Graphene based nanomaterials are being used experimentally to deliver therapeutic agents to cells or tissues both in vitro and in vivo. However, substantial challenges remain before moving to safe and effective use in humans. In particular, it is recognised that graphene molecules undergo complex interactions with solutes, proteins or cellular systems within the body, and that these interactions impact significantly on the behaviour or toxicity of the molecule. Approaches to overcome these problems include modification of the graphene or its combination with other molecules to accentuate favourable characteristics or modify adverse interactions. This has led to an emerging role for graphene as one part of highly-tailored multifunctional delivery vehicles. This review examines the knowledge that underpins present approaches to exploit graphene in therapeutics delivery, discussing both favourable and unfavourable aspects of graphene behaviour in biological systems and how these may be modified; then considers the present place of the molecule and the challenges for its further development.

CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P < .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P = .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.

A bis(cyclam)-capped cholesterol lipid designed to bind C-X-C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C-X-C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 μM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.

We explore the ability of amino acid solutions, of l-Trp, l-Tyr, or l-Val, to solvate pristine graphene flakes in an aqueous environment via atomistic molecular dynamics simulations and experimental characterization. In accord with previous theoretical work, simulations of single amino acid adsorption on graphene predict that l-Trp is most strongly bound, followed by l-Tyr and then l-Val. As the number of amino acids is increased in the simulations, steric hindrance at the graphene interface and amino acid clustering (most pronounced for l-Tyr) reduces the efficiency of interaction with graphene. Using atomic force microscopy and UV–vis absorption spectroscopy, we determine that all three amino acid solutions can exfoliate and suspend pristine graphene flakes in water. However, l-Trp and l-Tyr solutions are considerably more effective than l-Val: l-Trp produces the most stable suspensions and thinnest graphene flakes compared to l-Tyr, with a mean thickness of 6.4 nm, and a narrow distribution of diameter with a mean value of 16 nm, commensurate with the width of cell membranes. At high concentrations of l-Trp and l-Tyr, there was severe instability of the suspensions along with agglomeration and precipitation; this reflects clustering of amino acid molecules observed in molecular dynamics simulations. This study indicates the potential of amino acids to exfoliate and suspend pristine graphene as a step toward developing nontoxic graphene-based vehicles for drug delivery and other in vivo applications.

The Food Standards Agency (FSA) always seeks to ensure that itsrecommendations are made on the best-available evidence. Following a request from the FSA Chair, the Science Council have sought to provide a framework that can guide those seeking to submit uncommissioned evidence to the FSA on its scientific principles and standards.The Science Councils proposed framework is based on the principles of quality, trustand robustness. By being transparent about the FSA’s minimal expectations, we aim to help those who wish to submit evidence, typically in an effort to fill a perceived evidence gap orchange a relevant policy or legislation. The framework also seeks to provides assurance to others on the processes in place within the FSA to assess evidence it receives.When the FSA receives evidence, it will: be transparent about how the evidence is assessed and used to develop its evidence base, policy recommendations and risk communication; assess evidence in its proper context using the principles of quality, trust and robustness; seek to minimise bias in its assessments of evidence by using professional protocols, its SACs, peer review and/or multi-disciplinary teams be open and transparent about the conclusions it has reached about any evidence submitted to it.

Sara Carreira opened the discussion of the paper by Nicolas Barry: Why are your RuMs and OsMs so specic to cancer cells without using any targeting moiety?Nicolas Barry replied: We believe that the specicity comes from the size of the particles -passive targeting. Clinically-validated therapeutic and imaging NPs usually target cancer cells in a passive way. This is achieved by taking advantage of the enhanced permeability and retention (EPR) effect in tumor tissues. Tumor vasculature is highly disorganised, compared to the vasculature in normal tissues, and the vascular endothelium in tumors proliferates rapidly and discontinuously. This results in a higher number of fenestrations and open junctions (from 200 nm to 1.2 mm) than in normal vessels. Particles with a typical size of a few nanometres can therefore passively cross the tumor endothelial barrier through fenestrations, and accumulate at particular sites through blood hemodynamic forces and diffusion mechanisms.One of our objectives is to increase the size of our particles from 15 nm to a few hundred nanometres, in order to maximize this passive targeting. We also wish to introduce an active targeting moiety (e.g. specic peptides, antibodies) on the corona of the particles to increase this selectivity.Peter Dobson asked: Have you looked to see if any of your compounds are luminescent?Nicolas Barry responded: There are numerous examples of ruthenium compounds that are luminescent. Usually, arene Ru(II) complexes are not luminescent owing to the arene-metal interactions. Nonetheless, it is possible to introduce a luminescent ligand (such as a pyrene derivative) by functionalizing the 16-electron complexes (to make an 18-electron complex).This journal is