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Multi-functionalised graphene nanoflakes as tumour-targeting theranostic drug-delivery vehicles

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Abstract

Graphene nanoflakes (GNFs) consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid groups. Their high water solubility and relative ease of functionalisation using carboxylate chemistry means that GNFs are potential scaffolds for the synthesis of theranostic agents. In this work, GNFs were multi-functionalised with derivatives of (i) a peptide-based Glu-NH-C(O)-NH-Lys ligand that binds prostate-specific membrane antigen (PSMA), (ii) a potent anti-mitotic drug (R)-ispinesib, (iii) the chelate desferrioxamine B (DFO), and (iv) an albumin-binding tag reported to extend pharmacokinetic half-life in vivo. Subsequent 68Ga radiochemistry and experiments in vitro and in vivo were used to evaluate the performance of GNFs in theranostic drug design. Efficient 68Ga-radiolabelling was achieved and the particle-loading of (R)-ispinesib and Glu-NH-C(O)-NH-Lys was confirmed using cellular assays. Using dose–response curves and FACS analysis it was shown that GNFs loaded with (R)-ispinesib inhibited the kinesin spindle protein (KSP) and induced G2/M-phase cell cycle arrest. Cellular uptake and blocking experiments demonstrated that GNFs functionalised with the Glu-NH-C(O)-NH-Lys ligand showed specificity toward PSMA expressing cells (LNCaP). The distribution profile and excretion rates of 68Ga-radiolabelled GNFs in athymic nude mice was evaluated using time–activity curves derived from dynamic positron-emission tomography (PET). Image analysis indicated that GNFs have low accumulation and retention in background tissue, with rapid renal clearance. In summary, our study shows that GNFs are suitable candidates for use in theranostic drug design.

Graphical abstract: Multi-functionalised graphene nanoflakes as tumour-targeting theranostic drug-delivery vehicles

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Publication details

The article was received on 29 Jul 2019, accepted on 01 Aug 2019 and first published on 13 Aug 2019


Article type: Edge Article
DOI: 10.1039/C9SC03736E
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Multi-functionalised graphene nanoflakes as tumour-targeting theranostic drug-delivery vehicles

    J. Lamb, E. Fischer, M. Rosillo-Lopez, C. G. Salzmann and J. P. Holland, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC03736E

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