Multifunctional mitoxantrone-conjugated magnetic nanosystem for targeted therapy of folate receptor-overexpressing malignant cells

Journal of Nanobiotechnology

Research

George Cokous¹  Sajjad Khani²  Abolfazl Barzegari²  Mostafa Heidari Majd²  Vala Kafil³  Yadollah Omidi³  Davoud Asgari³  Mohammad Johari-Ahar³  Jaleh Barar³ 

[1] Ludwig Centre for Cancer Research, University of Lausanne, Lausanne, Switzerland;Ovarian Cancer Research Centre, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;Research Center for Pharmaceutical Nanotechnology, Tabriz, Iran;Research Center for Pharmaceutical Nanotechnology, Tabriz, Iran;Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran;

关键词: Magnetic nanoparticles;    Target therapy;    Folate receptor;    Cancer;    Apoptosis;    Mitoxantrone;    Nanomedicines;    Theranostics;   

DOI  :  10.1186/s12951-015-0083-7

 received in 2014-10-24, accepted in 2015-03-02,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundTargeted delivery of anticancer chemotherapeutics such as mitoxantrone (MTX) can significantly intensify their cytotoxic effects selectively in solid tumors such as breast cancer. In the current study, folic acid (FA)-armed and MTX-conjugated magnetic nanoparticles (MNPs) were engineered for targeted eradication of folate receptor (FR)-positive cancerous cells. Polyethylene glycol (PEG), FA and MTX were covalently conjugated onto the MNPs to engineer the PEGylated FA-MTX-MNPs. The internalization studies were performed using fluorescein isothiocyanate (FITC)-labeled FA-decorated MNPs (FA-FITC-MNPs) in both FR-positive MCF-7 cells and FR-negative A549 cells by means of fluorescence microscopy and flow cytometry. The cellular and molecular impacts of FA-MTX-MNPs were examined using trypan blue cell viability and FITC-labeled annexin V apoptosis assays and 4′,6-diamidino-2-phenylindole (DAPI) staining, DNA ladder and quantitative polymerase chain reaction (qPCR) assays.ResultsThe FR-positive MCF-7 cells showed significant internalization of the FA-FITC-MNPs, but not the FR-negative A549 cells. The FR-positive cells treated with the PEGylated FA-MTX-MNPs exhibited the IC50 values of 3 μg/mL and 1.7 μg/mL, 24 h and 48 h post-treatment, respectively. DAPI staining and DNA ladder assays revealed significant condensation of nucleus and fragmentation of genomic DNA in the FR-positive MCF-7 cells treated with the PEGylated FA-MTX-MNPs as compared to the FR-negative A549 cells. The FITC-labeled annexin V assay confirmed emergence of late apoptosis (>80%) in the FR-positive MCF-7 cells treated with the PEGylated FA-MTX-MNPs, but not in the FR-negative A549 cells. The qPCR analysis confirmed profound cytotoxic impacts via alterations of apoptosis-related genes induced by MTX-FA-MNPs in MCF-7 cells, but not in the A549 cells.ConclusionOur findings evince that the engineered PEGylated FA-MTX-MNPs can be specifically taken up by the FR-positive malignant cells and effectively demolish them through up-regulation of Bcl-2–associated X protein (Bax) and Caspase 9 and down-regulation of AKt. Hence, the engineered nanosystem is proposed for simultaneous targeted imaging and therapy of various cancers overexpressing FRs.

【 授权许可】

Unknown   
© Barar et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.