Directed Molecular Recognition through Next-Generation Hybrid Molecular Imprinting

Lead Research Organisation: De Montfort University
Department Name: School of Pharmacy

Abstract

The increasing demand for highly effective molecular recognition for sensing and separations has led researchers to search for synthetic substitutes for enzymes and antibodies with emphasis on materials with potential to outperform their biological counterparts in terms of cost, performance, stability and flexibility.

Molecularly Imprinted Polymers (MIPs) are elegant biomimetics that incorporate binding sites bearing steric and chemical functionality complementary to a given target. They represent a generic, versatile, scalable, cost-effective approach to the creation of synthetic molecular receptors and have uses in separation sciences, purification, sensors and catalysis.

In "classical" molecular imprinting, small functional monomers are used to create the binding sites. While this method has proven generally effective, a relatively high level of heterogeneity in rebinding is still observed which lowers the average binding constant and leads to much-reduced selectivity. This "Achilles Heel" has prevented MIPs from fulfilling their potential, and has led to only their limited application in niche areas. A solution to the heterogeneity problem would unleash the transformational potential of MIPs within the multi-billion-dollar diagnostic and analytical markets.

This heterogeneity arises because of the nature of the imprinting process, where functionality is introduced to the target in a random fashion, leaving no scope for the correction of errors that arise during the subsequent formation of the binding pocket in the polymeric matrix. We will address these issues by developing a novel two-step process towards the formation of imprinted polymeric nanoparticles of exceptionally high affinity and selectivity.

It will exploit a method developed by Fulton that introduces error-correction into the templating process, and a separate method developed by Turner to then fix the binding site within a rigid polymeric nanoparticle "scaffold". This hybridisation will deliver optimized binding sites "locked" into a more rigid structure - creating new synthetic biomimetics with reduced heterogeneity, while incorporating biocompatibility through component selection. These hybrid MIPs can truly challenge and replace their biological counterparts - creating significant impact in the field of molecular recognition and smart materials.

Two targets have been selected to drive the development of these chemistries. These differ in size and application: a protein and a bioactive (antibiotic) drug, but both targets have significant commercial potential, in clinical and environmental settings. Monitoring of antibiotics is key for understanding required effective dosage, but also for studying leakage into the environment from illegal use or overuse, which leads to numerous other serious issues such as bacterial resistance. The protein target offers a demonstration of the MIP nanoparticle ability to disrupt ligand-receptor binding, where the MIP itself can act with inhibitory "drug-like" properties. Through these models we aim to demonstrate the validity and potential of the proposed novel MIP systems.

The project will use facilities at De Montfort University and Newcastle University to develop the new approach. With an experienced project team this interdisciplinary proposal, which covers organic, polymer and analytical chemistry, will take a new approach to MIP synthesis, building on existing proof-of-concept ideas, and develop them further, translating the novel synthetic processes described here into viable options for artificial molecular recognition which can be exploited in several ways. Here we will develop the synthetic methods to be scalable through clear step processes, with automation in mind.

MIP Diagnostics are a UK company based in Bedford who will support the project by their detailed knowledge of MIP design, implementation, and application, with sight towards commercialisation of the technology.

Publications

10 25 50
 
Description This grant was transferred from DMU to Sheffield effective 28th Feb 2023. Information for this has been inputted on the submission for EP/V046594/2
Exploitation Route See above
Sectors Chemicals

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

 
Description This grant was transferred from DMU to Sheffield effective 28th Feb 2023. Information for this has been inputted on the submission for EP/V046594/2
First Year Of Impact 2023
Sector Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description New Synthetic Chaperones to Enhance Protein Activity
Amount £1,301,462 (GBP)
Funding ID EP/V056085/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 05/2022 
End 12/2023
 
Description Towards a `toothbrush sensor for passive biomarker monitoring for oral cancer
Amount £200,000 (GBP)
Funding ID Sens or Pass 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2023 
End 11/2024
 
