Professor, University College London
Delivering Peptides to the Brain
Central nervous system (CNS) disorders are rising in incidence; with unipolar and depressive disorders predicted to become the second largest cause of morbidity by 2030 1. Additionally chronic pain, which affects 20% of European adults, is poorly served by the existing range of approved therapeutics 2, 3. Only a quarter of patients with chronic pain experience relief with the current approved medicines 2. It is well known that peptides may be used to create potent drugs with few off-target effects and little to no toxic metabolites; however the delivery of peptides to the brain is hampered by a combination of the blood brain barrier and the fact that peptides are metabolically unstable 4. The ability to deliver peptides to the brain will enable new potent medicines, with exceptional specificity, to be developed for CNS diseases.
Over the last two decades, we have designed a variety of self-assembling polymers 5, 6 and self-assembling peptide prodrugs 7, 8 and used these to prepare peptide nanomedicines, which may be administered via the intravenous 7, 8, oral 5 or intranasal 6 routes. The intranasal route is particularly attractive as it is an effective route for the brain delivery of peptides in humans 9. Some of these preclinical stage nanomedicines, such as NM127 – an enkephalin based formulation, indicated for moderate to severe pain, have since been out-licensed for clinical development. NM127 demonstrates a number of differentiating features. In preclinical studies, NM127 is active in all pain models, shows no analgesic tolerance or reward seeking behaviour and is centrally acting and so unlikely to cause significant constipation 6.
These nanomedicines will be discussed in the talk.
1. Mathers, C. D.; Loncar, D. Projection of global mortality and burden of disease from 2002 to 2030. Plos Medicine 2006, 3, 2011 - 2030.
2. Nightingale, S. The neuropathic pain market. Nature Rev. Drug Discovery 2012, 11, 102-103.
3. Breivik, H.; Collett, B.; Ventafridda, V.; Cohen, R.; Gallacher, D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006, 10, (4), 287-333.
4. Lalatsa, A.; Schatzlein, A. G.; Uchegbu, I. F. Strategies to deliver peptide drugs to the brain. Mol Pharmaceutics 2014, 11, (4), 1081-93.
5. Lalatsa, A.; Lee, V.; Malkinson, J. P.; Zloh, M.; Schatzlein, A. G.; Uchegbu, I. F. A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain. Mol Pharmaceutics 2012, 9, (6), 1665-80.
6. Godfrey, L.; Iannitelli, A.; Garrett, N. L.; Moger, J.; Imbert, I.; King, T.; Porreca, F.; Soundararajan, R.; Lalatsa, A.; Schatzlein, A. G.; Uchegbu, I. F. Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. J Control Release 2017, 270, 135-144.
7. Mazza, M.; Notman, R.; Anwar, J.; Rodger, A.; Hicks, M.; Parkinson, G.; McCarthy, D.; Daviter, T.; Moger, J.; Garrett, N.; Mead, T.; Briggs, M.; Schatzlein, A. G.; Uchegbu, I. F. Nanofiber-based delivery of therapeutic peptides to the brain. ACS Nano 2013, 7, (2), 1016-26.
8. Lalatsa, A.; Schatzlein, A. G.; Garrett, N. L.; Moger, J.; Briggs, M.; Godfrey, L.; Iannitelli, A.; Freeman, J.; Uchegbu, I. F. Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration. J Control Release 2015, 197, 87-96.
9. Uchegbu, I.; Wang, Z.; Xiong, G.; Tsang, A.; Schatzlein, A. Nose to brain delivery. J Pharmacol Exp Ther 2019, doi.org/10.1124/jpet.119.258152
Ijeoma Uchegbu is Professor of Pharmaceutical Nanoscience at the UCL School of Pharmacy, University College London (UCL), UCL’s Pro-Vice Provost for Africa and The Middle East and Chief Scientific Officer of Nanomerics Ltd. Nanomerics is a UCL spin out company, which was founded by Ijeoma and Andreas G. Schätzlein (http://www.nanomerics.com/). Nanomerics recently licensed NM133 to Iacta Pharmaceuticals. Nanomerics also recently won first prize for its Molecular Envelope Technology at the Royal Society of Chemistry’s Emerging Technologies Competition 2017 in the Health category.
Ijeoma has been awarded various prizes for her work, notably the UK Department for Business Innovation Skills’ Women of Outstanding Achievement in Science Engineering and Technology award (http://www.theukrc.org/women/women-of-outstanding-achievement/2007-collection/professor-ijeoma-uchegbu), the Royal Pharmaceutical Society’s Pharmaceutical Scientist of the Year 2012 and the Academy of Pharmaceutical Sciences Innovative Science Award 2016. Ijeoma was elected to the Controlled Release Society College of Fellows in 2013 and was made an Eminent Fellow of the Academy of Pharmaceutical Sciences in 2013. Ijeoma is the editor of three books, a named inventor on 11 granted patents and has authored over 180 peer reviewed journal articles and book chapters. Ijeoma’s research has been featured on BBC Woman’s Hour and more recently in The Guardian.