRNA machinery. Upon entry into the cell, the sense strand of the double-stranded siRNA is cleaved. The antisense siRNA strand then acts as a guide for mRNA complementation. Perfect complementarity between the antisense siRNA strand and the target mRNA leads to mRNA degradation, while imperfect complementarity between the two leads to the mRNA translational repression.

Figure 2

Select examples of organic nanoparticles. Lipid nanoparticles include micelles and liposomes, which are composed of hydrophobic lipids that contain a hydrophilic head. Polymeric nanoparticles include dendriplexes and cyclodextrin nanoparticles. A dendrimer is a branched amphiphilic polymer and cyclodextrin is an amphiphilic cyclic oligosaccharide.

Figure 3

Current approaches using therapeutic siRNA nanoparticles in the treatment of TNBCs. A) siRNA nanoparticles delivering siRNA against FoxM1, CDK11/CK2, and CDK1 are demonstrated to significantly reduce primary tumor burden. B) siRNA nanoparticles silencing Twist and β3 integrin inhibits EMT. Nanoparticles delivering β3 integrin siRNA also reduce primary tumor burden, primary tumor recurrence, and metastasis in MDA-MB-231 mouse xenograft models. C) Complex nanoparticles utilize siRNAs to improve chemotherapeutic efficacy.