Description Academic LInk with University of Birmingham 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Working with Prof James Tucker, Prof Paula Mendes, Prof Mike Hannon, Dr Sam Jones Engagement with DNA synthesis for this proposal. Open discussions. Provision of target sequences and material for DNA synthesis. Tucker, Hannon and I were involved with a CDT bid that was taken to 2nd stage but ultimately unsuccessful. I am now Co-supervising a PhD student with Tucker Mendes, Jones and I are developing a proposal that step on from this work.
Collaborator Contribution Tucker/Mendes have provided with synthetic aptamers under our guidance and continue to do so, using instrumentation they have. Hannon/ Tucker were leading the CDT bid.
Impact 3 paper accepted. A 4th is under review (Tucker / Mendes) New joint grant application in process (mendes/Jones) New Joint grant application in process (Hannon)
Start Year 2020
 
Description Academic link with University of Strathclyde 
Organisation University of Strathclyde
Country United Kingdom 
Sector Academic/University 
PI Contribution New Activity (collaboration with Prof Damion Corrigan)
Collaborator Contribution They have been testing our aptaMIPs for performance on new sensor platform and for biological activity. We have passed aptaMIPs materials across which are been tested for activity via an electrochemical method.
Impact Preliminary data for grant submission achieved. Proposal prepared and sent to EPSRC
Start Year 2020
 
Description Aptamer Group 
Organisation Aptamer Group
Country United Kingdom 
Sector Private 
PI Contribution From the grant linked this has led to a new partnership in progress with The Aptamer group (York) for support of grant submission. This grant has provided an active collaboration and we are moving forward with discussions on further applications. We are working on development of hybrid materials using materials from the company. Several publications are in draft where we are improving aptamers through this method. A formal NDA/MTA is in place Aptamer group have supported with in-kind support a fellowship bid (EPSRC Dec 2020)
Collaborator Contribution AG are providing sequences for specific targets that we are using for basing the research on. Support for successful EPSRC Fellowship bid. (Dec 2020). engaging in patent discussions and applications of developed materials. Papers published with Aptamer Group as collaborative team
Impact https://pubs.rsc.org/en/content/articlelanding/2021/py/d1py00607j 2 further publications are in submission
Start Year 2015
 
Description Collaboration with Baker - Southampton Chemistry 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution We are exploring synthetic methods to make new phosphonamidites. My team are leading on this synthetically
Collaborator Contribution Yssy Baker is providing knowhow
Impact New compounds for application into polymer synthesis
Start Year 2022
 
Description Collaboration with Malmo University 
Organisation Malmö University
Country Sweden 
Sector Academic/University 
PI Contribution PDRA visited the Malmo group, gave a talk and engaged in a 2 week placement research trip. He provided technical assistance, data collection and continued work at Sheffield with this.
Collaborator Contribution Provision of materials for testing, access to an ITC. Preparation of three manuscripts
Impact PDRA visited the Malmo group, gave a talk and engaged in a 2 week placement research trip. Three manuscripts are in publication cycle (2 research and 1 review)
Start Year 2023
 
Description Collaboration with U Delaware 
Organisation University of Delaware
Country United States 
Sector Academic/University 
PI Contribution After visit and collaborative agreement signed and research started. Sheffield preparing materials to send to Delaware. Joint proposal written
Collaborator Contribution collaborative agreement signed and research started. Delaware planning on sending researcher to UK. Joint proposal written
Impact Joint proposal sent to NSF-EPSRC. NT supporting a further NSF bid as partner/mentor.
Start Year 2023
 
Description Collaborative Partnership - MIP Discovery 
Organisation MIP Diagnostics
Country United Kingdom 
Sector Private 
PI Contribution While at DMU a collaborative agreement was in place with MIP Discovery based on a long-term collaboration and prior NDA. Since moving to Sheffield, a new agreement is currently under progress to be signed. As such there is a hiatus in collaborative work which is expected to resume in Q3 2025. My team bring knowhow and access to certain instrumentation that is unavailable to the SME.
Collaborator Contribution Support knowhow/ facilities on grants. We have also been discussing potential joint projects.
Impact Joint research currently being undertaken. this has led to two joint publications that are under review.
Start Year 2022
 
