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Multifunctional Nanographene Oxide for Targeted Gene-Mediated Thermochemotherapy of Drug-resistant Tumour.

ABSTRACT: Drug resistance remains a major challenge for anticancer treatment, and one of the major mechanisms of drug resistance is the overexpression of drug efflux transporters in cancer. A new approach for defeating drug resistance is the use of a co-delivery strategy that utilizes small interfering RNA (siRNA) to silence the expression of efflux transporters together with a suitable anticancer drug for drug-resistant cells. In this work, multifunctional graphene capable of integrating multiple functions in one system was employed as a novel co-delivery system for siRNA and doxorubicin (Dox), as well as for the controlled release of intracellular pH-triggered and heat-triggered Dox. Additionally, it was used as a synergistic therapy based on the photothermal effect of graphene oxide (GO) under near-infrared (NIR) irradiation and the chemotherapeutic effect of Dox. The nanocomplex exhibited high drug and siRNA loading. Furthermore, the dual delivery of siRNA and Dox by folic acid (FA)-conjugated polyethylenimine-modified PEGylated nanographene (PPG-FA/siRNA/Dox) exhibited a satisfactory gene silencing effect as well as efficient intracellular delivery of Dox. Thus, Dox could access the nucleus and induce greater cytotoxicity compared with siRNA-absent delivery systems. Significantly, under irradiation, the combined treatment showed more synergistic effect for overcoming drug resistance compared with chemotherapy effect alone.

SUBMITTER: Zeng Y

PROVIDER: S-EPMC5341118 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Multifunctional Nanographene Oxide for Targeted Gene-Mediated Thermochemotherapy of Drug-resistant Tumour.

Zeng Yiping Y Yang Zhangyou Z Li Hong H Hao Yuhui Y Liu Cong C Zhu Lin L Liu Jing J Lu Binghui B Li Rong R

Scientific reports 20170308

Drug resistance remains a major challenge for anticancer treatment, and one of the major mechanisms of drug resistance is the overexpression of drug efflux transporters in cancer. A new approach for defeating drug resistance is the use of a co-delivery strategy that utilizes small interfering RNA (siRNA) to silence the expression of efflux transporters together with a suitable anticancer drug for drug-resistant cells. In this work, multifunctional graphene capable of integrating multiple functio ...[more]

PMID: 28272412

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Project description:BackgroundDoxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer. It has, however, been shown that doxorubicin can induce drug resistance resulting in poor patient prognosis and survival. Studies reported that the interaction between signalling pathways can promote drug resistance through the induction of proliferation, cell cycle progression and prevention of apoptosis. The aim of this study was therefore to determine the effects of doxorubicin on apoptosis signalling, autophagy, the mitogen-activated protein kinase (MAPK)- and phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, cell cycle control, and regulators of the epithelial-mesenchymal transition (EMT) process in murine breast cancer tumours.MethodsA tumour-bearing mouse model was established by injecting murine E0771 breast cancer cells, suspended in Hank's Balances Salt Solution and Corning® Matrigel® Basement Membrane Matrix, into female C57BL/6 mice. Fourty-seven mice were randomly divided into three groups, namely tumour control (received Hank's Balances Salt Solution), low dose doxorubicin (received total of 6?mg/ml doxorubicin) and high dose doxorubicin (received total of 15?mg/ml doxorubicin) groups. A higher tumour growth rate was, however, observed in doxorubicin-treated mice compared to the untreated controls. We therefore compared the expression levels of markers involved in cell death and survival signalling pathways, by means of western blotting and fluorescence-based immunohistochemistry.ResultsDoxorubicin failed to induce cell death, by means of apoptosis or autophagy, and cell cycle arrest, indicating the occurrence of drug resistance and uncontrolled proliferation. Activation of the MAPK/ extracellular-signal-regulated kinase (ERK) pathway contributed to the resistance observed in treated mice, while no significant changes were found with the PI3K/Akt pathway and other MAPK pathways. Significant changes were also observed in cell cycle p21 and DNA replication minichromosome maintenance 2 proteins. No significant changes in EMT markers were observed after doxorubicin treatment.ConclusionsOur results suggest that doxorubicin-induced drug resistance and tumour growth can occur through the adaptive role of the MAPK/ERK pathway in an effort to protect tumour cells. Previous studies have shown that the efficacy of doxorubicin can be improved by inhibition of the ERK signalling pathway and thereby treatment failure can be overcome.

Dataset Information

Multifunctional Nanographene Oxide for Targeted Gene-Mediated Thermochemotherapy of Drug-resistant Tumour.

Publications

Multifunctional Nanographene Oxide for Targeted Gene-Mediated Thermochemotherapy of Drug-resistant Tumour.

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