Integrated radiomaterials chemistry for simultaneous multi-component tracking of nanomedicines in biological matrices

Lead Research Organisation: University of Liverpool
Department Name: Chemistry

Abstract

The current global clinical use of nanomedicines benefits patients daily and has considerable market value; global estimates = US$75bn ('11), predicted to be $US160bn by 2015. The decision to develop new nanomedicines balances the needs of patients (are conventional medicinal approaches failing or unable to help?), type of disease/threat to health (is the disease potentially terminal?) and dosing regimes (oral or injectable administration; chronic or acute dosing?). Many therapies require long-term dosing to maintain health over prolonged periods. For example, >33 m people (incl. children) are currently living with HIV/AIDS and the optimised daily dosing (over decades) of highly active antiretroviral therapies helps to prevent progression of HIV to AIDS, and allows a life for many patients that is as close to normal as possible. In contrast, due to the acute nature of cancer (imminent threat to life) short-term interventions, including highly toxic therapies, are required for rapid cure. Cancer research has seen many nanomedicine benefits including the targeting of poorly soluble drugs to solid tumours. Similar contrasts are seen in antiepileptic and cholesterol-lowering therapies (long term health maintenance) versus systemic fungal infections or acute respiratory distress (immediate cure required). Most nanomedicines are enabled by polymer science ranging from polymer-bound drugs through to polymers stabilising drug nanoparticles or forming nanosized drug encapsulants. Nanomedicine expansion to long-term dosage forms and chronic diseases will increase and the behaviour/fate of polymeric materials in the body must be studied to generate safety and toxicology information, to increase the speed-to-clinic (ie patient benefits) and enable decision-making of pharmaceutical companies and regulatory bodies.

Currently, the study of low concentrations of polymeric materials in complex environments is extremely difficult. The use of radioactive isotopes for biomedical research is well established with drugs labelled to allow rapid quantification and tracing, however, very few reports describe radiolabelled polymeric components of candidate nanomedicines and facilities for polymer radiochemistry have largely disappeared in UK Universities. The University of Liverpool has created facilities to enable radiomaterials chemistry, providing new academic UK skills and enabling pharmacological studies of polymers used in nanomedicine strategies and other applications. This 3 year programme aims to conduct the first nanomedicine studies that simultaneously monitor drug AND enabling polymeric materials, whilst exploring the synthesis of radiolabelled polymers with the most up-to-date techniques. This will place UK nanomedicine research at the forefront of understanding and provide an engagement platform for global pharmaceutical companies and regulatory bodies as the huge potential for nanomedicine is realised for patients of all ages across multiple disease areas.

Planned Impact

The key focus of the proposal addresses the lack of radiomaterial studies within UK academia and underpins nanomedicine research aimed at improving delivery of new patient benefits.

Whilst new material concepts are developed in global research programmes to enhance drug delivery and action, these materials require BOTH safety and performance studies to ensure they are appropriate and safe for use in new medicines. We aim to engage researchers in the utilisation of radiomaterials approaches to demonstrate the potential patient benefits of their prospective drug delivery methods. Within the field of nanomaterials and nanomedicine, a series of ongoing societal and governmental debates continue to discuss the safety and application of nanoscale technologies. Uniquely, this programme aims to introduce new techniques to facilitate this debate (and future scientific developments) whilst developing a Radiomaterials Laboratory within UK academia that can continue to provide benefits, across multiple scientific activities, for many years after the term of the funding. We will also seek to engage directly with regulatory authorities with clear data that may impact future policies.

The proposal is a collaboration across the sciences of chemistry, nanotechnology, pharmacology and toxicology. It involves a multi-national company keen to invest in the provision of UK academic radiomaterials capabilities, through the recognition that a) the UK is severely lacking in these skills, and b) considerable benefits for universities, industry and the UK economy may be gained by taking a leading position within this science area. This skills gap has been recognised by EPSRC/MRC working groups, citing the need for "multidisciplinary collaboration", highlighting a "shortages of research leaders...in radiochemistry and a need to establish more Principal Investigator level researchers" and stating "radiochemistry research that can develop new chemistry and probes is key".

