newsletter9 - euronanomed...december 2019 1 newsletter9 euronanomed iii december 2019 euronanomed...

DECEMBER 2019 1

NEWSLETTER9EuroNanoMed III December 2019

EuroNanoMed III Results of the Joint Transnational call 2019

“European Innovative Research & Technological Development Projects in Nanomedicine ”

13 successful consortia are funded with a total investment of over 11 million € for three years

EuroNanoMed III is funded under the ERA-NET Cofund scheme of the Horizon 2020 Research and Innovation Framework Programme of the European Commission

Research Directorate-General, Grant Agreement No. 723770

According to the new EU General Data Protection Regulation (GDPR) the ENMIII webpage informs on respective policies

euronanomed.net

DECEMBER 2019 2

2 4 6 8 10 12 14 16

FranceGreece

SpainNorway

LatviaRomania

TaiwanItaly

CanadaTurkey

CanadaPoland

Czech RepublicBulgariaSlovakia

Latvia

66 Research Groups From 14 Participating Countries

Female researchers participate with 29% in all projects Female researchers participate with 23% as coordinators

66 Research Groups participate in 13 funded projects Scientific Area for Funded Projects

29%

57% 69%18%

23%

7%24%

23%

71%77%

DECEMBER 2019 3

NANO4GLIONanomedicine for glioblastoma therapy

Coordinator: Valentín Ceña, CIBERNED-ISCIII, Spain

Contact:[email protected]

Partners:Jean-Pierre Majoral, CNRS Sciences Chimiques, France René Roy, Universite du Quebec, Canada Hui-Ting Chen, Kaohsiung Medical University, Taiwan Daniel Boismenu, Glycovax Pharma Inc., CanadaMaria Angeles Vaz, Ramon y Cajal University Hospital, Spain

Glioblastomas are among the most aggressive and difficult-to-treat cancers. Besides advances in treatment, most of the tumors relapse and become refractory to treatment, leading to a 2-year-survival rate as low as 10-15 %.This project aims to establish the experimental bases for a new treatment approach for glioblastoma. This approach is based on the combination of specific short fragments of genetic material (siRNAs) that will specifically eliminate proteins involved in the proliferation of glioblastoma cells and the increase uptake of anticancer drugs such as temozolomide by glioblastoma cells. For this purpose, we will use nanoparticles as carriers for both compounds (siRNA and an anticancer drug). These nanoparticles will deliver their cargo selectively to the glioblastoma cells using specific molecules attached to them that will find complementary molecules located in the tumor.

Valentín Ceña

DECEMBER 2019 4

DRNANODALLNanodiagnosis for Betalactam Hypersensitivity

Coordinator: María José Torres. Instituto de Investigación Biomédica de Málaga (IBIMA). Málaga, Spain


Partners:Ezequiel Pérez-Inestrosa. Universidad de Málaga-BIONAND. Málaga, SpainJean Louis Gueant. Inserm and University of Lorraine. Nancy, FranceRosa Pettinato. IRCCS Associazione Oasi Maria SS. – ONLUS. Troina, ItalyDavid Rodríguez. DIATER Laboratorio de Diagnósticos y Aplicaciones Terapéuticas, S.A. Madrid, Spain

Allergy to betalactam antibiotics is the most common allergy to an antibiotic drug. This has significant implications for patients’ safety and Health Systems’ costs, since prescribing alternative antibiotics could induce bacterial resistance, be more expensive, and be potentially more toxic. IgE-mediated allergy tends to change over time and differs among European countries, depending on betalactam consumption.

Betalactam allergy diagnosis is challenging as it relies on patient clinical history, in which previous reaction evidence is often inaccurately reported; and on drug provocation and/or skin tests, which are not risk-exempt and require specialized healthcare professionals. In vitro tests stand out as the more rational alternative diagnostic method, showing however various limitations, hampering the fulfilment of the clinician’s needs.DrNanoDAll proposes the development of dendrimeric antigen-nanoparticles, innovative solutions to surpass the current in vitro diagnostics limitations. In this proposal nanotechnological and immunological approaches will be combined with clinical expertise, implementing a multi-omics workflow and involving the industry for scaling up nanomaterials and clinical test validation steps.

