Enzyme-responsive Microgels

Dynamic biological processes are tightly regulated by the catalytic activity of enzymes. The ability to direct, or otherwise interfere with, these processes holds promise for next generation medical interventions. It is in this context that we aim to develop new microgel particles that convert biocatalytic action of enzymes into mechanical responses. Our previous work has demonstrated that this is possible, in principle, and we now wish to explore this area further and address four challenges that will bring us a step closer to biomedical applications. They are: (i) establishing enzyme-responsive microgel particles that are two orders in magnitude smaller in size compared to our previously reported hydrogel beads and should have much faster response times; (ii) establishing enzyme-responsive microgel dispersions that display controlled mechanical response in the form of reversible fluid-to-gel transitions; (iii) establishing fully reversible systems that respond to combinations of enzymes (kinase/phosphatase); (iv) demonstrating, for the first time, the possibility of directing cellular responses using these enzyme-responsive microgel particles. Microgels are sub-micrometer sized polymer colloid particles that expand (swell) in a good solvent or when the particle charge increases. We will functionalise these microgel particles with peptide actuators that are recognised and cleaved by enzymes, thereby triggering a departure from the charge balance in the particles Uniquely, these enzyme-responsive microgels will operate locally, under aqueous conditions at constant pH and temperature which provides very significant advantages over existing stimuli-responsive materials in the context of biomedical applications. This collaborative project will provide two PhD students with exciting, multi-disciplinary projects in top class research environments. A successful outcome will open up new avenues of bioresponsive (nano) technologies for on demand drug delivery and minimally-invasive soft tissue repair.

This proposal seeks to establish microgel dispersions that can form macroscopic gels in the presence of specific enzymes. The gels (and microgel particles) should also show enzyme-triggered release of solutes (e.g., drugs). These enzyme-responsive microgels may have longer term application as biomaterials for drug delivery and regenerative medicine. If this project is successful, they could enable advances in minimally invasive treatments for a range of conditions that currently require invasive surgical procedures; including metastatic disease and intervertebal disc repair. Because of this the beneficiaries from a successful outcome of this research will be patients, the NHS and UK pharmaceuticals and biomedical companies. Microgels have a number of factors that favour their potential use in the body for delivery. The dispersions have good colloidal stability and the particles are highly porous. Approaches that enable triggering of their swelling and collapse by direct interaction with enzymes could enable targeted delivery in the body. The present proposal aims to provide a range of enzyme-responsive microgels that could release drugs in the presence of enzymes. The dispersions will also form macroscopic gels when triggered by specific enzymes, and provide a mechanical response under constant solution conditions. One of the enzymes we will use (metalloproteinase, MMP) is involved in metastatic disease. A successful outcome could enable enzyme-responsive microgels to be used in non-surgical methods (injections) for treating metastatic disease. The triggered gel formation of concentrated enzyme-responsive dispersions could also be used in the longer term as an injectable cell delivery system and provide structural support for regenerative medicine applications. For both of the possible applications discussed above (drug delivery and regenerative medicine) patients would benefit from reduced durations in hospital and faster recovery times. Clinicians would benefit from a reduction in surgical procedures. This would also reduce cost for the NHS. UK pharmaceutical companies could beneift from delivering existing disease control agents (cytotoxic drugs etc.) more effectively within the body. An injectable dispersion that behaved as a load bearing implant and tissue scaffold could provide benefit for UK medical device companies interested in lower back and knee treatment strategies (e.g., Smith and Nephew and Depuy). For these areas there continues to be a pressing need toward developing minimally-invasive technologies. The beneficiaries listed above could only benefit directly from this research if the results were translated into new medical devices. The key first step for this is patent protection. Once obtained, and supported by high impact peer-reviewed journal articles, the PIs will actively pursue licencing or spin-out opportunities with companies that have mutual development interests in this area. The PIs have a strong track record of collaborating with UK industry. They both have networks of UK pharmaceutical and medical device companies that will be used to explore collaborative development of the new drug delivery and regenerative medicine platforms that should emerge from this project. The dissemination of the results in the wider media will occur through joint university press releases (after peer-reviewed publication in high impact journals). The applicants have found this to be an excellent means for attracting interest from UK and international companies.