NANOFOL

Folate-based nanobiodevices for integrated diagnosis/therapy targeting chronic inflammatory diseases

Context and project objectives

It is estimated that inflammatory diseases affect more than 80 million people worldwide leading to untold suffering, economic loss and premature death. Considering life expectancy in Europe, these numbers are expected to increase in the next 20 years. Moreover, studies have shown that disorders such as rheumatoid arthritis (RA) can shorten life span by 10 years. The treatment of chronic inflammatory disorders, including RA, remains a challenge for the medical and scientific community. The emergence of new drugs creates new options though it also entails high costs, complicated drug administration, allergic reactions and potentially fatal side effects. Therefore more efficient strategies have to be identified in order to improve inflammatory disease treatment while decreasing the side effects with an improved cost-benefit ratio. Nano-enabled drug delivery systems will take therapy of chronic inflammatory disorders to a new level by creating a new, highly specific and efficient strategy, with reduced treatment costs. The NANOFOL project has adopted a specific risk amelioration strategy to attain objectives in a step-by-step approach in order to gradually improve the concept (specificity, stability, side effects and efficacy) from lower to higher risk solutions ensuring reduced animal testing and high human safety. NANOFOL will improve treatment of chronic inflammatory diseases by fulfilling the following objectives: Design, development and production of nanobiodevices directly targeting effector cells Experimental design that will enable minimal animal experimentation. Development of a strategy to assess potential life cycle risks ensuring safe nanobiodevice-mediated delivery. Setting-up better citizen awareness on nanomedicine-based therapies and training activities.

Work performed and main results achieved

NANOFOL has acomplished until now the overall objectives established in the initial plan. The consortium discussed and defined several possibilities for the global nanodevice strategy, in order to reach delivery technology products with therapeutic potential. In these eighteen months the optimal conditions were established for the production of Folate Based Nanobiodevice (FBN) prototypes, incorporating components which provide both target specificity and improved stability. Liposomal and protein-based nanoparticles with encapsulated drugs such as celecoxib have been produced and are currently being tested. These FBN, which demonstrated low cytotoxicity in vitro, have been assayed for

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internalization in FR- and FR+ cells and results suggest target cell specificity, in particular with liposomal FBN. The consortium will continue to promote optimization of production methodologies, such as the proposed development of microreactor systems which would allow the scale-up of liposome production. Several in vitro models for testing specific cell uptake of nanodevices, as well as the molecular and biochemical effects of exposure to such particles, have been established. Candidate genes for downregulation in activated macrophages by RNA interference were identified. Special attention is being given to minimizing the use of animal testing by establishing in vitro models. It has become evident that the macrophage differentiation scheme (M1 versus M2 macrophages), in particular in humans, must be further clarified. This will contribute not only to improve basic scientific knowledge of rheumatoid arthritis (RA) but also to valid protocols for testing activated macrophagetargeting therapies. The first anti-FR monoclonal antibodies have been produced and the quest for relevant macrophage-associated target antigens for the antibody-based bispecific nanobiodevice is underway.

Expected final results, intensions for use and impact

NANOFOL nanobiodevices targeting activated macrophages may become an interesting theranostics solution, i.e. simultaneous treatment and diagnosis site of inflammation in RA patients. The production of a validated, stable, specific FBN with incorporated imaging agent and therapeutic agent (drugs or siRNAs) by the NANOFOL consortium will have immediate application in all inflammatory diseases where activated macrophages contribute to the disease process.

NANOFOL Consortium Coordinator

Pr. Artur CAVACO-PAULO, artur@det.uminho.pt, Universidade do Minho Portugal

www.nanofol.eu Partners
Suanfarma SA Spain Technische Universitaet Graz Austria Nederlandse Organisatie Voor Toegepast Natuurwetenschappelijk Onderzoek Netherlands Instituto de Biologia Molecular e Celular Portugal Institut National de la Sant et de la Recherche Mdicale France Medizinische Universitaet Wien Austria Aurel Vlaicu University of Arad Romania Synovo GmbH Germany Institut National de lEnvironnement et des risques France Exbio Praha AS Czech Republic ALMA Consulting Group SAS France ALFAMA Investigacao e Desenvolvimento de Produtos Farmaceuticos, Lda Portugal

Acknowledgements
The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n NMP4-LA-2009-228827 NANOFOL.

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