Nasal Delivery of Peptide Nanofibers for Acute Ischaemic Stroke

This 3-year self-funded PhD will be based in the School of Pharmacy and Biomedical Sciences and will be supervised by Dr Aikaterini Lalatsa, Professor Arthur Butt and Dr Andrea Bucchi.

Stroke is a brain attack caused by the blood supply to the brain being cut resulting in damage and death of brain cells.

Every two seconds, someone in the world will suffer from a stroke with stroke being the fourth biggest single cause of death in the UK. Two thirds of stroke survivors will leave hospital with a disability (weakness in limbs, problems with speech, reading, writing, eyesight, memory, thinking and swallowing) costing the NHS 1.7 billion annually in treatment and rehabilitation.

Although restoring blood flow as quickly as possible is critical, the use of clot-dissolving agents such as tissue plasminogen activator (tPA) is limited by the risk of haemorrhagic events and delayed hospitalisation, so only 3% of patients can be treated within the 4.5 hour-long window in which the tPA, the only available treatment, is effective.

Novel and ideally non-invasive treatments which can be administered by paramedics and reduce the risk of haemorrhage are therefore needed, in order to minimise the severity of the ischaemic attack and limit the morbidity and mortality of stroke.

Recent research has demonstrated that short neuropeptides belonging to the Angiotensin family can exert cerebrotective effects in ischaemic stroke, and when administered intracerebrally they can reduce the infarct size and prolong survival.

However, the inability of these peptides to cross the blood-brain barrier in adequate quantities and their very short biological half-lives (below 2 minutes) are key challenges limiting their translation into non-invasive therapies for stroke.

Our group has recently shown that lipidising neuropeptides can result in peptide amphiphiles able to self-assemble in long-axial nanofibers (Leite et al 2015 Curr Top Med Chem 15 (22): 2277–2289) that possess excellent biological stability, are able to cross the blood-brain barrier and activate receptors within the brain parenchyma, eliciting a pharmacodynamic response via an intravenous (Lalatsa 2015 J Control Release 197:87–96, Leite 2017 ACS Nano In preparation) but also via an intranasal route (PCT/GB2014/ 053254, Godfrey, L et al 2017 Nanoparticulate peptide intranasal delivery exclusively to the brain, to produce centrally mediated, tolerance free analgesia. (ACS Nano Submitted).

This projects aims to develop a non-invasive peptide based nanomedicine presented as microparticles appropriate for nasal delivery for the treatment of stroke.

The project presents an opportunity to work at the meeting point between bionanomaterial engineering, cellular and molecular medicine and drug delivery aiming to address challenges in relation to permeation across the BBB and translation of novel endocrine targets into non-invasive targeted delivery strategies for stroke.

The successful candidate will gain experience and receive training in design of lipidised peptide analogues in silico, solid-phase peptide synthesis and characterisation, physicochemical and morphological characterisation of self-assembled nanofibers , preparation and characterisation of nano in micro particles for nasal delivery, stability of peptide nanofibers in plasma, brain, liver and nasal mucosa homogenates, studies on brain slices exposed to oxygen-glucose deprivation (OGD) coupled with pharmacological activation or blockade of targeted receptors, measurement of reactive oxygen species, computational flow dynamics and permeability studies across an in vitro BBB model, and receptor binding studies using single molecular force spectroscopy (in collaboration with University of Linz.

Depending on the success of the project in vivo pharmacokinetic (LC-MS) and pharmacodynamics studies in a rat stroke model can be performed in collaboration with University of Rouen.

Fees and funding

Funding Availability: Self-funded PhD students only

PhD full-time and part-time courses are eligible for the UK Government Doctoral Loan (UK and EU students only).

How to apply

Please contact Dr Aikaterini Lalatsa (Katerina.lalatsa@port.ac.uk) to discuss your interest before you apply, quoting the project code.

When you're ready to apply, you can use our online application form. Make sure you submit a personal statement, proof of your degrees and grades, details of two referees, proof of your English language proficiency and an up-to-date CV.

Our ‘How to Apply’ page offers further guidance on the PhD application process.

To be considered for this self-funded PhD opportunity quote project code PHBM4810219 when applying.

October start

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February start

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