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Khaled AbouAitah,1,2 Anna Swiderska-Sroda,1 Ahmed Kandeil,3 Asmaa MM Salman4,†, Jacek Wojnarowicz,1 Mohamed A Ali,3 Agnieszka Opalinska,1 Stanislaw Gierlotka,1 Tomasz Ciach,5 Witold Lojkowski1 1Laboratory of Nanostructures and Nanomedicine, Institute of High Pressure Physics, Polish Academy of Sciences, Warsaw, Poland; 2Medicinal and Aromatic Plants Research Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), P.C.12622, Dokki, Giza, Egypt; 3Center of Scientific Excellence for Influenza Viruses, Water Pollution Research Department, Environmental Research Division, National Research Centre (NRC) P.C.12622, Dokki, Giza, Egypt; 4Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), P.C. 12622, Dokki, Giza, Egypt; 5Biomedical Engineering Laboratory, Faculty of Chemical and Process Engineering, Warsaw University of Technology, Warsaw, Poland†AMM Salman passed away on June 3, 2019Correspondence: Khaled AbouAitah; Witold Lojkowski Email k.abouaitah@labnano.pl; w.lojkowski@labnano.plBackground: Combating infectious diseases caused by influenza virus is a major challenge due to its resistance to available drugs and vaccines, side effects, and cost of treatment. Nanomedicines are being developed to allow targeted delivery of drugs to attack specific cells or viruses.Materials and Methods: In this study, mesoporous silica nanoparticles (MSNs) functionalized with amino groups and loaded with natural prodrugs of shikimic acid (SH), quercetin (QR) or both were explored as a novel antiviral nanoformulations targeting the highly pathogenic avian influenza H5N1 virus. Also, the immunomodulatory effects were investigated in vitro tests and anti-inflammatory activity was determined in vivo using the acute carrageenan-induced paw edema rat model.Results: Prodrugs alone or the MSNs displayed weaker antiviral effects as evidenced by virus titers and plaque formation compared to nanoformulations. The MSNs-NH2-SH and MSNs-NH2-SH-QR2 nanoformulations displayed a strong virucidal by inactivating the H5N1 virus. They induced also strong immunomodulatory effects: they inhibited cytokines (TNF-α, IL-1β) and nitric oxide production by approximately 50% for MSNs-NH2-SH-QR2 (containing both SH and QR). Remarkable anti-inflammatory effects were observed during in vivo tests in an acute carrageenan-induced rat model.Conclusion: Our preliminary findings show the potential of nanotechnology for the application of natural prodrug substances to produce a novel safe, effective, and affordable antiviral drug.Keywords: virucidal action, influenza H5N1 virus, immunomodulatory and anti-inflammatory, nanoformulations-drug delivery system, shikimic acid and quercetin natural prodrugs, mesoporous silica nanoparticles

Elisa Dassie,1,2,* Diletta Arcidiacono,2,3,* Iga Wasiak,4 Nunzio Damiano,5 Luigi Dall’Olmo,6 Cinzia Giacometti,7 Sonia Facchin,3 Mauro Cassaro,7 Ennio Guido,8 Franca De Lazzari,8 Oriano Marin,9,10 Tomasz Ciach,4 Suzanne Fery-Forgues,11,12 Alfredo Alberti,1,2 Giorgio Battaglia,13 Stefano Realdon13 1Department of Molecular Medicine, University of Padua, 2Venetian Institute of Molecular Medicine, 3Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; 4Faculty of Chemical and Process Engineering, Warsaw University of Technology, Warsaw, Poland; 5Department of Biomedical Sciences, University of Padua, Padua, 6Department of Emergency Medicine, “Santi Giovanni e Paolo” Hospital, Venice, 7Anatomic Pathology Unit, ULSS 15, Alta Padovana, Camposampiero, 8Gastroenterology Unit, Sant’Antonio Hospital, 9Interdepartmental Research Centre for Innovative Biotechnologies (CRIBI), University of Padua, 10Proteomics Facility, Azienda Ospedaliera di Padova, Padua, 11CNRS, ITAV-USR 3505, Toulouse, France; 12Université de Toulouse, ITAV-USR 3505, Toulouse, France; 13Endoscopy Unit, Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy *These authors contributed equally to this work Abstract: For many years, novel strategies for cancer detection and treatment using nanoparticles (NPs) have been developed. Esophageal adenocarcinoma is the sixth leading cause of cancer-related deaths in Western countries, and despite recent advances in early detection and treatment, its prognosis is still very poor. This study investigated the use of fluorescent organic NPs as potential diagnostic tool in an experimental in vivo model of Barrett’s esophageal adenocarcinoma. NPs were made of modified polysaccharides loaded with [4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran] (DCM), a well-known fluorescent dye. The NP periphery might or might not be decorated with ASYNYDA peptide that has an affinity for esophageal cancer cells. Non-operated and operated rats in which gastroesophageal reflux was surgically induced received both types of NPs (NP-DCM and NP-DCM-ASYNYDA) by intravenous route. Localization of mucosal NPs was assessed in vivo by confocal laser endomicroscopy, a technique which enables a “real time” and in situ visualization of the tissue at a cellular level. After injection of NP-DCM and NP-DCM-ASYNYDA, fluorescence was observed in rats affected by esophageal cancer, whereas no signal was observed in control non-operated rats, or in rats with simple esophagitis or Barrett’s esophagus mucosa. Fluorescence was observable in vivo 30 minutes after the administration of NPs. Interestingly, NP-DCM-ASYNYDA induced strong fluorescence intensity 24 hours after administration. These observations suggested that NPs could reach the tumor cells, likely by enhanced permeability and retention effect, and the peptide ASYNYDA gave them high specificity for esophageal cancer cells. Thus, the combination of NP platform and confocal laser endomicroscopy could play an important role for highlighting esophageal cancer conditions. This result supports the potential of this strategy as a targeted carrier for photoactive and bioactive molecules in esophageal cancer diagnosis and treatment. Keywords: confocal laser endomicroscopy, Barrett’s esophagus, diagnostics, esophageal adenocarcinoma, fluorescent nanoparticles, heptapeptide