We aim to advance the understanding of nanomedicines and considerably improve the potential for further development into products and the delivery of future improved patient outcomes. It is hoped that, within 10 years of the start date, the outputs of this research will provide key considerations for global research studies and regulatory bodies when de-risking new nanomedicine candidates.

The beneficiaries of the research therefore are diverse and include scientists, clinicians, general public, patients and industry. It is expected that non-medical disciplines may also benefit strongly (eg engineering/ nanotechnology/data storage/coatings/environmental studies/sustainability) and ongoing research programmes may be enhanced by new understanding. Within our targeted field of nanomedicine, we aim to interact internationally to complement nanomedicine activities focussed on drug delivery benefits and increase the potential for therapy options that will be commercially protected and attractive for industrial exploitation. With the conversion of therapy options into medicines, the potential impact will widen to patients over coming years.

It is important to note that NO NEW DRUGS are being developed but rather the performance and safety of proposed new drug delivery strategies is being studied. If sufficient data can be produced to understand behaviour and direct future research towards fruitful studies, the production of platforms capable of generating benefits across multiple diseases will lead current drugs to better safety profiles and improved performance with the goal of cheaper, more targeted and more appropriate dosing to patients globally.

Publications

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Cauldbeck H (2016) Controlling drug release from non-aqueous environments: Moderating delivery from ocular silicone oil drug reservoirs to combat proliferative vitreoretinopathy. in Journal of controlled release : official journal of the Controlled Release Society

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Cauldbeck H (2018) Modulated release from implantable ocular silicone oil tamponade drug reservoirs. in Journal of polymer science. Part A, Polymer chemistry

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Hern, F Xanthate Mediated Sequential Thiol-Acrylate Michael Addition in 8th ECNP International Conference on Nanostructured Polymers and Nanocomposites

 
Description Polymer excipients used in nanomedicine have the potential to accumulate within the body and "insoluble" ingredients that are utilised to form nanoparticles do not necessarily accumulate at the same sites as the "encapsulated" drug compounds
Exploitation Route We are yet to publish these findings but we will be discussing these at length with the EU Nanocharacterisation Laboratory
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The approaches used within the grant have been utilised to select candidate nanomedicines for progression through to human clinical evaluation
First Year Of Impact 2016
Sector Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description Membership of Innovate UK Emerging Technologies and Industries Steering Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description CRUK Multidisciplinary award
Amount £1,054,422 (GBP)
Funding ID 21094 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description USAID PEPFAR ART Simplification
Amount $5,000,000 (USD)
Funding ID AID-OAA-A-15-00069 
Organisation United States Agency for International Development 
Sector Public
Country United States
Start 10/2015 
End 09/2020
 
Title Chemical composition comprising nanoparticles of atovaquone and injectable formulation of atovaquone nanoparticles 
Description A solid compn. comprising nanoparticles of atovaquone dispersed within one or more carrier materials, wherein the atovaquone is present in an amt. of at least 10 wt%. Also described is an i.m.- or s.c.-injectable formulation of nanoparticles of atovaquone. 
IP Reference WO2017216564 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact First prophylactic injection demonstration for malaria
 
Title Mucoadhesive emulsions using branched polymer emulsifiers 
Description The present invention relates to a branched amphiphilic polymer, suitable for stabilizing an emulsion, comprising a plurality of polymer chains comprising hydrophobic chain ends; a plurality of polymer chains comprising functional chain ends capable of assocg. to a biol. substrate; and a plurality of branching units. The present invention also relates to pharmaceutical compns. contg. said branched amphiphilic polymers, their methods of use, and methods for their prepn. 
IP Reference WO2018029462 
Protection Patent application published
Year Protection Granted 2018
Licensed Commercial In Confidence
Impact Generation of Innovate UK funding and commercial evaluation
 
Title OPHTHALMIC COMPOSITIONS 
Description A composition comprises: a base oil; an additive comprising a copolymer comprising hydrophobic and hydrophilic units; and a drug. The copolymer may for example have a comb structure in which the hydrophobic units and hydrophilic units are pendant chains on a backbone of the copolymer. The hydrophobic units and hydrophilic units may for example comprise polydimethylsiloxane moieties and ethylene glycol residues respectively. The composition may for example be used as a tamponade or as a component for a tamponade administered to the eye. The invention is useful for solubilising and/or releasing drugs. 
IP Reference WO2018029476 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact Engagement with industry including interactions in further EPSRC HIPS funding
 
