Graphene as Nanocarrier in Drug Delivery

Pristine Graphene (pG) could represent a new and promising nanomaterial for medicine applications, because it does not catalyze the production of ROS (Reactive Oxgen Species), being in total absence of oxygenated functional groups. In fact, pG either in a dispersed or aggregated form, does not increase mitochondrial oxidant generation or induce apoptosis in lung macrophages, working at room temperature. pG presents another problem due to its thermal instability. In fact, it is very well known that pG spontaneously wrap up forming nanotubes (which result highly toxic for humans, because of their typical asbestos like structures). On the other hand, Graphene Oxide (GO) provokes severe lung injury that persists for more than 21 days after administration. In cultured alveolar macrophages and epithelial cells, GO induces the generation of mitochondrial ROS, by participating in redox reactions with components of the mitochondrial electron transport chains. Several data, described in literature, suggest that all the chemical-physical processes that maintain the nanoscale dispersion of GO is suitable to reduce the potential health consequences of workplace or environmental exposures and likely facilitate emerging graphenebased biomedical applications. Contrary to pG, the rolling up into the nanotube structures is less favored in presence of GO. It follows that, the GO toxicity is only related to the oxygenated functional groups (as primary sources of OHradical species, O2 − and H2 O2 ). However, the functional groups could be deactivated if involved in the formation of stable covalent bonds, which provide the coating of graphenic nano sheets, with suitable biopolymers. The degree and the chemical composition of the oxygenated functionalities results the principal feature, strictly related to the biocompatibility of grapheen nano sheets, but also the two-dimensional planar structure (G is a 2D nanomaterial), the nanometer scale dimensions, the large surface area (∼ 3000 m2 /g) andthe exceptional optical properties (as the auto-fluorescence), certainly contribute to design graphene materials, as new potential carrier for drugs. Finally, the high electrical and thermal conductivity and the good antibacterial/antimicrobial properties are not to be neglected for graphene, too. In this review, authors present an up-dated state of the art concerning the recent advances in this field of research. Briefly, this work describes current strategies for the large scale production of G and the surface chemistry modification of graphene-based nanocarriers, their biocompatibility and toxicity properties. At the same, the review reports on the most relevant cases of study suitable to demonstrate the role of graphene and graphene derivatives(GD) as nanocarrier of anti-cancer drugs and genes (i.e. miRNAs). Especially,the controlled release mechanisms (inside the cell compartments) are also mentioned and explored in terms of ∆pH, ∆μ (ionic strength variation), chemico-physical mutual interactions, thermal, photo-(i.e. NIR) and electromagnetic induction. Especially the nanodispersion and/or the accumulation/aggregation status of GO, into human cell lines, results mainly pH-sensitive.This pH-activated processesare expected to promote/catalyze targeted therapeutics release in the acidic environment of tumor cells or in intracellular compartments, such as endosome. For this purpose, an important biological factor like blood pH (and ionic strenght) are necessary to discuss in the review. The review also summarizes, future prospects and challenges ingraphene derivatives applications for nanobiomedicine, especially in drug deliveryfield applications. ABBREVIATIONS pG: Pristine Graphene; G: Graphene; GO: Graphene Oxide; GD: Graphene Derivatives; CBNs: Carbon Based Nanomaterials; NBCs: NanoBio Composites INTRODUCTION The advanced drug delivery systems, combining the ability to improve the therapeutic efficacy and to reduce side effects of drugs represent a challenge for medicine. Nanotechnology offers a wide range of new strategies to produce innovative nanomaterials, suitable for the development of a large number of smart drug delivery systems [1,2], ranging from carbon