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New nanomaterials for neural stem cells drug delivery

Periodic Reporting for period 1 - NANOSTEM (New nanomaterials for neural stem cells drug delivery)

Reporting period: 2018-06-01 to 2020-05-31

Brain conditions such as neurodegenerative diseases, stroke, and traumatic injuries are a significant burden in modern society. Multiple therapeutic approaches are being investigated, however, a key limitation is the permeation of the blood-brain barrier. A very interesting approach is based on the use of neuro stem cells available within the brain and on the delivery of active therapeutic agents to specifically promote proliferation and differentiation. The NANOSTEM project is studying the use of nanomaterials for the delivery of active drugs to control the biological activity of neuronal stem cells. The project will focus on three main targets: (i) synthesis of the nanomaterials and uploading of the therapeutics; (ii) evaluation of the permeation and efficacy of the formulations against in vitro model systems; (iii) in vivo studies to assess the toxicity of the most successful formulations.

The project is organised into three scientific work packages:
WP1 - Synthesis and characterisation of novel nanomaterials The main objective of WP1 is to develop advanced nanostructure materials with the ability to transport drugs across the BBB, targeting the Neural stem cells.
WP2 - Permeation and bioactivity studies. WP2 focuses on the development of in vitro human BBB models to screen formulations, in both healthy and diseased settings.
WP3 - In vivo evaluation of nano-delivery systems(QMUL, CNC, KI, CHUC, HMGU). This last work package aims to (i) target and control the activity of neural stem cells, and (ii) demonstrate the effect of inductive platforms in vivo.

NANOSTEM has recruited 14 ESRs that are being trained in areas including organic and polymer chemistry, cell biology, pharmacology, neuroscience, nanobiotechnology and clinical sciences. The project is also providing a substantial training program in complementary skills, targeting both professional and personal development, and translation of research and entrepreneurship.

The project brings together six academic partners, one hospital and two industrial teams as full partners, complemented by four associate partners, one of which is an industrial team, distributed over a total of seven European Union member states. The consortium connects groups with very interdisciplinary expertise ranging from nanoparticle synthesis and characterization, computational modelling, in vitro Blood Brain Barrier (BBB) models and BBB transport, neural stem cells, animal testing and clinical expertise.
The work being done by the Teams belonging to the Nanostem consortium is targeting a very important scientific question related to understanding how nanoparticles may have the potential to overcome the current problems of permeating the blood-brain barrier. Any new discovery in this area is likely to lead to significant and impactful novel therapeutic applications.
"The consortium has recruited a total of 14 ESRs and has delivered to date a total of 3 Network events, that were well attended also by external participants.
- The kick-off meeting was attended by all PIs.
- The ESR workshop where all the 14 ESRs attended.
- The first NANOSTEM international meeting and first Summer School

Some of the fellows already completed some of their scheduled secondments, while others have had to delay it as a result of the COVID 19 pandemic.
The project has already achieved three of its scientific deliverables, focused on the preparation of the different types of nanomaterials and also on the development of in vitro models for the blood-brain barrier.
The researchers have successfully synthesised and characterised a library of methacrylate nanogels that show thermo-responsive properties and have the potential to be used as a drug delivery system. Also, other nanoparticles based on poly(ester) have been obtained and characterised. Results showed that these nanoparticles are not toxic and able to permeate through in vitro blood-brain barrier.

All the NANOSTEM fellows have engaged in outreach activities with more planned in the coming months. For example, the ERSs actively took part to events like ""Science at the Cathedral"", ""Science is Wonderful"", ""European Researchers Night"", amongst many others, reaching out to hundreds of people of all ages.
Unfortunately, some activities were cancelled because of COVID 19 pandemic. For example, ESRs 1, 2, and 14 were scheduled to take part to the ""Big Bang Fair"" in Birmingham (11th - 14th March 2020), but this event was cancelled as well as the ""6th Walk for stroke of the national stroke patient day"" scheduled to take place in Coimbra on the 28th of March, 2020 (ESRs 5, 6, 7, and 10).

To date, the Network has achieved 2 publications, while 4 manuscripts that have been submitted to scientific journals and are currently under review. The fellows have attended a number of different conferences and other training events.
The NANOSTEM website was created at the start of the project (https://www.nanostem.qmul.ac.uk/) and has been successful as a dissemination vehicle The newsletter, created every 4 months is also uploaded on the website and widely available."
All teams are actively engaged in research that will bring considerable progress beyond the state of the art. A number of novel nanomaterials have been prepared and characterised. Some key information is being gathered regarding the importance of the chemical structure in determining interaction with biological entities, in particular proteins. Data on protein corona formation is being obtained using a combination of different techniques that will enhance the understanding and also prediction of bioavailability of these particles. Some of the preparations are currently evaluated in vitro together with initial studies on permeation of the blood-brain barrier model. It is expected that a larger amount of data will be collected over the next couple of years. As a result of COVID19 the project has in actual fact lost 5 months of experimental work. The next 12 months will see a lot more data acquisition both in the area of nanoparticles synthesis and protein corona studies, but also with data on the biological aspects of the project. The key step will also be to start carrying out initial experiments on drug uploading using both small molecules and large biopharmaceuticals.
The project is focused on research that is still in its fundamental stage, therefore the most significant socio-economic impact will be in the form of new discoveries that will be patented and further exploited by the beneficiaries. The team based at the hospital of the University of Coimbra is carrying out really important work looking at data already available in the literature to establish key parameters for the evaluation of stroke patients and this could present a positive impact in clinical practice.
The fellows of the Network have been very active and fully engaged with a large number of outreach events. These have resulted in the dissemination of the work and on the education of the general public on the issues, associated with neurodegenerative diseases and their therapeutic challenges, as a result of the presence of the blood brain barrier.
The multidisciplinary training provided by the Network is contributing to develop researchers that will be fully equipped to work in this key area of science.