Description Nanoparticles 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution I have strong links with the research group of Professor Piletsky, prior of Cranfield, but now Leicester Chemistry. We have regular research meetings to discuss current projects and future ideas. We also share equipment and methods.
Collaborator Contribution Discussions on nanoparticle production and use of specialized equipment based at Leicester. Support on successful EPSRC submission (letter of support as project partner) Joint submission of papers. Joint submission of grants (CRUK - EPSRC)
Impact Several papers as found in Publications. Latest of which was published in 2022 Grant submissions
 
Description Research Collaboration - Bhavik Patel 
Organisation University of Brighton
Country United Kingdom 
Sector Academic/University 
PI Contribution Preparation of materials for electrochemical detection of disease states (biomarkers). Submission of two proposals (awaiting results) Joint supervision of PhD student - linked to grants Research leading to manuscript submission
Collaborator Contribution Submission of two proposals (awaiting results) Joint supervision of PhD student - linked to grants Electrochemical experiment leading to publication submission
Impact One submission of manuscript (under review) 2 joint proposals which were not successful. a third has been prepared for submission to BBSRC
Start Year 2021
 
Description Research Collaboration with Booth, UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Based on my expertise from the following two grants and my move to Uni of Sheffield, i was part of the team who led a CDT submission. This partnership was joint across three universities. Engaged with stakeholders, prepared writing . From this a new collaboration with Mike Booth (UCL Chemistry) has started
Collaborator Contribution Booth brings novel modification chemistry to enable aptamip preparation
Impact CDT submission. New research collaboration
Start Year 2022
 
Description Sensor Collaboration - Peeters 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Prof Marloes Peeters (Engineering Manchester ) on sensor design. We have provided access to instrumentation and knowhow for polymer development. We have provided data on their materials which has led to 2 publication submissions. I have also engaged with proposal writing with Prof Peeters.
Collaborator Contribution Two projects have been focus of the interaction. Both targeting protein templates. We have provided material performance analysis using EPSRC supported instrumentation. Data provided has gone into two manuscripts
Impact 2 Paper manuscript in submission process. Archived in 2023/4. awaiting peer review. A proposal is under preparation
Start Year 2020
 
Description Sensor Design Partnership 
Organisation Albert Ludwig University of Freiburg
Country Germany 
Sector Academic/University 
PI Contribution PDRA visited Freiburg, prepared materials and developed a new sesnor platform with Dr Dincer
Collaborator Contribution Dincer's team ran samples, engaged in design and hosted PDRA to learn about new sensor platform
Impact Data was generated and a paper is under submission. Dincer will visit UK for a talk and potentially a PDRA/ PhD Student will visit to learn techniques
Start Year 2023
 
Description Interview by Guardian Newspaper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed for article on Aptamer technology - supporting Apatmer Group profile article in the guardian
Year(s) Of Engagement Activity 2022
URL https://www.theguardian.com/business/2022/dec/25/aptamer-york-biotech-cancer-treatments
 
Description Invited Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited Talk to present research at:
University of Sheffield

This led to being approached by University for Job Offer
Year(s) Of Engagement Activity 2022
 
Description Invited Talk - Research trip (University of Delaware) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk and research visit to develop collaboration.
Collaborative agreement signed and active research ongoing.
Grant submission to NSF-EPSRC 1st stage submitted.
Year(s) Of Engagement Activity 2023
 
Description Invited lectures - Conferences (Biosensors 2023, Bordeaux 2023, Pittcon 2024, Macro 2024, Oxford Aptamer 2024) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Multiple; invited lectures at conferences.
Year(s) Of Engagement Activity 2023,2024
 
Description Lecture Tour (Sweden) - Malmo, Lund, Kalmar, Stockholm 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited tour to visit 4 Swedish universities to build collaboration towards industrial engagement (Pharmista) and ERC proposals
Year(s) Of Engagement Activity 2024
 
Description Multiple Invited Lectures at University (Lincoln, UCLan, Strathclyde, Newcastle) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited Lectures at multiple universities
Year(s) Of Engagement Activity 2023,2024