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Multifunctional Molecular Beacon Micelles for Intracellular mRNA Imaging and Synergistic Therapy in Multidrug-Resistant Cancer Cells.

ABSTRACT: Multidrug resistance (MDR) resulting from overexpression of P-glycoprotein (Pgp) transporters increases the drug efflux and thereby limits the chemotherapeutic efficacy. It is desirable to administer both an MDR1 gene silencer and a chemotherapeutic agent in a sequential way to generate a synergistic therapeutic effect in multidrug-resistant cancer cells. Herein, we rationally designed an anti-MDR1 molecular beacon (MB)-based micelle (a-MBM) nanosystem, which is composed of a diacyllipid core densely packed with an MB corona. One of Pgp-transportable agents, doxorubicin (DOX), was encapsulated in the hydrophobic core of the micelle and in the stem sequence of MB. The a-MBM-DOX nanosystem showed an efficient self-delivery, enhanced enzymatic stability, excellent target selectivity, and high drug-loading capacity. With its relatively high enzymatic stability, a-MBM-DOX initially facilitated intracellular MDR1 mRNA imaging to distinguish multidrug-resistant and non-multidrug-resistant cells and subsequently downregulated the MDR1 gene expression owing to an antisense effect. After that, the MB corona was degraded, destroying the micellar nanostructure and releasing DOX, which resulted in a high accumulation of DOX in OVCAR8/ADR cells and a high chemotherapeutic efficacy owing to successful restoration of drug sensitivity. This micelle approach has the potential for both visualizing MDR1 mRNA and overcoming MDR in a sequential and synergistic way.

SUBMITTER: Zhang R

PROVIDER: S-EPMC5646829 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Multifunctional Molecular Beacon Micelles for Intracellular mRNA Imaging and Synergistic Therapy in Multidrug-Resistant Cancer Cells.

Zhang Ruili R Gao Shi S Wang Zhongliang Z Han Da D Liu Lin L Ma Qingjie Q Tan Weihong W Tian Jie J Chen Xiaoyuan X

Advanced functional materials 20170530 31

Multidrug resistance (MDR) resulting from overexpression of P-glycoprotein (Pgp) transporters increases the drug efflux and thereby limits the chemotherapeutic efficacy. It is desirable to administer both an <i>MDR1</i> gene silencer and a chemotherapeutic agent in a sequential way to generate a synergistic therapeutic effect in multidrug-resistant cancer cells. Herein, we rationally designed an anti-<i>MDR1</i> molecular beacon (MB)-based micelle (a-MBM) nanosystem, which is composed of a diacy ...[more]

PMID: 29056886

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Project description:Background and Purpose:The development of multiple drug resistance (MDR) to chemotherapy and single modal therapy remains unsatisfied for the eradication of tumor, which are major obstacles in cancer therapy. This novel system with excellent characteristics for inhibition of P-glycoprotein (P-gp), and for near-infrared fluorescence (NIRF) imaging-guided chemo-photothermal therapy (PTT), has been identified as a promising way to MDR and achieve synergistic cancer therapy. Methods:In this study, we successfully synthesized a multifunctional theranostic system, which was developed through FDA-approved self-assembling drugs, which contain anticancer drug doxorubicin (Dox), imaging and high photothermal conversion drug indocyanine green (ICG) and P-gp regulator TPGS (the system named T/Dox-ICG). We studied the characterization of T/Dox-ICG NPs, including the TEM, SEM, DLS, UV-vis-NIR, zeta potential, CLSM, in vitro FL imaging, in vitro photothermal effect, in vitro Dox and ICG release. We used CLSM to verify the location of intracellular distribution of Dox in SCG 7901/VCR cells, Western blot was performed to demonstrate the TPGS-mediated inhibition of P-gp. And, the cytotoxicity of materials against SCG 7901/VCR cells was studied by the MTT assay. Results:The TEM showed the T/Dox-ICG NPs had good monodispersity with diameters of 19.03 nm, Dox and ICG could be released constantly from T/Dox-ICG NPs in vitro. In vitro cell experiments demonstrated higher Dox accumulation and retention in the nucleus. Western blot showed TPGS could obviously inhibit the expression of P-gp. In vitro cytotoxicity assay showed more significant cytotoxicity on MDR cells (SCG 7901/VCR) with only 8.75% of cells surviving. Conclusion:MDR cancer therapy indicates that it may be important to develop a safer system that can simultaneously inhibit the drug transporters and monitor the delivery of chemotherapeutic agents, and combination therapy have raised widespread concern on tumor treatment.

Dataset Information

Multifunctional Molecular Beacon Micelles for Intracellular mRNA Imaging and Synergistic Therapy in Multidrug-Resistant Cancer Cells.

Publications

Multifunctional Molecular Beacon Micelles for Intracellular mRNA Imaging and Synergistic Therapy in Multidrug-Resistant Cancer Cells.

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