Targeting Glut1-overexpressing MDA-MB-231 cells with 2-deoxy-d-g1ucose modified SPIOs
Introduction
Based on the characteristics of hyper metabolism and relatively rapid proliferation, carcinoma cells require much more glucose than normal cells [1]. This inherent metabolic need could be in tumor cell membranes, there exist a much higher glucose transporter (Glut) expression, for example Glut-1 and/or Glut-4. Among all the glucose transporters, the Glut-l subtype is expressed in almost all tumor cell lines and tumor tissues. Analogs are available that have similar structure to d-glucose and can be transported by Glut-l to Glut-4, at that time the increased metabolic needs of the tumor cells cause increased uptake of these analogs. These analogs block the catalytic activity of hexose phosphate isomerase to transform d-glucose-6-phosphate into 1,6-diphosphate. This blockade in the pathway causes an inability for further metabolism and thus remains in the cell. In tumor tissues, the glucose receptor GLUT-1 has already been successfully carried out in positron emission tomographic (PET) studies with fluorodeoxyglucose [2], [3], [4].
Several diagnostic compounds based on the above-mentioned targeting vectors have been developed and used in positron emission tomography, single-photon emission computed tomography [5], [6], optical imaging [7], [8], [9], and magnetic resonance imaging [10], [11]. However, magnetic resonance imaging contrast agents reported in documents are preparations with Gadolinium, Superparamagnetic iron oxide nanoparticles (SPIO-NPs) is one of magnetic resonance imaging contrast agents, it's paramagnetism is 6 times than gadolinium-containing agents. Magnetic resonance imaging (MRI) is a highly desirable modality for molecular imaging because it provides not only high spatial resolution but also excellent soft tissue contrast. However, the low sensitivity of MRI to contrast agents often reduces the success of imaging approaches with targeted contrast agents. Currently, more and more attention has been paid to developing the second generation of SPIO-NPs targeted to specific cells for MRI [12], tissue repair [13], targeted drug delivery [14] and hyperthermia [15]. SPIOs conjugated with folic acid targeting epithelial tumor overexpressing receptors of folic acid [16], and conjugated with RGD peptide targeting tumor vascular endothelial cells [17] were testified effectively in vitro and vivo. By far, analogs of d-glucose conjugating with SPIOs have not been reported.
Thus, in this study, γ-Fe2O3 nanoparticles (γ-Fe2O3 NPs) core were coated with dimercaptosuccinic acid (DMSA) including –COOH in surface, it is abbreviated as γ-Fe2O3@DMSA NPs. The γ-Fe2O3@DMSA NPs reacted with d-dextrosamine including –NH3, thus γ-Fe2O3@DMSA NPs marked with 2-deoxy-d-g1ucose (2-DG) were constructed, it is abbreviated as γ-Fe2O3@DMSA-DG NPs to target overexpressing Glut1 tumor cells. We show that these particles subsequently accumulate in the cytoplasm of MDA-MB-231 cells testified by Prussian blue stain, transmission electron microscope observation, and magnetic resonance imaging.
Section snippets
Materials
Breast cancer cell line MDA-MB-231 purchased from Shanghai Cytobiology Research institute; DMEM cell culture medium purchased from Gibcol (USA), fetal bovine serum purchased from HyClone (USA), rabbit anti-person Glut 1 polyclonal antibody purchased from NeoMarkers; 2-amino-2-deoxy-d-glucose hydrochloride purchased from Alfa Aesar GmbH & Co. KG (Germany), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide purchased from Pierce Chemical Co. (USA), N-hydroxysuccinimide purchased from Pierce Chemical
Preparation of γ-Fe2O3 NPs and Fe2O3@DMSA-DG NPs
Conjugation of 2-DG to the surface of γ-Fe2O3 NPs was realized by acylamino group as a result of reaction between carboxylic acid and amino group. The morphology of particles was observed by TEM. The particle size is calculated by an image analysis program for all prepared samples on at least 300 particles. As shown in Fig. 1 most of the particles are quasi-spherical and with an average diameter of 10 nm. There are no significant different between the TEM image of γ-Fe2O3@DMSA NPs and γ-Fe2O3
Discussion
In this study, DMSA-coated SPIOs[0]-2-DG conjugates were developed and their ability to specifically enter into cytoplasma in MDA-MB-231 cells overexpressing Glut1 was investigated in vitro. In contrast to most previous molecular MRI approaches using dextran-coated particles, the SPIOs used in this study were coated with DMSA. This coating provides the significant advantage that the presence of carboxyl groups on the particle surface can easily be used to covalently attach specific ligands and
Conclusion
We have designed, synthesized, and tested a novel functional 2-DG based contrast agent for MR molecular imaging. The SPIO (γ-Fe2O3) can be easily modified with 2-DG to endow them with the cancer cell targeting functions. γ-Fe2O3@DMSA-DG NPs bind more efficiently to the cancer cells with Glut1 overexpression, leading to a higher quantity of SPIOs being transported into these cells. Our study showed the potential of the synthesized γ-Fe2O3@ DMSA-DG NPs to serve as a nanocarrier system for MRI
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgments
This work was partly supported by National Basic Research Program of China (Nos. 2011CB933503 and 2007CB936002) and National Natural Science Foundation of China (No. 81001412).
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