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This work is going to show the activities performed in the frame of my PhD studies at the University of Bologna, under the supervision of Prof. Mauro Comes Franchini, at the Department of Industrial Chemistry “Toso Montanari”. The main topic of this dissertation will be the study of organic-inorganic hybrid nanostructures and materials for advanced applications in different fields of materials technology and development such as theranostics, organic electronics and additive manufacturing, also known as 3D printing. This work is therefore divided into three chapters, that recall the fundamentals of each subject and to recap the state-of-the-art of scientific research around each topic. In each chapter, the published works and preliminary results obtained during my PhD career will be discussed in detail.

Silvia Tortorella, Veronica Vetri Buratti, Mirko Maturi, Letizia Sambri, Mauro Comes Franchini, Erica Locatelli Department of Industrial Chemistry “Toso Montanari”, Alma Mater Studiorum – University of Bologna, Bologna 40136, ItalyCorrespondence: Erica Locatelli Email erica.locatelli2@unibo.itAbstract: Presently, a plenty of concerns related to the environment are due to the overuse of petroleum-based chemicals and products; the synthesis of functional materials, starting from the natural sources, is the current trend in research. The interest for nanocellulose has recently increased in a huge range of fields, from the material science to the biomedical engineering. Nanocellulose gained this leading role because of several reasons: its natural abundance on this planet, the excellent mechanical and optical features, the good biocompatibility and the attractive capability of undergoing surface chemical modifications. Nanocellulose surface tuning techniques are adopted by the high reactivity of the hydroxyl groups available; the chemical modifications are mainly performed to introduce either charged or hydrophobic moieties that include amination, esterification, oxidation, silylation, carboxymethylation, epoxidation, sulfonation, thiol- and azido-functional capability. Despite the several already published papers regarding nanocellulose, the aim of this review involves discussing the surface chemical functional capability of nanocellulose and the subsequent applications in the main areas of nanocellulose research, such as drug delivery, biosensing/bioimaging, tissue regeneration and bioprinting, according to these modifications. The final goal of this review is to provide a novel and unusual overview on this topic that is continuously under expansion for its intrinsic sophisticated properties.Keywords: nanocelluse, surface modification, drug delivery, scaffold, tissue engineering

Erica Locatelli,1,* Yan Li,2,* Ilaria Monaco,1 Wei Guo,3 Mirko Maturi,1 Luca Menichetti,4 Paolo Armanetti,4 Robert C Martin,2 Mauro Comes Franchini1 1Department of Industrial Chemistry “Toso Montanari”, Bologna, Italy; 2Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA; 3Department of Hematology, The First Hospital of Jilin University, Changchun, China; 4Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy *These authors contributed equally to this work Introduction and purpose: Cancer stem cells (CSCs) present a higher capacity to evade being killed by cancer agents and developing chemoresistance, thus leading to failure of conventional anticancer therapeutics. Nanomaterials specifically designed for targeting and treating not only tumor cells, but also CSCs, may encompass therapeutic and diagnostic tools, thus successfully eradicating the tumor. Materials and methods: Polymeric micelles simultaneously loaded with gold nanorods (GNRs) and Adriamycin were prepared and used as a novel therapeutic and diagnostic weapon. Epithelial cell adhesion molecule (EpCAM) is an important CSC surface marker and has been exploited in this work as an active targeting agent. Photoacoustic imaging was applied for GNR individuation and tissue recognition. Results: The nanosystem was demonstrated to be able to elicit effective targeting of cancer cells and cause their killing, in particular under laser ablation. Moreover, ex vivo photoacoustic imaging is able to clearly identify tumor regions thanks to GNR’s contrast. Conclusion: The nanosystem can be considered a powerful and promising theranostic weapon for hepatocellular carcinoma treatment. Keywords: gold nanorods, drug delivery, photoacoustic imaging, photothermal therapy, EpCAM, cancer stem cells

The research project discussed in this PhD thesis concerns the development of drug delivery and theranostic systems for nanomedicine applications in cancer treatments. In the first part, polymeric nanoparticles have been exploited as drug delivery systems for the treatment of Glioblastoma Multiforme. For this purpose, two different biomolecules, in one case Cholotoxin, a small peptide, and in the other case an antiPDGFRs-aptamer (GINT.4), have been employed as targeting agents conjugated on the polymeric nanoparticles surface. The second section of the project has been focused on the development of metallic nanoparticle for photothermal therapy, a cancer treatment consisting in the exposition of body tissue to an increasing of temperature (42-45°C) to induce cytotoxic effects on cancer cells. For this purpose, gold nanorods (GNRs) have been investigated as photothermal agent for the treatment of Barrett’s esophageal. On the other hand, one pot-synthesis of chitosan coated magnesium nanoparticle has been fine-tuned in order to obtain high biocompatible nanoparticles characterized by a promising unexpected photothermal behaviour. In the last part of the project, the synthesis of multicomponent nanosystems suitable for multimodal imaging or theranostic agents have been investigated. Two different multifunctional nanomaterials based on the incorporation of iron oxide and gold nanoparticles in the same nanosystem, have been realized. The first system consisted in dumbbell-like gold-iron oxide nanoparticles coated with chitosan that showed photothermal behaviour and also good capabilities as photoacoustic imaging contrast agents. The second system consisted in core−shell Fe3O4@SiO2@Au NPs entrapped in polymeric nanoparticles decorated with folic acid, have been tested in vivo for photoacoustic and magnetic resonance imaging detection of ovarian cancer.