Nanotechnology paves the way for innovative and efficient therapeutic and diagnostic agents and tools. Still, treatment of neurodegenerative disorders remains a challenging field due to therapeutic necessity to reach the brain by crossing the blood-brain barrier (BBB), one of the best gate-keeper. Multifunctional nanoparticles (NPs) offer new and improved platform to solve issues about efficacy, bioavailability and targeting ability by translocating drugs through the BBB. The ultimate goal of proposed project is development of multifunctional nano-enabled drug delivery systems for brain (BRaiND) for efficient and safe treatment of abnormalities that follow debilitating brain conditions linked to aging and degeneration. This will be achieved by following specific objectives: - design, preparation and characterization of BRaiND; - evaluation of BRaiND stability and fate in biological media; - mechanistic and quantitative assessment of interaction of BRaiND with BBB; - efficacy and safety profiling of BRaiND by a combined in vitro and in vivo approach. BRaiND will be based on selenium or gold NPs, stabilized with polyethylene gylcol and functionalized with proteins that target the brain receptors. Such multifunctionalized system will be loaded with model neuroactive agents to demonstrate its efficacy, quality and safety. Careful in vitro and in vivo testings will be performed including stability and interactions of BRaiND in different biological media, BBB permeability, and efficacy of targeting specific brain sites, neuroprotective activity, and safety profiling. SENDER work plan is based on validated and standardized methodologies, as well as emerging new experimental techniques. Considering the major challenges of translational research in neurodegenerative diseases, SENDER strategy is based on the Safe-by-Design approach and enabled by nanotechnological tools that analyze and manipulate biological processes at the nanoscale, where diseases initiate and progress.

Poisoning by organophosphorus compounds (OP) is a serious worldwide public and military health issue. OP nerve agents present a threat in terrorist attacks and conflicts (civil war in Syria). The acute toxicity of OP agents results from their irreversible inhibition of acetylcholinesterase (AChE), which regulates cholinergic transmission in the peripheral and centralnervous system (CNS). Emergency treatment consists of administration of pyridiniumoxime antidotes for reactivation of AChE. Yet, none of them are effective reactivators of all OP-inhibited AChE and their efficiency against phosphoramidate (tabun) is limited. Moreover, these oximes do not readily cross the Blood-Brain-Barrier (BBB) to reactivate AChE in the central nervous system. Furthermore, none of them are efficient on OP-inhibited butyrylcholinesterase (BChE), the back-up enzyme to AChE. As a consequence, remediation of both acute and chronic intoxications of civilian and military populations by OP continues to be a challenge of paramount importance. Recent crystallographic studies provided insight into the interactions between reactivator molecules within the AChE active site, revealing that oxime antidotes possessing vastly improved efficiency could be discovered through rational design. Around the world, teams are engaged in the design of new reactivators of OP-inhibited AChE. Teams from the EU, gathered in this consortium, have made the most promising discoveries. Our goal is thus to develop more efficient antidotes and improve the medical treatment of poisoning by highly toxic OP. The objective of this innovative project is to discover new multifunctional reactivators of AChE- and BuChE inhibited by organophosphorus nerve agents. In order to successfully achieve the objective of this exciting and challenging European project, the skills of scientists with skills spanning several disciplines will be required. Critically, the consortium also has access to facilities able to work with OP nerve agents safely.

Engineered nanomaterials (ENMs) are covered by REACH/CLP regulations; the general opinion is that the risk assessment (RA) approach routinely used for conventional chemicals is also applicable to ENMs. However, as acknowledged by OECD and ECHA, the OECD and ISO Test Guidelines (TGs) and Standard Operating Procedures (SOPs) need to be verified and adapted to be applicable to ENMs. RiskGONE will support the standardization and validation process for ENM by evaluating, optimizing and pre-validating SOPs and TGs and integrating them into a framework for risk governance (RG) of ENMs. The framework will comprise modular tools and will rely heavily on current strategies for the RA of conventional chemicals, complemented by methods for estimating environmental, social and economic benefits. It will incorporate ethical aspects and societal risk perception and will manage acceptable and unacceptable risks through transfer or mitigation. The focus of RiskGONE will be to produce nano-specific draft guidance documents for application to ENM RA; or, alternatively, to suggest ameliorations to OECD, ECHA, and ISO/CEN SOPs or guidelines. Rather than producing assays and methods ex novo, this will be achieved through Round Robin exercises and multimodal testing of OECD TGs and ECHA methods supporting the “Malta-project”, and on methods not yet considered by OECD. This process will be accelerated by guidance documents for data storage/curation/accessibility optimisation, applied to well-characterized reference ENMs typifying the main physicochemical and toxicological features of ENMs. The conditions for a transparent and self-sustained organisational form for science-based RG, representing EU stakeholders, member states, industry and civil society, will be established. The RG framework and methods developed by RiskGONE will be transferred to the organisational form for RG.

Toxic metals (such as lead, cadmium, mercury or arsenic) are ubiquitous environmental pollutants that occur in the ecosystem naturally or through human activity. Ill effects are related to metal overload due to external exposure or genetic factors (disturbed copper or iron metabolism), and to the deficiency or imbalance of essential metals and metalloids in the body (iron, copper, zinc, calcium, selenium). Women and children are vulnerable groups for ill effects of metals due to specific physiological features that can result in increased metal accumulation during childbearing age, gestation, lactation, and during child growth and development. The aim of this project is an integrated assessment of exposure, biological effects, and interactions of toxic (cadmium, mercury, lead) and essential elements (iron, zinc, copper, selenium) during pregnancy/prenatal period and postnatal development. Sources of exposure will be evaluated by analysing metal content in food, soil, and selected tissues of wild animals, and using epidemiological variables in women. Metal concentrations in human placentas, in maternal and umbilical cord blood, and in organs and tissues of experimental animals exposed to toxic metal (cadmium or mercury) will serve as biomarkers of internal exposure. The effects of metal exposure will be assessed through steroid hormone concentrations in human and animal placental tissue. In experimental animals, we will also evaluate the methods for decreasing metal retention, such as supplementation with mineral (e.g. essential element selenium), vitamin (e.g. vitamin C) and/or chelation treatment (by deferoxamine, D-penicillamine, succimer, unithiol, deferiprone, or Prussian blue). The efficacy of these treatments in alleviating metal toxicity will be assessed through indicators of metal-induced oxidative stress. The proposed research will provide a new insight into the reproductive and perinatal toxicology of metals, into their toxicokinetics, and into the antidotal therapy in the young. Possibilities of research application are in public health measures, which include detection and prevention of metal exposure in vulnerable population groups, women in childbearing age and infants, as well as procedures for reduction of toxic metal body retention in postnatal period.