María José Torres

DECEMBER 2019 5

GOTTARGGlutamate Oxaloacetate Transaminase Nanoparticles targeted to the Brain for Neuroprotection in Ischemic Stroke

Coordinator: Marc A Gauthier, Institut National de la Recherche Scientifique (INRS), Varennes, Canada


Partners:María Pérez-Mato, Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Clinical University Hospital (CHUS), SERGAS, Santiago de Compostela, SpainDevrim Gozuacik, Sabanci University Nanotechnology Research and Application Center (SUNUM), Sabanci University, Istambul, TurkeyEspen Mariussen, Norwegian Institute for Air research, Kjeller, Norway

The aim of this project is to develop and test the first targeted and long-acting nanomedicine with neuroprotective properties for ischemic stroke, that will also have potential application in other neurological diseases related with glutamate excitotoxicity. Our first aim is to demonstrate that the targeted delivery of a long-acting glutamate oxaloacetate transaminase (GOT) nanoparticle to- or near to- the brain enhances the neuroprotection in a model of ischemic stroke. Our second aim is to investigate the mechanism of neuroprotection to conclude pre-clinical studies and place the research project team in a position to embark upon clinical testing.

Marc A Gauthier

DECEMBER 2019 6

CELLUXCeO2 Nanoparticles-assisted stem-cell therapy: an innovative nanopharmaceutical approach to treat retinal degenerative diseases

Coordinator: Anna Duarri, Vall d’Hebron Institut de Recerca, Barcelona, Spain


Partners:Maria Dusinska, NILU-Norwegian Institute for Air Research, Kjeller, NorwayLuisa Diomede, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milan, ItalyAlena Sevcu, Technical University of Liberec, Liberec, Czech RepublicEls Verhoeyen, Centre International de Recherche en Infectiologie (CIRI)/ INSERM U1111, Lyon, FranceIgnasi Gispert, Applied Nanoparticles, Barcelona, Spain

Chronic inflammation is now regarded as a major pathogenic pathway common in many different pathologies. Age-related Macular Degeneration (AMD) is a neurodegenerative and complex disorder with multifactorial etiology, currently inevitable and orphan of treatment, that represents a major cause of blindness in people over 50 and affects millions of people worldwide. Its progression is associated to an increase of oxidative stress and inflammatory response in the eye leading to retinal cell death. Recently, a new agent has been added to the group of antioxidant/anti-inflammatory substances with therapeutic properties: cerium oxide nanoparticles (CeO2NPs). CeO2NPs have a unique electronic structure that when reduced

to the nanoscale, oxygen defects appear at their surface, behaving as sites for free radical scavenging. Thus, the main objective of CELLUX is to develop a novel pharmaceutical-based CeO2NPs eye drops to treat AMD that in combination with stem cell-based therapeutic strategies, will not only stop degeneration but restore vision.

Anna Duarri

DECEMBER 2019 7

NAN-4-TUM Development of CXCR4 targeting-nanosystem-A1:LK39 for molecular imaging of cancer cells and tumor microenvironment.

