Iterative Synthesis with Organic Solvent Nanofiltration for Precision Manufacture of High Value Sequence-Controlled Polymers (ItSyN)

Lead Research Organisation: Imperial College London
Department Name: Department of Chemical Engineering

Abstract

This project will develop a new manufacturing process for making high value sequence-controlled polymers in a precise way. Sequence-controlled polymers include (bio)polymers such as DNA, RNA (together, "oligos") and peptides. They also include synthetic polymers for which precise control of polymer length or monomer order is necessary. These polymers are in demand by the pharmaceutical industry, where they are used as biologically active materials ("drugs"), and as parts of molecular assemblies that are used to deliver and protect drugs; and have emerging non-biological uses.
Nature makes sequence-controlled polymers such as oligos or peptides by sequentially adding different monomers in a prescribed sequence. The exact order of that these monomers are added is absolutely crucial to the function of the final polymer. These same polymers are made by industrial chemistry in a way that apes Nature, through a sequence of monomer additions (we call this iterative synthesis), and a great deal of care is taken to remove the residues of unreacted monomer before the next cycle, to avoid errors in the sequence.
A very effective way of doing this is to attach the growing polymer to a solid support phase, which is washed with clean solvents to remove the residues, before the next monomer is added. When polymer growth is complete, it is cleaved from the solid support. However this process is expensive, because more monomer must be used to ensure the reaction reaches completion on the solid support, and because the supports themselves are expensive. For synthetic polymers where we want to control the molecular weight exactly, for example poly(ethylene glycols) (PEGs), which are widely used to stabilise drugs and make them last longer in the body, we could add the same monomer over and over until we reach a desired chain length, and then cleave the final polymer from the support. This is not done at present, because the cost of solid supported iterative synthesis is too high and/or the chemistry is not available.
There are other problems with solid supported synthesis. The solid supports are variable, and hard to make in a precisely repeatable way; in fact small differences in the supports can lead to quite big changes in the reactions used to link the monomers onto the growing polymer. Also, it is very hard to carry out analyses on the reaction mixture to tell whether the reactions are proceeding correctly, because the molecules of interest are inside the pores of a support material.
Recent research at Imperial College has developed Organic Solvent Nanofiltration (OSN), using membranes that are stable in solvents, and able to separate small molecules from large molecules. Our key innovation is to use these membranes at each stage of sequence-controlled polymer synthesis to separate the growing polymer from the unreacted monomers. This process will be carried out in the liquid phase and analysis would be far more straightforward; and the reactions to grow the polymer will be faster and more efficient, and use less monomer. Further, if two or more of the growing polymers are connected to a hub molecule to create a homostar complex, this will make the solute to be retained by the membrane larger and promotes a more efficient separation. We propose this Iterative Synthesis with OSN, or ItSyN for short, as a new approach to precisely manufacture sequence-controlled polymers.
The multidisciplinary team of chemical engineers and chemists who will work on the ItSyN project will develop the process chemistry to make the purification better; construct Lab Plant synthesisers so that the process can be automated, select solvents and explore solvent recovery, and use quality by design to make the process more efficient. If we are successful, the project will result in a new technology for sequence-controlled polymer manufacture, and will lead to more precise polymers being available for applications in healthcare and beyond.

Planned Impact

The economic benefits of the research proposed are the business around manufacturing and selling the high value sequence-controlled polymers that the new technology produces, and the economic and societal benefits of the applications of these materials.

The separations research group at Imperial College has a strong demonstrated record in the commercialisation of membranes derived from its research. Evonik MET, based in West London, is the only dedicated manufacturing facility for organic solvent nanofiltration membranes in the world. The fundamental processes they use were developed at Imperial College with EPSRC research funding. Therefore the group has experience in the development of manufacturing processes and commercialisation of research.

If the proposal is successful, it will generate a revolutionary new technology for sequence-controlled polymer synthesis, with high potential in pharmaceutical manufacturing and beyond. The most immediate likely interest in this technology and the materials it produces will come from pharmaceutical manufacturers working with macro drugs such as oligos and peptides, and companies actively manufacturing and supplying PEG molecules to the pharmaceutical industry. These companies may license the ItSyN technology for use in their own manufacturing sites. Since it is based on liquid phase synthesis, it should be easy to retrofit a membrane separation unit to an existing reaction vessel to create a viable process. Alternatively, there may be the opportunity for creation of new companies to develop and market either or both of the ItSynN technology ore the products that it is used to manufacture, where this makes more economic sense, or where risk hinders larger companies from getting involved. In either case, economic benefits will derive, including investment in capital equipment and creation of skilled jobs, from the manufacture of these sequence-controlled precision polymers, and from installation of suitable assets for the manufacturing process.

