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Remote control healing: Next generation mechano-nano-therapeutics

Periodic Reporting for period 2 - DYNACEUTICS (Remote control healing: Next generation mechano-nano-therapeutics)

Reporting period: 2020-07-01 to 2021-12-31

Exercise has been shown to have beneficial effects in many aspects of human physiology and disease prevention but often requires mobilisation and activity. Promoting an active society is a key aim for prevention of many chronic conditions and reduction in age related illnesses. How do we ‘bottle’ an agonist like a drug which can mimic exercises without activity and influence or regulate mechano-sensors on the cell membrane in the same way? How do we control these receptors as a therapeutic target for treatment of disease and tissue repair ? This project tackles this complex interdisciplinary question. We aim to develop new nanotechnologies and protocols by which we can control cell behaviour in patients undergoing regenerative medicine and other therapeutic treatments using injectable solutions.
Specifically, we aim to expand and develop a breakthrough platform technology where we can tag and activate the mechano- sensing cell membrane receptors on stem cells and design injectable solutions. Using magnetic particle tagging, we can remotely direct cells in our in vitro 2D and 3D models which will help to develop the strategy for human therapeutic purposes in regenerative medicine approaches.
Specifically our project aims to:
• To identify mechano-receptor binding sites on stem and mature cells which will enable remote activation of signalling pathways via magnetic fields
• To design and test magnetic particles with tailored tagging strategies using single cell through 3D human models to in vivo preclinical models
• To tailor and design external remote control devices
• To create dynamic tissue assays for use in high-throughput drug screening and identification of dynamic relevant molecules which will expand new drug targets in pharmaceutical interventions.
• To create clinically relevant treatment modalities for remote control healing
This proposal aims to harness a unique opportunity to launch a new dynamic treatment platform, DYNACEUTICS, which we propose will extend the therapeutic horizon and provide a new form of remote controlled healing.
DYNACEUTICS set out to explore the use of magnetic nanoparticles (MNP) in regenerative medicine and tissue engineering. Our ultimate aim has been to control delivery, tracking and differentiation of therapeutic stem cells following delivery to patients using our novel MICA technology. The project has been split into multiple elements and in general progress has been good despite the issues of COVID lab closures. We are now at a stage where we have the confidence to start our translation towards first in man studies during the final phase of the project. Alongside this we have been exploring new and exciting avenues for receptor targeting using mechano-activation for immunotherapies and new applications for dynamic drug screening where progress is outlined below.
Our lab has designed test systems for enabling 3D models which can be used in developing our clinically relevant protocols. We have been working on studying multiple receptors. We have studied and contrasted different ways to attach to the receptor which includes the use of antibodies, proteins and small molecules for MNP coatings in our 3D cell models. Using these approaches, we have identified a patented peptide sequence which allows mechanical activation of the Wnt receptor in contrast to static bound protein activation using bound Wnt 3A. We have also begun to explore the use of patented aptamer approaches for tagging which can target specific regions. These studies have considered how magnetic fields can be used for controlling neuronal fibre outgrowth in 2D and 3D models (Bongaeraet et al 2020, In J. Mol. Sci.) Part of the multidisciplinary nature of our project has involved the design of magnetic devices which enable remote control of MNPs applied to single cell, monolayer, 3D cultures, pre-clinical and clinical studies. In addition, we have been experimentally and mathematically modelling the use of magnetic fields to control delivery of our MNP tagged cells to the sites of repair with our collaborator, Professor Sarah Waters, Maths, Oxford ( Yeo et al 2021, J. Roy. Soc. Inter).
Part of the project has been directed towards developing a new dynamic drug screening platform for dynamic drug absorption assays which we plan to take to market for use by CROs and Pharma companies. The assay can align to monolayer 96/ 6/24 well screening platforms as well as organoid cultures and organ on a chip applications. Initially we have progressed with the ADME CACO2 cell absorption assay. We have developed a remote MNP assay, DYNASCREEN, which provides an 'add on' to an existed regulated assay for drug screening which is being translated to commercial market. Our efforts to define a clinically relevant protocol for first in man has progressed. We have gained understanding as to how we can track our MNP tagged cells using current mdical imaging modalities such as Magnetic Resonance Imaging or MRI. In this way, we can assess dosing of how many MNPS are required and MNP tagged cell survival. We followed the fate of our MNPs in an ovine model for short term evaluation histologically with Orthopaedic clinicians from Nottingham Univ ( Markides et al 2021, Cells) and longer term using MRI with Cambridge Univ (Kaggie et al 2020 Scientific Reports). We have found that our MNPs are biocompatible without deleterious side effects and that they enable cell tracking in short term and longer term studies. Our in vivo studies to determine the remote control of MNP tagged stem cells in rodent and ovine models have been delayed due to COVID. Recently, animal studies with our collaborator, Prof Manuela Gomez, 3Bs, Minho have started using a rodent tendon repair model to test our magnetic box design for mechano/magnetic activation of the Activin IIA receptor. We hope to commence our next phase of preclinical trials in the next phase of the project.
The remote dynamic MNP tagging of cells is a novel methodology with multiple applications across a wide interdisciplinary area. The impact has the potential to be far reaching and we are researching at the forefront of the field. In the first instance, we will move forward with a dynamic CACO2 absorption drug screening assay to license and commercialise. Our long term aim is to apply for ERC POC funding in 2022 to take this in vitro assay forward to commercialise.

In addition, our overarching aim by the end of the project is to have reached a stage where we can take our magnetic tagged approach to first in man using our clinic ready technology. Currently, we are progressing this through pre clinical small animal trials for 3 applications, spinal fusion and bone repair, tendon repair and immunotherapy which we aim to complete by the end of the project. In addition, we are working with clinical colleagues to identify challenges and opportunities for different clinical indications. The key development beyond the state of the art is to obtain data which we can talk to regulatory bodies to obtain approvals for a first in man trial.
Tendon overview