Tufano, Immacolata (2022) Oil core- functionalized graphene oxide shell as multifunctional theranostic nanotool for cancer therapy. [Tesi di dottorato]

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Despite considerable progress in the comprehension of the mechanisms involved in the origin and development of cancer, with improved diagnosis and treatment, this disease remains a major public health challenge with a considerable impact on the social and economic system, as well as on the individual. One way to improve effectiveness and reduce side effects is to consider responsive stimuli delivery systems that provide tailor-made release profiles with excellent spatial and temporal control. 2D nanomaterials possess special physicochemical properties (e.g. light, ultrasonic and magnetic responses) and biological behaviors such as endocytosis, biodistribution, biodegradation, and excretory pathways, which lead to their use in various biomedical applications. In particular, among 2D nanomaterials, graphene and its derivatives, namely graphene oxides nanomaterials, have attracted enormous attention in cancer diagnosis and therapy because they combine, in a unique material, extremely small size, NIR absorption, delocalized electrons, extremely high surface area, and versatile surface functionality. To develop a multifunctional theranostic system for cancer therapy, we considered this fascinating material. For applications in nanomedicine, it is essential to obtain GO sheets with narrow lateral distribution and lateral dimensions below 50 nm. However, GO obtained using the classic liquid-phase exfoliation of graphite has very large lateral dimensions from 100-200 µm up to tens of nm. The approaches to reducing the lateral dimensions of the GO are divided into the oxidation of graphite in the nanoscale or post-treatment of the large GO. However, post-treatment of large GO is undesirable as it could undermine the degree of oxidation. To obtain a starting material with more homogeneous dimensions, we have considered mechanical milling. The graphite obtained with this method has a low degree of oxidation, sufficient to create stable aqueous suspensions, and constitutes a good substrate for the subsequent oxidation reaction. At the same time, we became aware of the important environmental impact of the classical oxidation reaction of graphite which enormously limits the potential applications of GO, especially in the biomedical field. With this in mind, we have proposed a new method to obtain GO without the use of concentrated acids and strong chemical oxidants. This method exploits the low oxidation degree of ball-milled graphite and the Fenton reaction catalyzed by UV light. Through this approach, a nanomaterial with a good degree of oxidation was obtained, but further studies are necessary to increase the yield of the product and for its purification. The graphene oxide obtained from ball-milled graphite and oxidized with traditional chemistry does not have the dimensional properties necessary to interact with biological systems, so we evaluated an oxidative cutting previously reported for carbon nanotubes, and only recently for graphene oxide. This type of oxidative cutting uses hydrogen peroxide and ammonia to reduce the size of the carbonaceous material and at the same time functionalize the active surface with NH2 groups. With this approach, graphene oxide nanosheets with uniform lateral dimensions less than 20 nm were obtained. The nano-GO obtained were functionalized with hyaluronic acid by exploiting the NH2 groups present on their surface and were tested to evaluate their biocompatibility, the ability to penetrate into cells and tissues, the ability to load and release pharmacologically active molecules in different conditions, and the ability to stimulate a local increase in temperature following irradiation of NIR light (photothermal effect). In order to realize the multistep approach, graphene oxide nanosheets coated with hyaluronic acid were deposited by electrostatic interaction on an O/W emulsion coated with a chitosan layer. The formed system has high stability over time and high biocompatibility.

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