Coordinator: Dr. Stefania Scala, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Italy


Partners:Dr. Ling Peng, cAix-Marseille University, French National Scientific Research Center (CNRS), FranceDr. Diego Arango del Corro, Vall d’Hebron Institute of Oncolog, SpainDr. Hajdúch Marián, Palacký University Olomouc, Czech RepublicDr. Sebastien Wälchli, Oslo University Hospital, NorwayDr. Kao Chai-Lin, Kaohsiung Medical University, Taiwan

The lifetime probability to develop an invasive cancer in Europe is approximately 35-40% with solid cancers representing more than 90%. Early diagnosis and precise follow-up constitute essential elements for successful cancer management. For diagnosis and follow up the majority of patients undergo diagnostic imaging through computed tomography scan (CT) and Positron Emitting Tomography (PET) evaluation. Nevertheless the widely utilized PET tracer,

18Fluorodeoxyglucose ([18F]-FDG), have several limitations in terms of specificity and sensitivity thus cancer lesions result often undetectable. The use of next generation nano-tracer may allow tumor specific molecular targeting that could overcome [18F]-FDG limitations. The chemokine receptor C-X-C chemokine-receptor-4 (CXCR4) is overexpressed in the majority of solid tumors characterizing the cellular most aggressive components and their microenvironment (TME). We recently developed a new anti-CXCR4 PET probe ([68Ga]NOTA-Ahx-R54) that is able to detect CXCR4-expressing tumor lesions. Coupling CXCR4 targeting -PET probe with nanotechnology

could magnify the specificity and the sensitivity through increased tumor accumulation, multiple targeting ligands per particle and amplification of contrast signal. In this project we aim to develop a new CXCR4 targeting nanovectors -specific PET tracer (CXCR4-PET-NAN) to improve early diagnosis of primary/secondary cancer lesions which overexpress CXCR4, such as breast, colon, melanoma, pancreas, lung and neuroendocrine tumors (NETs). In addition, the information that will be achieved by targeting TME cells CXCR4 expressing, will assist the characterization of TME and identification of therapeutical targets.

Dr. Stefania Scala

DECEMBER 2019 8

REASON“Regenerating the diabetic heart and kidney by using stress-specific thyroid hormone nanocarriers”

Coordinator: Christodoulos Xinaris, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy


Partners:Mourouzis Iordanis, National and Kapodistrian University of Athens, Athens, GreeceIatrou Hermis National and Kapodistrian University of Athens, Athens, GreeceNedyalkova Miroslava, University of Sofia, Sofia, BulgariaZelphati Olivier, OZ BIOSCIENCES SAS, Marseille Cedex 9, France

Diabetic cardiomyopathy (DC) and diabetic nephropathy (DN) are two major complications of diabetes that account for more than two thirds of deaths in the diabetic population. The primary hallmarks of these conditions are cell dedifferentiation, hypertrophy and maladaptive proliferation through the reactivation of classic developmental pathways. Previous studies have indicated that thyroid hormone (TH) treatment could be a potential strategy for reversing or preventing this maladaptive recapitulation of organ development. However, the high doses of TH that are needed to induce tissue repair and regeneration may cause several adverse effects. To maximise the therapeutic efficacy of TH and minimise its adverse effects we aim to develop innovative nanoparticle-based drug delivery systems that will be able to target and deliver L-triiodothyronine (T3) to diabetes-injured cells and hopefully regenerate damaged tissue. To this end, we will develop smart T3-nanocarriers that will be functionalised for a molecule that can specifically bind stressed-injured cardiomyocytes and podocytes. In parallel we will develop a targeting strategy that will confine the drug to a magnetically targeted site after injection. We will evaluate the therapeutic efficacy of the system in animal models of DC and DN with intention to bring the treatment of DC and DN one step closer to clinical translation.

Christodoulos Xinaris

DECEMBER 2019 9

TENTACLESTEmperature-responsive Nanogels for TArgeted delivery of miCroRNAs in wound heaLing and tissue rEgeneration applicationS

Coordinator: Dr. Andrea Masotti, Bambino Gesù Children’s Hospital-IRCCS, Italy


External Collaborators:Dr. Andrea Caporali, University/Bhf Centre For Cardiovascular Science, FranceDr.Nicolas Cassinelli, Spain

