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ACS Nano. 2019 Jan 22;13(1):274-283. doi: 10.1021/acsnano.8b05639. Epub 2018 Dec 21.

Regulation of Ca2+ Signaling for Drug-Resistant Breast Cancer Therapy with Mesoporous Silica Nanocapsule Encapsulated Doxorubicin/siRNA Cocktail.

Wang S1,2, Liu X2,3, Chen S4, Liu Z1,2, Zhang X1,2, Liang XJ2,4,5, Li L1,2,5.

Author information

1
Beijing Institute of Nanoenergy and Nanosystems , Chinese Academy of Sciences , Beijing 100083 , P. R. China.
2
School of Nanoscience and Technology , University of Chinese Academy of Sciences , Beijing 100049 , P. R. China.
3
CAS Key Laboratory of Bio-Inspired Materials and Interfacial Science, CAS Center for Excellence in Nanoscience, Technical Institute of Physics and Chemistry , Chinese Academy of Sciences , Beijing 100190 , P. R. China.
4
Laboratory of Controllable Nanopharmaceuticals, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety , National Center for Nanoscience and Technology , Beijing 100190 , P. R. China.
5
Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience , Beijing 100190 , P. R. China.

Abstract

Multidrug resistance (MDR) is the key cause that accounts for the failure of clinical cancer chemotherapy. To address the problem, herein, we presented an alternative strategy to conquer drug-resistant breast cancer through the combinatorial delivery of Ca2+ channel siRNA with cytotoxic drugs. Mesoporous silica nanocapsules (MSNCs) with mesoporous and hollow structure were fabricated for co-delivery of T-type Ca2+ channel siRNA and doxorubicin (DOX) with high drug loading efficiency. The DOX/siRNA co-loaded MSNCs showed a synergistic therapeutic effect on drug-resistant breast cancer cells MCF-7/ADR, while had only an additive effect on the drug-sensitive MCF-7 counterpart. It was found that the combination of T-type Ca2+ channel siRNA and DOX had a similar effect on MCF-7 and MCF-7/ADR in the knockdown of overexpressed T-type Ca2+ channels and decrease in cytosolic Ca2+ concentration ([Ca2+]i), but it specifically induced G0/G1 phase cell-cycle arrest and intracellular drug accumulation enhancement in MCF-7/ADR. The in vitro and in vivo results demonstrated that the MSNCs with good biocompatibility had a high efficiency for conquering the drug-resistant breast cancer with the DOX/calcium channel siRNA cocktail co-delivery. It provides a biological target for drug/gene delivery enhanced cancer therapy with nanoformulations.

KEYWORDS:

Ca2+ channel; Ca2+ signaling; mesoporous silica nanocapsules; multidrug resistance; siRNA delivery

PMID:
30566319
DOI:
10.1021/acsnano.8b05639

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