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

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Version: author
Serval ID
serval:BIB_D3C3F085EE13
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Multifunctional mitoxantrone-conjugated magnetic nanosystem for targeted therapy of folate receptor-overexpressing malignant cells.
Journal
Journal of Nanobiotechnology
Author(s)
Barar J., Kafil V., Majd M.H., Barzegari A., Khani S., Johari-Ahar M., Asgari D., Coukos G., Omidi Y.
ISSN
1477-3155 (Electronic)
ISSN-L
1477-3155
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
13
Number
1
Pages
26
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
BACKGROUND: Targeted 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.
RESULTS: The 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.
CONCLUSION: Our 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.
Keywords
Antineoplastic Agents/administration & dosage, Antineoplastic Agents/chemistry, Apoptosis/drug effects, Apoptosis/genetics, Cell Line, Tumor/drug effects, Cell Survival/drug effects, DNA Fragmentation/drug effects, Folate Receptors, GPI-Anchored/metabolism, Folic Acid/administration & dosage, Folic Acid/chemistry, Gene Expression Regulation, Neoplastic/drug effects, Humans, MCF-7 Cells/drug effects, Magnetite Nanoparticles/administration & dosage, Magnetite Nanoparticles/chemistry, Microscopy, Atomic Force, Mitoxantrone/administration & dosage, Mitoxantrone/chemistry, Molecular Targeted Therapy/methods, Particle Size, Polyethylene Glycols/chemistry
Pubmed
Web of science
Open Access
Yes
Create date
01/05/2015 17:08
Last modification date
20/08/2019 15:53
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