Partners:Dr. Sobolevs Arkadijs, Latvian Institute of Organic Synthesis (LIOS), LatviaDr. Chmielewski Marcin K., FutureSynthesis. Sp. z o.o. (FS) ë Ë, PolandDr. Le Hégarat Ludovic, Anses - Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES), FranceDr. Monika Sramkova, Cancer Research Institute, Biomedical Research Center SAS, Slovakia

The development of novel therapeutically active wound dressings which provide the wound protection from ‘environmental’ effects as well as wound healing promotion has an advantageous potential for clinical applications. Nanotechnology-based materials incorporated into scaffolds allow the creation of nanocomposite smart materials with unique physicochemical and biological properties to promote skin regeneration. Our aim is to develop an innovative multifunctional nanogel that will integrate the protective and healing functions within one nanocomposite smart structure made by polymer-based nanohydrogel, iron oxide nanoparticles and targeted miRNAs. The heating mediated by iron oxide nanoparticles will promote the induction of heat shock proteins (HSPs) involved in fibrogenesis and the production of extracellular matrix (ECM) production and transforming growth factor-β1 (TGF-β1), which is essential to fibrosis. Specific miRNA molecules will promote wound healing via expression/modulation of particular genes. The proposed innovation could revolutionize wound healing therapeutical strategy particularly for diabetic or long stay recovered patients.

Dr. Andrea Masotti

DECEMBER 2019 10

IMPLANTNANONano-delivery system for one-shot regenerative therapy of peri-implantitis

Coordinator: Janis Locs, Riga Technical University, Riga, Latvia


Partners:Assem Soueidan, Nantes University/Inserm, Nantes, FranceDiego Mantovani, Laval University, Quebec City, CanadaAnthony Bresin, HTL Biotechnology, Javené, France

Despite being the most effective treatment method for replacing missing teeth, Ti-based dental implants are associated with diseases such as peri-implantitis which are caused by bacteria adhering and proliferating on the implant surface and might result in implant loss. Thus, peri-implantitis is a true threat in today’s advancement of implant reliability and performance. The multidisciplinary ImplantNano project aims to develop an innovative ready-to use composite-nano drug delivery systems for one-shot effective treatment of peri-implantitis based on an easily applicable construct composed of nano-hydroxyapatite (nHAp) particles immobilized within Ti-adhesive silated hyaluronic acid (Si-HYA) hydrogel at the “bone level” with the main purpose to stabilize the nano-device, namely, Ti-adhesive silated hydroxypropylmethil cellulose (Si-HPMC)/chitosan hydrogel-based membrane at the site, i.e., “bone/gum interface”. With this technique, the physiological wound healing process will be supported by preventing the ingrowth of the epithelial/connective soft tissues and promoting osseous regeneration around implant and by the delivery of antibacterial Ga3+ ions and/or antibiotics incorporated in nHAp”.

Janis Locs

DECEMBER 2019 11

NANOLIGHT Photosensitive nanotools for neuronal stimulation and rescue of degenerative blindness

Coordinator: Fabio Benfenati, IRCSS – Ospedale Policlinico San Martino, Genova, Italy


Partners:Gáspár Szilveszter, International Centre of Biodynamics, Bucharest, RomaniaSerge Picaud, Sorbonne Université, Paris, FranceJaume Esteve Tintó, Consejo Superior de Investigacion Cientificas (CSIC), Bellaterra (Barcelona), SpainAnne Labouret, SOLEMS S.A., Palaiseau, France Daniel Perez, Nanoimmunotech, S.L., Edificio CITEXVI, Vigo, Spain