The second economic and societal impact will come through the application of high value sequence-controlled polymers to healthcare and other sectors. We envisage that they will be used as biologically active agents (oligos and peptides), or in drug delivery and nanotechnology (PEGs, and other classes of synthetic polymers). Information on prices of oligos and peptides is hard to find, but one can obtain information on the value of PEG monodispersity from catalogue prices. Current technology appears to be limited to monodisperse PEGs of around 2,000 g mol-1. Where as monodisperse PEG1000 is sold for around US$500 g-1, monodisperse PEG2000 sells for around $2,000 g-1.The ItSyN approach can in principle extend monodisperse PEGs to MW > 5,000 g mol-1; so it is clear from these figures that this would represent significant value for the material, and prices well over $2,000 g-1.

PEG is simply the first sequence-controlled synthetic polymer that we will manufacture using ItSyN technology. Scientists are already suggesting multiple uses for other classes of sequence-controlled synthetic polymers, and so their manufacture could be developed as a specialist high value sector of the UK chemical economy. This would lead to a major impact on jobs and capital investment across a broad part of the UK pharma / chemical sector.

These economic benefits have parallel social benefits. The installation of manufacturing processes, and the manufacture of high value polymers, creates high level and knowledge intensive employment, and improves the national accounts through exports achieved. The development of a technology to make sequence-controlled polymers more accessible will in all likelihood also lead to high societal benefits due to the advances in healthcare technology that it underpins.
 
Description POLYMERS COMPRISE A SERIES OF MONOMERS LINKED ONE AFTER THE OTHER IN A CHAIN. IT IS VERY DIFFICULT TO CONTROL THE SEQUENCE OF MONOMERS IN SYNTHETIC POLYMERS. WE HAVE DEVELOPED A NEW WAY OF SOLVING THIS PROBLEM AND CAN MAKE POLYMERS WITH DEFINED MONOMER SEQUENCES.
Exploitation Route We have started a new company, EXACTYMER (as in exact polymers) to commercialise the new types of polymer we can now produce.
Sectors Chemicals,Environment,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description We have used the findings to apply for patents on the methods we have devloped for making polymers with exquisitely accurately controlled polymer sequences.
First Year Of Impact 2016
Sector Chemicals,Energy,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
 
Description EXACTYMER
Amount € 2,499,000 (EUR)
Funding ID 786398 
Organisation European Commission H2020 
Sector Public
Country Belgium
Start 07/2018 
End 06/2022
 
Description GSK Engineered Medicines Laboratory
Amount £1,400,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 01/2016 
 
Description Synthetic Biopharmaceuticals (Millipore)
Amount £897 (GBP)
Organisation Merck 
Department MilliporeSigma
Sector Private
Country United States
Start 03/2017 
 
Title New defined monomer sequence polymers process 
Description New process for preparing defined monomer sequence polymers, in which a backbone portion of the polymer is first prepared by performing one or more sequential monomeric coupling reactions with intervening membrane diafiltration purification/isolation steps, followed by a step of decorating the backbone portion with one or more side chains at predetermined positions along its length. 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? No  
Impact The process represents an improvement on prior art techniques, which impose limitations on the size of the side chains that may be present. 
 
Title Defined Monomer Sequence polymers 
Description Processes of preparing defined monomer sequence polymers are disclosed, in which a backbone portion of the polymer is first prepared by performing one or more sequential monomeric coupling reactions with intervening membrane diafiltration purification/isolation steps, followed by a step of decorating the backbone portion with one or more side chains at predetermined positions along its length. The process represents an improvement on prior art techniques, which impose limitations on the size of the side chains that may be present. Defined monomer sequence polymers that are obtainable by the processes are also disclosed. New process for defined monomer sequence polymers. 
IP Reference US20180244845 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Leading to PCT/GB2016/052801
 
Title Process 
Description New interative synthesis process. 
IP Reference GB1609873.3 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Not known
 
Description Imperial Festival 2016 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Imperial Festival provides an important route for staff and students across College to engage with priority audiences, including funders, alumni and policy makers, as well as the general public. It is also a significant platform to put our public engagement skills into practice. The achievements of our previous Festivals have been heavily dependent on the significant, high-quality contributions from colleagues across College, for which we continue to be very grateful. In 2015 the event attracted over 15,000 people.

The team demonstrated - to the wider public - the superiority of membrane technology by running two electricity generating bicycles, one connected to a membrane unit and one to an evaporation unit, and comparing the amount of water priced by both.
Over 350 visitors visited this specific demonstration.
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.imperial.ac.uk/be-inspired/festival/