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Tubular Supramolecular Polymers: A new class of therapeutic polymers

Periodic Reporting for period 3 - TUSUPO (Tubular Supramolecular Polymers: A new class of therapeutic polymers)

Reporting period: 2018-07-01 to 2019-12-31

This research programme will establish a new class of materials and develop them into functional devices for biomedical applications. We will design tubular supramolecular polymers (supramolecular polymer brushes, SPBs), based on the self-assembly of cyclic peptide – polymer conjugates. The synergy between the cyclic peptide, which directs the formation of the SPBs and the polymer conjugate, which provides functionality, will open the route to a wealth of new functional structures. We will build on our initial work and expand our research to generate new synthetic routes for the ligation of polymers to peptides, develop new protocols for the characterisation of the materials, and establish the mechanism of supramolecular polymerisation.

This research programme will open new horizons in the fundamental understanding and production of supramolecular polymers. In particular, beyond the generation of new materials, the functionality of these systems may allow the development of supramolecular living polymers, a long-standing goal in polymer chemistry that is still elusive. The functionality and versatility of the SPBs obtained in this work open the route to a wealth of applications, and we will focus on one specific target: the fabrication of drug delivery vectors. We will exploit the unique combination of features presented by this new class of polymer therapeutics, such as multiple attachment points for one or more drug(s) / targeting ligands / markers, the ability to self-disassemble into smaller and easy-to-excrete components, and an elongated shape that enables diffusion and interaction with cells more efficiently than traditional globular delivery systems. We will study the pharmacology properties of the SPBs, including their stability, toxicity, mode of cell penetration and ability to deliver a single or a combination of bioactive agent(s) (in the case of concerted mechanisms).

The field of research described in this application is rapidly evolving and expanding. This research program will underpin advances in both bio– and nanotechnology, emerging fields in which it is crucial that Europe maintain research excellence to remain internationally competitive. The project will have significant impact on fundamental research and build research capacity in polymer science and biomaterials.

Europe is traditionally a strong research hub in the fields of supramolecular chemistry and living radical polymerisation. This latter field of research, in which Perrier is a significant contributor, has surged internationally over the last 15 years. It has become one of the most rapidly developing areas of chemistry and polymer science, and a key scientific subject that provides solution to a variety of contemporary issues, in domains as diverse as materials, medicine and environment. Indeed, the market for products made from this process is expected to reach $20 billion/year. This application will further strengthen Europe’s position as an international leader in this very important field. In addition, if successful in developing a living supramolecular polymerisation system, this research program will deliver a new class of materials, and expand the scope of supramolecular polymerisation.

The fundamental knowledge to be gained in the self-assembly of peptide / polymer conjugates will enhance our understanding of how such conjugates can be tailored for specific applications and greatly facilitate the introduction of novel polymer science into applications of new hybrid biomaterials, such as in drug-delivery, biosensors, antibiotics and in the broader medical sector. Beyond the biomedical application described in this proposal, the range of uses of these tubular materials expands to other fields such as microelectronics and catalysis. This research project will establish a near-universal route to the production of a wide range of nanotubes, and therefore place European research at the cutting edge of this rapidly developing field.

The program will provide significant training opportunities for postgraduate and postdoctoral researchers in a range of skills encompassing organic synthesis, polymer synthesis, compound characterisation and physical measurements (using techniques which are required for employment in Europe’s growing bio- and nanotechnology industry) and biology.
In this first period of the grant we have focused on the fabrication of our supramolecular nanostructures (WP1). We have established new synthetic routes for the synthesis of cyclic peptide / polymer conjugates (WP 1.1) by exploring different polymerisation technqiues, namely RAFT and poly(oxazoline)s polymerisation, different conjugation protocols, including isocyanate chemistry and starined alkyne – azide coupling (copper free click chemistry). We have also studied the self-assembly of the structures by neutron scattering and electron microscopy (WP1.2) and have started elucidating the mechanism of self-assembly.
We have established the stability in physiological conditions (WP2.1) and toxicity profiles (WP2.2) of a library of materials, based on peptide conjugated to PEG, Pox, PHPMA and also asymmetric systems based on poly(PEG) and PolyBuA). We started exploring the cell internalisation mechanism of these materials, and established that most enter cells through endocytosis (WP2.3). Early success in WP2.3 has enabled us to move forward with specific materials, and we have already tested the SPBs based on HPMA conjugates to deliver an anticancer drug based on Iridium into cancer cells. The work has led to a recent publication in Biomacromolecules.
- We have established an approach to tune the length of the nanotubes by using charged polymers. These findings were published in an article in ACS Macro Lett: Catrouillet, S.; Brendel, J.; Larnaudie, S.; Barlow, T.; Jolliffe, K.; Perrier, S. Tunable length of cyclic peptide-polymer conjugate self-assemblies in water, ACS Macro Lett., 2016, 5 (10), 1119–1123 DOI: 10.1021/acsmacrolett.6b00586

- We have also establish the fundamental understanding of polymer conjugates structure on their ability to be uptaken by cells: Moraes, J.; Peltier, R.; Gody, G.; Blum, M.; Recalcati, S.; Klok, H.-H.; Perrier, S. Influence of block versus random monomer distribution on the cellular uptake of hydrophilic copolymers, ACS Macro Lett., 2016, 5 (12), pp 1416–1420, DOI: 10.1021/acsmacrolett.6b00652

- We have shown the structures assemble in a dynamic process thus suggesting their ability to self-disassemble in site, to enable rapid clearance when used in vivo: Rho, J.Y.; Brendel, J.C.; MacFarlane, L.R.; Mansfield, E.D.H.; Peltier, R.; Rogers, S.; Hartlieb, M.; Perrier, S. Probing the Dynamic Nature of Self-Assembling Cyclic Peptide–Polymer Nanotubes in Solution and in Mammalian Cells, Adv. Funct. Mater. 2017, 1704569 DOI: 10.1002/adfm.201704569

- We have shown teh SPBs are effective drug delivery vectors for Iridium based anticancer drugs: Larnaudie, S.C.; Brendel, J.C.; Romero-Canelón, I; Sanchez-Cano, C; Catrouillet, S; Sanchis, J; Coverdale, J.P.C; Song, J; Habtemariam, A; Sadler, P.J; Jolliffe, K.A.; Perrier, S. Cyclic Peptide–Polymer Nanotubes as Efficient and Highly Potent Drug Delivery Systems for Organometallic Anticancer Complexes, Biomacromolecules, 2018, 19 (1), pp 239–247 DOI: 10.1021/acs.biomac.7b01491