One of the grand challenges of biomedical engineering is to develop methods for interfacing light stimuli with the nervous system. nanoLight will exploit the revolutionary concept of focalized neuronal stimulation without using microelectrodes or planar prosthetic devices and avoiding genetic manipulations. The goal is to compensate for nervous system pathologies in which neuronal degeneration has induced a specific loss of function. This will be obtained by developing novel photosensitive nanotools (PNTs) that, by virtue of their sub-micrometer size, can achieve a spatial discrimination that goes beyond single-cell resolution. PNTs can be delivered to the tissue with minimally invasive microinjections and be anchored

to the membranes of target neurons to convert light stimuli into an electrical stimulation. In view of therapeutic applications to human diseases, nanoLight PNTs will target photoreceptor degeneration in Retinitis Pigmentosa (RP) and age-related macular degeneration (AMD). The project will focus on three parallel strategies exploiting both organic and inorganic PNTs: (i) organic PNTs based on conjugated polymers; (ii) inorganic PNTs based on silicon photodiodes; and (iii) hybrid PNTs based on both inorganic semiconductors and conjugated polymers. We were able to previously show that 1st generation PNTs are not endocytosed and preserve their extracellular location in cells and tissue for a long time. Preliminary results indicate that subretinally injected PNTs are effective in rescuing light sensitivity and spatial discrimination in an animal model of RP. This will guide nanoLight biomedical engineering to develop new methods for interfacing optical stimuli with the nervous system for healing pathologies in which neuronal degeneration has induced a specific and irreversible loss of function.

Fabio Benfenati

DECEMBER 2019 12

GLIOSILKSilk-fibroin interventional nano-trap for the treatment of glioblastoma

Coordinator: Emmanuel Garcion, INSERM, Cancer and Immunology Research Centre Nantes-Angers, Angers, France


Partners:Carmen Alvarez-Lorenzo, IDIS (Instituto de Investigación Sanitaria de Santiago de Compostela), Santiago de Compostela, SpainFrançois Berger, Centre Hospitalier Universitaire Grenoble Alpes (CHUGA), Grenoble, FranceFranco Valzania, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia (AUSL-IRCCS), Reggio Emilia, ItalyMiguel Abal, NASASBIOTECH S.L., Coruña, Spain

Brain-tumor glioblastoma (GB) is still considered as one of the worst unmet clinical need in spite of implementation of the therapeutic arsenal available and recent developments in nanomedicine and immunotherapy. With inevitable relapse its prognosis remains devastating. The reasons behind this failure are the tumor heterogeneity and the peritumoral infiltrative niche. A complex interaction between the initial tumor location, its attraction by the peritumoral microenvironment defines a heterogeneous pathway that is probably the more relevant target if we want to develop more curative therapies. In contrast with direct targeting of infiltrated cancer cells for their elimination, GLIOSILK aims to evaluate new bio-interactive interventional silk-fibroin (SF)-based nano-implants in their capability to recruit in controlled brain areas the cells submitted to a chemo-attractant SDF-1α signal. By developing biocompatible SF-based nano-scaffold and use of well mastered cross-cutting methods, the capability of newly built bio-interactive deposits to define a confined in situ gradient and to effectively trap GB cells before elimination (eg. by radiations) while ameliorating the evolution of the disease will be determined. Overall, this multidisciplinary work’s purpose is to make significant breakthrough in overcoming treatment resistance in GB, and other solid tumors toward clinical transfer.

Emmanuel Garcion

DECEMBER 2019 13

ENAMEP Exosomes as innovative Nanomedicine Approaches to reverse obesity and its MEtabolic and Psychotic complications with specific targeting of the hypothalamus

Coordinator: Dr. Ramaroson Andriantsitohaina, Université d’Angers, Stress oxydant et pathologies métaboliques - SOPAM Laboratory, France


Partners:López Perez Miguel Antonio (Miguel López), Instituto de Investigación Sanitaria, Santiago de Compostela (IDIS), SpainJohan Anders Fernø, Haukeland University Hospital, NorwayMarc Grégoire, Institut national de la santé et de la recherche médicale (INSERM), France

