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Abstract
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.
Highlights
Of different solid tumors, breast cancer is one of the most common life-threatening cancers among women
To delineate the apoptosis pathway observed in the folate receptor (FR)-positive MCF-7 cells treated with the PEGylated FAMTX-magnetic nanoparticles (MNPs), we studied the gene expression profile of several essential genes related to the mitochondrial apoptosis pathway
We developed FAarmed MNPs conjugated with MTX to target the FR-positive MCF-7 cells and effectively deliver the MTX molecules to the target cells
Summary
Breast cancer is one of the most common life-threatening cancers among women. Breast cancer treatment modalities are based on surgery, radiotherapy, hormone-therapy and chemotherapy [2] Of these treatment modalities, chemotherapy agents are used to induce cytotoxic impacts in cancerous cells through various mechanisms such as DNA detriments and inhibition of cell division and growth. MTX as one of the chemotherapeutic agents is commonly used for the treatment of metastatic breast cancer, acute myeloid leukemia and non-Hodgkin’s lymphoma. It hinders cell proliferation through inhibition of topoisomerase II and disruption of DNA repair/synthesis [3], intercalation of DNA [4], DNA damage and apoptosis via inhibition of the mitochondrial pathway [5]. 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
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