Title OPHTHALMIC COMPOSITIONS 
Description A composition comprises: a base oil; an additive; and a drug. The additive has segments which are conjugated, e.g. covalently linked, together. A first segment facilitates solubility in the base oil, whereas a second segment facilitates drug solubility and/or modifies drug release or other behaviour. The first segment may for example comprise a poly(dimethylsiloxane) - containing moiety. The second segment may for example resemble a drug molecule. The composition may for example be used as a tamponade or as a component for a tamponade administered to the eye. 
IP Reference WO2018029477 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact Engagement with industry including support for further EPSRC HIPS funding
 
Title Oil-in-water nanoemulsion, method for producing nanoemulsion and pharmaceutical composition 
Description An oil-in-water emulsion comprises an emulsifier which is a non-gelled branched polymer (e.g., a branched vinyl polymer), wherein the ends of at least some of the chains of the polymer terminate in an alkyl chain of = 5 carbon atoms, and wherein the oil-in-water emulsion takes the form of particles having a z-av. diam. of = 1000 nm. This is useful in facilitating the carrying of hydrophobic materials within aq. systems to enhance oral drug delivery. 
IP Reference WO2016124925 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Innovate UK funding for mucoadhesive emulsions and further patents
 
Title Ophthalmic compositions 
Description A compn. comprises: a base oil; an additive comprising a copolymer comprising hydrophobic and hydrophilic units; and a drug. The copolymer may for example have a comb structure in which the hydrophobic units and hydrophilic units are pendant chains on a backbone of the copolymer. The hydrophobic units and hydrophilic units may for example comprise polydimethylsiloxane moieties and ethylene glycol residues resp. The compn. may for example be used as a tamponade or as a component for a tamponade administered to the eye. The invention is useful for solubilising and/or releasing drugs. 
IP Reference WO2018029476 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact Radio techniques adopted have generated very accurate drug solubility data that was not previously available
 
Title Ophthalmic compositions 
Description A compn. comprises: a base oil; an additive; and a drug. The additive has segments which are conjugated, e.g. covalently linked, together. A first segment facilitates soly. in the base oil, whereas a second segment facilitates drug soly. and/or modifies drug release or other behavior. The first segment may for example comprise a poly(dimethylsiloxane) - contg. moiety. The second segment may for example resemble a drug mol. The compn. may for example be used as a tamponade or as a component for a tamponade administered to the eye. 
IP Reference WO2018029477 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact The research is being evaluated for clinical application. Also, the methodology utilised here has generated more accurate data for drug solubility than previously available
 
Description Colorectal Therapies Healthcare Technologies Co-operative Workshop Nanoparticle-Enhanced Radiotherapy, UCL, London 27th October 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Dissemination and discussion of optimal approaches that may be taken for therapy options for colorectal cancer
Year(s) Of Engagement Activity 2017
 
Description Industrial engagement in ongoing research activities 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Solid drug nanoparticle technology evaluation for industrial uptake
Year(s) Of Engagement Activity 2018,2019
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The international Pint of Science public engagement science festival aiming to communicate contemporary scientific developments to the general public in an interesting, engaging and approachable way by bringing scientists to the pub and other accessible places.
Year(s) Of Engagement Activity 2017
URL https://news.liverpool.ac.uk/2017/04/03/drink-think-pint-science-festival-coming-liverpool/
 
Description Princes Teaching Institute CPD 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact CPD for teachers. Presentation designed to update teachers with up to date information to allow teaching knowledge in Nanomedicine
Year(s) Of Engagement Activity 2014
 
Description Schools Outreach activity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Vardean College/RSC Sixth former science meeting. Engagement with 6th formers to explain current progress in Nanomedicine
Year(s) Of Engagement Activity 2016
 
Description University of Liverpool Open House 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public engagement activity to engage public with UoL research and Nanomedicine
Year(s) Of Engagement Activity 2018