Obesity is reaching pandemic proportions worldwide. It is directly and indirectly causing thousands of deaths per year. Currently, there is not an efficient treatment against obesity, apart from quite invasive bariatric surgery. Thus, there is an urgent need for new therapies and preventiveapproaches. The aim of ENAMEP project is to develop a “nanobiomedicine” approach to harness nanoscale cell-derived extracellular vesicles, namely exosomes, as “cargos” of specific therapeutic molecules. The aim is to deliver specific DNA in the hypothalamic area, modulating energy balance and tackling thermogenesis for the treatment of obesity. This can be obtained via specific inhibition of lipid metabolism targets in the ventromedial nucleus of the hypothalamus by the use of peripherally administered engineered exosomes. Controlling central regulation of obesity wouldspawn new strategies to monitor efficacy of therapy with minimal side effects. The use of engineered exosomes is the only way to target specific hypothalamic area by intravenous delivery, making them affordable for therapeutic use.

Dr. Ramaroson

Andriantsitohaina

DECEMBER 2019 14

NANONETTargeting breast tumors with anti-Netrin-1 A1:LK39 as a promoter of immunity

Coordinator: Patrick Mehlen: Cancer Research Centre of Lyon- University of Lyon 1- CNRS- Lyon, France


Partners:Benjamin Gibert (co-coordinator), Cancer Research Centre of Lyon- CRCL- Lyon, France Ilaria Marigo. Istituto Oncologico Veneto IOV-IRCCS, Padova, ItalySteeve Roffler, Academia Sinica, Taipei, TaiwanBenjamin Ducarouge, Netris Pharma, Lyon, France

Immunotherapy with checkpoint inhibitors is currently revolutionizing cancer treatment in the clinic, but only a little fraction of patients respond. Triple negative breast cancer is an extremely aggressive subtype that in most cases is not responsive to immunotherapy. There is thus an urgent need for new treatments to cure this disease. To escape cell death, cancer cells secrete survival factors. In our NanoNET project, we will develop a new combinatorial nano-approach to specifically target one of these factors to induce an immune reactivity able to improve the effects of checkpoint inhibitors. Our goal is to improve the standard of care used in the clinic.

Patrick Mehlen

DECEMBER 2019 15

RUNNINGGut-targeted RNA-based nanoparticles for fibrostenotic Crohn’s Disease: a novel therapeutic approach

Coordinator: Silvio Danese, IRCCS Istituto Clinico Humanitas- Humanitas Mirasole SPA, IBD Center, Rozzano, Italy


Partners:Ruth Schmid, SINTEF Industry, Department of Biotechnology and Nanomedicine, Trondheim, NorwayGeorge Loudos, Institution BioEmission Technology Solutions (BIOEMTECH), Athens, GreeceDidier Betbeder, VAXINANO, Lille, FranceMichele Iafisco, National Research Council of Italy (CNR), Faenza, Italy

Intestinal fibrosis, i.e. the reaction of intestinal tissue to the damage inflicted by chronic inflammation, is a common and potentially serious complication of Crohn’s Disease (CD) that, to date, has no effective medical treatment. We previously observed that specific proteins are causally involved in the development of intestinal fibrosis and that calcium phosphate (CaP) nanoparticles conjugated with active compounds against these targets, may represent a valuable drug delivery system and a new therapeutic approach for future treatments of fibrostenotic CD patients. The overall goal of this project is to conceive an innovative nanoparticle-based drug delivery system to the fibrotic gut mucosa, featuring various routes of administration, cell specific targeting, efficient drug release, and maximal retention time in tissues. Furthermore, using a multi-disciplinary approach, we aim at promoting innovation and creativity in specific drug-loaded CaP formulations or preparations, that will be validated both in human primary cell lines derived from fibrotic patients, and in animal model of intestinal fibrosis, thus enhancing the translational aspect of this study. The proposed project is a unique

opportunity to make a jump in our understanding of CD-related intestinal fibrosis, possibly opening new ways for more focused therapy. Additionally, the use of nanoparticles is suggested as a possible way for imaging intestinal fibrosis evolution and treatment, which could potentially open the way to new diagnostic and monitoring methods.

Silvio Danese

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