Delivery of short hairpin RNAs by transkingdom RNA interference modulates the classical ABCB1-mediated multidrug-resistant phenotype of cancer cells

RNA interference (RNAi) is a powerful tool for studying gene function owing to the ease with which it can selectively silence genes of interest, and it has also attracted attention because of its potential for therapeutic applications. Chemically synthesized small interfering RNAs (siRNAs) and DNA vector-based short hairpin RNAs (shRNAs) are now widely used as RNAi triggers. In contrast to expressed shRNAs, the use of synthetic shRNAs is limited. Here we designed shRNAs modeled on a precursor microRNA (pre-miRNA) and evaluated their biological activity. We demonstrated that chemically synthetic pre-miRNA-based shRNAs have more potent RNAi activity than their corresponding siRNAs and found that their antisense strands are more efficiently incorporated into the RNA-induced silencing complex. Although greater off-target effects and interferon responses were induced by shRNAs than by their corresponding siRNAs, these effects could be overcome by simply using a lower concentration or by optimizing and chemically modifying shRNAs similar to synthetic siRNAs. These are challenges for the future.

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Photostable and Biocompatible Fluorescent Silicon Nanoparticles for Imaging-Guided Co-Delivery of siRNA and Doxorubicin to Drug-Resistant Cancer Cells

Nano-Micro Letters ◽

10.1007/s40820-019-0257-1 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 11

Author(s):

Daoxia Guo ◽

Xiaoyuan Ji ◽

Fei Peng ◽

Yiling Zhong ◽

Binbin Chu ◽

...

Keyword(s):

Breast Cancer ◽

Rna Interference ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Silicon Nanoparticles ◽

Multidrug Resistant ◽

Rnase A ◽

Drug Resistant ◽

Fluorescent Silicon Nanoparticles ◽

P Glycoprotein

Abstract The development of effective and safe vehicles to deliver small interfering RNA (siRNA) and chemotherapeutics remains a major challenge in RNA interference-based combination therapy with chemotherapeutics, which has emerged as a powerful platform to treat drug-resistant cancer cells. Herein, we describe the development of novel all-in-one fluorescent silicon nanoparticles (SiNPs)-based nanomedicine platform for imaging-guided co-delivery of siRNA and doxorubicin (DOX). This approach enhanced therapeutic efficacy in multidrug-resistant breast cancer cells (i.e., MCF-7/ADR cells). Typically, the SiNP-based nanocarriers enhanced the stability of siRNA in a biological environment (i.e., medium or RNase A) and imparted the responsive release behavior of siRNA, resulting in approximately 80% down-regulation of P-glycoprotein expression. Co-delivery of P-glycoprotein siRNA and DOX led to > 35-fold decrease in the half maximal inhibitory concentration of DOX in comparison with free DOX, indicating the pronounced therapeutic efficiency of the resultant nanocomposites for drug-resistant breast cancer cells. The intracellular time-dependent release behaviors of siRNA and DOX were revealed through tracking the strong and stable fluorescence of SiNPs. These data provide valuable information for designing effective RNA interference-based co-delivery carriers.

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