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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

Weizhong Zhang,1 Xuanyi Li,2 Mauro Comes Franchini,3 Ke Xu,1 Erica Locatelli,3 Robert C Martin,2 Ilaria Monaco,3 Yan Li,2 Shusen Cui11Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of China; 2Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA; 3Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Bologna, ItalyAbstract: We introduced curcumin-loaded nanomicelles into a tendon-healing model to evaluate their effects on tendon healing and adhesion. Three groups consisting of 36 rats underwent rupture and repair of the Achilles tendon. The treatment group received an injection of curcumin-loaded nanomicelles (gold nanorods [GNRs]-1/ curcumin in polymeric nanomicelles [curc@PMs] at a dosage of 0.44 mg curcumin/kg in 0.1 mL saline) into the surgical site and exposed to laser postoperatively at weeks 1, 2, and 3, for three times 10 seconds each, on the surgical site in the rats that underwent tendon rupture and repair, while the other two groups received 0.44 mg curcumin/kg in 0.1 mL saline and 0.1 mL of saline, respectively. The specimens were harvested at 4 weeks and subjected to biomechanical and histological evaluation. The scoring results of tendon adhesion indicated that GNRs-1/curc@PMs group was in the lowest grade of peritendinous adhesions compared to the other groups. Histological assessment further confirmed the preventive effect of GNRs-1/curc@PMs on tendon adhesion. These findings indicated greater tendon strength with less adhesion in the group treated with GNRs-1/curc@PMs combined with laser exposure, and that nanoparticle-based therapy may be applied to prevent adhesion in clinical patients.Keywords: nanorods, peritendinous adhesion, curcumin

Giovanni Baldi,1 Costanza Ravagli,1 Filippo Mazzantini,1 George Loudos,2 Jaume Adan,3 Marc Masa,3 Dimitrios Psimadas,2 Eirini A Fragogeorgi,2 Erica Locatelli,4 Claudia Innocenti,5,6 Claudio Sangregorio,5,7 Mauro Comes Franchini4 1CERICOL, Sovigliana-Vinci, Italy; 2Technological Educational Institute of Athens, Athens, Greece; 3Leitat Technological Center, Barcelona, Spain; 4Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, 5Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), 6Dipartimento di Chimica U Schiff, Università di Firenze, Firenze, 7Centro Nazionale delle Ricerche (ICCOM – CNR), Firenze, Italy Abstract: Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with 99mTc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431 human tumor cell line. Following radiolabeling with 99mTc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma. Keywords: magnetic nanoparticles, polymeric nanocarriers, skin cancer, hyperthermia, single-photon emission computed tomography, imaging

Jennifer Vandooren,1 Nele Berghmans,1 Chris Dillen,1 Ilse Van Aelst,1 Isabelle Ronsse,1 Liron Limor Israel,2 Ina Rosenberger,3 Jörg Kreuter,3 Jean-Paul Lellouche,2 Shulamit Michaeli,4 Erica Locatelli,5 Mauro Comes Franchini,5 Miren K Aiertza,6 Laura Sánchez-Abella,6 Iraida Loinaz,6 Dylan R Edwards,7 Louis Shenkman,8 Ghislain Opdenakker1 1Rega Institute for Medical Research, University of Leuven, Leuven, Belgium; 2Department of Chemistry and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 3Institut für Pharmazeutische Technologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany; 4The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 5Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy; 6New Materials Department, Fundación CIDETEC, San Sebastián, Spain; 7School of Biological Sciences, University of East Anglia, Norwich, UK; 8Tel Aviv University, Ramat Aviv, Tel Aviv, Israel Abstract: The need for test systems for nanoparticle biocompatibility, toxicity, and inflammatory or adaptive immunological responses is paramount. Nanoparticles should be free of microbiological and chemical contaminants, and devoid of toxicity. Nevertheless, in the absence of contamination, these particles may still induce undesired immunological effects in vivo, such as enhanced autoimmunity, hypersensitivity reactions, and fibrosis. Here we show that artificial particles of specific sizes affect immune cell recruitment as tested in a dermal air pouch model in mice. In addition, we demonstrate that the composition of nanoparticles may influence immune cell recruitment in vivo. Aside from biophysical characterizations in terms of hydrodynamic diameter, zeta potential, concentration, and atomic concentration of metals, we show that – after first-line in vitro assays – characterization of cellular and molecular effects by dermal air pouch analysis is straightforward and should be included in the quality control of nanoparticles. We demonstrate this for innate immunological effects such as neutrophil recruitment and the production of immune-modulating matrix metalloproteases such as MMP-9; we propose the use of air pouch leukocytosis analysis as a future standard assay. Keywords: nanoparticles, biocompatibility, toxicity, air pouch, immunologyA Letter to the Editor has been received and published for this article.

Erica Locatelli,1 Larraitz Gil,2 Liron Limor Israel,3 Lorena Passoni,4,5 Maria Naddaka,1 Andrea Pucci,1 Torsten Reese,6 Vanessa Gomez-Vallejo,2 Paolo Milani,5,7 Michela Matteoli,4,8 Jordi Llop,2 Jean Paul Lellouche,3 Mauro Comes Franchini11Department of Industrial Chemistry “Toso Montanari”. University of Bologna, Italy; 2Radiochemistry Department, Molecular Imaging Unit, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain; 3Department of Chemistry, Nanomaterials Research Centre, Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel; 4Department of Medical Biotechnology and Translational Medicine, University of Milano, Italy; 5Fondazione Filarete, Milano, Italy; 6Imaging Department, Molecular Imaging Unit, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain; 7CIMAINA and Department of Physics, University of Milano, Italy; 8Humanitas Clinical and Research Center, Rozzano, ItalyAbstract: A novel nanocarrier system was designed and developed with key components uniquely structured at the nanoscale for early cancer diagnosis and treatment. In order to perform magnetic resonance imaging, hydrophilic superparamagnetic maghemite nanoparticles (NPs) were synthesized and coated with a lipophilic organic ligand. Next, they were entrapped into polymeric NPs made of biodegradable poly(lactic-co-glycolic acid) linked to polyethylene glycol. In addition, resulting NPs have been conjugated on their surface with a 2,2'-(7-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ligand for subsequent 68Ga incorporation. A cell-based cytotoxicity assay has been employed to verify the in vitro cell viability of human pancreatic cancer cells exposed to this nanosystem. Finally, in vivo positron emission tomography-computerized tomography biodistribution studies in healthy animals were performed.Keywords: maghemite nanoparticles, organic coating, polymeric nanoparticles, magnetic resonance imaging, radiolabeling, positron emission tomography