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


Lamb, Jennifer; Fischer, Eliane; Rosillo-Lopez, Martin; Salzmann, Christoph G; Holland, Jason P (2019). Multi-functionalised graphene nanoflakes as tumour-targeting theranostic drug-delivery vehicles. Chemical Science, 10(38):8880-8888.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > General Chemistry
Uncontrolled Keywords:General Chemistry
Language:English
Date:1 January 2019
Deposited On:07 Feb 2020 15:37
Last Modified:13 Aug 2020 00:00
Publisher:Royal Society of Chemistry
ISSN:2041-6520
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/c9sc03736e
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P2_163683
  • : Project TitleAdvanced radiochemical methods for multi-modal imaging with nanomedicines
  • : FunderH2020
  • : Grant ID676904
  • : Project TitleNanoSCAN - Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways
  • : FunderH2020
  • : Grant ID725271
  • : Project TitleCarbon – Ice Composite Materials: Water Structure and Dynamics at the Carbon Interface
  • : FunderKrebsliga
  • : Grant IDKLS-4257-08-2017
  • : Project Title
  • : FunderRoyal Society
  • : Grant IDUF100144
  • : Project TitleUniversity Research Fellowship

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