Nanotubes from polymer conjugated cyclic peptides as a drug carrier for cancer therapy
Preparatory and Physical Chemistry of Polymers
Final Report Abstract
Cyclic peptides consisting of an even number of amino acids with an alternating chirality are a unique material as they form nanotubes by hydrogen bonding. Due to their inherent membrane activity these systems were utilized for antimicrobial applications. However, a major drawback in this regard was always the lack of selectivity between host-cells and pathogen resulting in diminished biocompatibility. A potential solution for this issue is the attachment of polymers to the periphery of the nanotubes, shielding them from unspecific interactions. To generate materials able to increase their membrane activity on demand, a cleavable connection between nanotube and polymer can be used to induce detachment of the macromolecule by a predefined stimulus, possibly associated with the presence of pathogenic bacteria. Within this project stimuli responsive cyclic peptide nanotube-polymer conjugates were developed. Using a reduction sensitive connection, Poly(2-ethyl-2-oxazoline) of various length were connected to cyclic peptides. Resulting conjugates were analysed by various methods including light and neutron scattering and found to self-assemble into nanotubes. The molecular weight of the polymer had an influence on the length of the formed supramolecular polymer. More importantly, it was shown that the polymers could be cleaved under reductive conditions leading to the aggregation and, ultimately, to precipitation of the nanotube. Polymer length had also an impact on the kinetics regarding the cleaving process with shorter polymers leading to shorter response times. In addition, using artificial membrane models, the effect on this material on the integrity of phospholipid bilayers could be shown demonstrating the potential of these compounds could have in antimicrobial applications. To pursue this task a second generation of conjugates was synthesized using amphipathic CP connected to a hydrophilic bottle brush copolymer by a peptide linker sequence. This connection could be cleaved by the presence of LasB, an elastase secreted by the pathogenic bacterium pseudomonas aeruginosa. The bottle brush copolymer prevents stacking prior to polymer abstraction leading to unimeric species in aqueous solution, where the cleavable peptide sequence can be accessed by the elastase. The initial peptide sequence, as well as the final conjugates was shown to be responsive towards the presence of LasB. The presented research is an ideal platform for the development of such stimuli responsive nanotubes and offers a guideline for their design as well as property optimization. Future studies will show whether the designed materials will be able to kill bacteria in a stimuli responsive fashion and if the hydrophilic shielding is sufficient to protect the active CP from undesired interactions with mammalian cells. As we recently discovered that CPNT can mix by the exchange of unimers in solution, even within a complex biological environment, a further approach, which will be investigated is the transport of active CP by co-assembling them with polymer conjugated (stimuli responsive) nanotubes.
Publications
- Antimicrobial polymers: mimicking amino acid functionality, sequence control and three-dimensional structure of host-defense peptides. Current Medicinal Chemistry, Vol. 24. 2017, Issue 19, pp. 2115 - 2140.
M. Hartlieb, E. G. L. Williams, A. Kuroki, S. Perrier, K. E. S. Locock
(See online at https://dx.doi.org/10.2174/0929867324666170116122322) - Sequence Control as a Powerful Tool for Improving the Selectivity of Antimicrobial Polymers. ACS Applied Materials & Interfaces, Vol. 9. 2017, Issue 46, pp. 40117–40126.
A. Kuroki, P. Sangwan, Y. Qu, R. Peltier, C. Sanchez-Cano, J. Moat, C. G. Dowson, E. G. L. Williams, K. E. S. Locock, M. Hartlieb, S. Perrier
(See online at https://doi.org/10.1021/acsami.7b14996) - Well-defined hyperstar copolymers based on a thiol–yne hyperbranched core and a poly(2-oxazoline) shell for biomedical applications. Polym. Chem. 2017, 8, 2041-2054.
Hartlieb, M.; Floyd, T.; Cook, A. B.; Sanchez-Cano, C.; Catrouillet, S.; Burns, J. A.; Perrier, S.
(See online at https://doi.org/10.1039/c7py00303j) - Cationic and hydrolysable branched polymers by RAFT for complexation and controlled release of dsRNA. Polymer Chemistry, Vol.9. 2018, pp. 4025-4035.
A. B. Cook, R. Peltier, M. Hartlieb, G. Moriceau, R. Whitfield, J. A. Burns, David M. Haddleton, S. Perrier
(See online at https://doi.org/10.1039/C8PY00804C) - Probing the Dynamic Nature of Self-Assembling Cyclic Peptide–Polymer Nanotubes in Solution and in Mammalian Cells. Advanced Functional Materials, Vol. 28. 2018, Issue 24 (Special Issue: Bio‐Materials for Light Management) , 1704569.
J. Y. Rho, J. C. Brendel, L. R. MacFarlane, E. D. H. Mansfield, R. Peltier, S. Rogers, M. Hartlieb, S. Perrier
(See online at https://doi.org/10.1002/adfm.201704569) - Systematic study of the structural parameters affecting the self-assembly of cyclic peptide-poly(ethylene glycol) conjugates. Soft Matter, Vol. 14. 2018, pp. 6320-6326.
M. Hartlieb, E. D. H. Mansfield, S. Catrouillet, J. Y. Rho, S. C. Larnaudie, S. E. Rogers, J. Sanchis, J. C. Brendel, S. Perrier
(See online at https://doi.org/10.1039/C8SM01133H) - Dual self-assembly of supramolecular peptide nanotubes to provide stabilisation in water. Nature Communications, Vol. 10. 2019, Article number: 4708.
J. Y. Rho, H. Cox, E. Mansfield, S. H. Ellacott, R. Peltier, J. C. Brendel, M. Hartlieb, T. A. Waigh, S. Perrier
(See online at https://doi.org/10.1038/s41467-019-12586-8) - Hyperbranched poly(ethylenimine-co-oxazoline) by thiol-yne chemistry for non-viral gene delivery: improving the gold standard branched PEI. Polymer Chemistry, Vol. 10. 2019, pp. 1202-1212.
A. B. Cook, R. Peltier, J. Zhang, P. Gurnani, J. Tanaka, J. A. Burns, R. Dallmann, M. Hartlieb, S. Perrier
(See online at https://doi.org/10.1039/C8PY01648H) - Stimuli-Responsive Membrane Activity of Cyclic-Peptide-Polymer Conjugates.
Chemical Science, Vol. 10. 2019, pp. 5476-5483.
M. Hartlieb, S. Catrouillet, A. Kuroki, C. Sanchez-Cano, S. Perrier
(See online at https://doi.org/10.1039/C9SC00756C) - Targeting intracellular, multi-drug resistant Staphylococcus aureus with guanidinium polymers by elucidating the structure-activity relationship.
Biomaterials, Vol. 217. 2019, 119249.
A. Kuroki, A. Kengmo-Tchoupa, M. Hartlieb, R. Peltier, K. Locock, M. Unnikrishnan, S. Perrier
(See online at https://doi.org/10.1016/j.biomaterials.2019.119249) - Probing the effect of rigidity on the cellular uptake of core-shell nanoparticles: Stiffness effects are size dependent. Small, Vol. 18. 2022, Issue 38, 2203070.
P. Gurnani, C. Sanchez-Cano, H. Xandri-Monje, J. Zhang, S. Ellacott, E. Mansfield, M. Hartlieb, R. Dallmann, S. Perrier
(See online at https://doi.org/10.1002/smll.202203070)
