Research Article: Multifunctional graphene oxide/iron oxide nanoparticles for magnetic targeted drug delivery dual magnetic resonance/fluorescence imaging and cancer sensing

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Roberto Gonzalez-Rodriguez, Elizabeth Campbell, Anton Naumov, Claudia Tortiglione.

http://doi.org/10.1371/journal.pone.0217072

Abstract

Graphene Oxide (GO) has recently attracted substantial attention in biomedical field as an effective platform for biological sensing, tissue scaffolds and in vitro fluorescence imaging. However, the targeting modality and the capability of its in vivo detection have not been explored. To enhance the functionality of GO, we combine it with superparamagnetic iron oxide nanoparticles (Fe3O4 NPs) serving as a biocompatible magnetic drug delivery addends and magnetic resonance contrast agent for MRI. Synthesized GO-Fe3O4 conjugates have an average size of 260 nm and show low cytotoxicity comparable to that of GO. Fe3O4 nanoparticles provide superparamagnetic properties for magnetic targeted drug delivery allowing simple manipulation by the magnetic field and magnetic resonance imaging with high r2/r1 relaxivity ratios of ~10.7. GO-Fe3O4 retains pH-sensing capabilities of GO used in this work to detect cancer versus healthy environments in vitro and exhibits fluorescence in the visible for bioimaging. As a drug delivery platform GO-Fe3O4 shows successful fluorescence-tracked transport of hydrophobic doxorubicin non-covalently conjugated to GO with substantial loading and 2.5-fold improved efficacy. As a result, we propose GO-Fe3O4 nanoparticles as a novel multifunctional magnetic targeted platform for high efficacy drug delivery traced in vitro by GO fluorescence and in vivo via MRI capable of optical cancer detection.

Partial Text

Graphene is a gapless semiconductor that is now actively used in microelectronics and materials science.[1, 2] Due to complexity of scalable fabrication, its functional derivatives provide higher benefit for some of the applications. For instance graphene oxide (GO) due to its ease in production, water solubility and optical properties offers an advantageous alternative for applications in biomedicine and optoelectronics.[3–6] Graphitic surface in GO is derivatized with epoxy, hydroxyl and carboxyl groups, that allow it to form water suspensions stabilized by hydrogen bonds.[7–9] These functional groups perturb graphitic structure resulting into ~2eV band gaps enabling GO fluorescence in the visible.[10, 11] Additionally, GO has a high surface area available for functionalization and superior mechanical properties,[12, 13] which altogether makes it attractive for optoelectronics (LED devices and solar cells), tissue engineering and drug delivery.[14–18] GO is utilized as a basis for nanoscale sensors serving for the detection of small molecules such as NO2 in automovite emissions,[19] proteins,[20] influenza viral strains [21] and fluorescence-based pH-sensing that can be used to detect cancerous environments.[22] GO exhibits efficient internalization and stable fluorescence emission inside the cells, and has low cytotoxicity at the concentrations used in imaging.[22–24]. This makes GO a potential candidate for drug delivery and imaging in vitro or ex vivo concomitantly allowing for the cancer detection. However, the lack of targeting capabilities and the inability of in vivo tracking hampers the utilization of GO as an effective drug delivery system in vivo.

In this work we have successfully synthesized and tested the feasibility of multifunctional GO-Fe3O4 conjugates with capabilities of dual magnetic resonance/fluorescence imaging, magnetic manipulation for targeting, optical pH sensing and drug delivery. These novel nanoparticles have an average size of 250nm suitable for cellular internalization and show comparable to GO low cytotoxicity at imaging concentrations of 15 μg/mL. The relaxation properties of GO-Fe3O4 conjugates are comparable to existing free nanoparticle analogs, GO-Fe3O4 conjugates have potential of as negative MRI contrast agents. GO-Fe3O4 conjugates can be effectively manipulated by a magnet in suspension which allows for direct magnetic targeted accumulation in a specific therapeutic site. The GO surface contains a variety of functional groups for covalent attachment of molecular therapeutics or a substantial hydrophobic graphene platform for non-covalent functionalization with aromatic-based drugs with poor water solubility. In our work GO-Fe3O4 conjugates show efficient intracellular delivery of non-covalently attached Doxorubicin with considerable drug loading and over 2.5-fold improvement in its efficacy over free drug at low concentrations. This in turn allows using 8 times lower dose of Doxorubicin to achieve the same therapeutic effect of ~62% cancer cell death. The therapeutic delivery is tracked by the intrinsic green fluorescence of GO-Fe3O4 complex that indicates efficient internalization at 3 hours post transfection with further excretion from the cells. The pH-dependence of this emission allows using the ratios of emission intensity in green (535 nm) to red (635 nm) to differentiate between cancer (MCF-7 and HeLa) and healthy (HEK-293) extracellular environments with a substantial 4 to 5-fold difference. As a result, we propose GO-Fe3O4 as a unique multifunctional nanomaterial for magnetic-targeted drug delivery, dual in vitro fluorescence and in vivo MRI imaging and optical detection of cancerous environments.

 

Source:

http://doi.org/10.1371/journal.pone.0217072

 

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