Nasal Delivery of Peptide Nanofibers for Acute Ischaemic Stroke

  • Application end date: 11th February 2018
  • Funding Availability: Funded PhD project (EU/UK students only)
  • Department: School of Pharmacy and Biomedical Sciences
  • PhD Supervisor: Dr Aikaterini Lalatsa, Prof Arthur Butt, Dr Andrea Bucchi

Project code: PHBM3810918

Project description

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 single cause of death in the UK. Two thirds of stroke survivors will leave the 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, thus only 3% of the patients can be treated within the 4.5 hours window during which the tPA, the only available treatment, is effective. Thus developing novel treatments that ideally are non-invasive and able to be administered by paramedics and with reduced risk of haemorrhage are needed 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 interface 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).

The PhD project will be supervised in collaboration with Prof Arthur Butt (http://www.port.ac.uk/institute-of-biological-and-biomedical-sciences/cell-biology-and-pharmacology/arthur-butt/) and Dr Andrea Bucchi (http://www.port.ac.uk/school-of-engineering/staff/dr-andrea-bucchi.html).

Supervisor profiles

Dr Aikaterini Lalatsa

Prof Arthur Butt

Dr Andrea Bucchi

Admissions criteria

You’ll need a good first degree from an internationally recognised university (depending upon chosen course, minimum second class or equivalent) or a Master’s degree in an appropriate subject. Exceptionally, equivalent professional experience and/or qualifications will be considered. English language proficiency at a minimum of IELTS band 6.5 with no component score below 6.0.

Enquiries

Informal enquiries are encouraged and can be made to Dr Aikaterini Lalatsa at katerina.lalatsa@port.ac.uk (02392 843929) or Prof Arthur Butt at arthur.butt@port.ac.uk (02392 842156).

For administrative and admissions enquiries please contact sci-pgr-enquiries@port.ac.uk.

How to Apply

You can apply online at www.port.ac.uk/applyonline. You are required to create an account which gives you the flexibility to save the form, log out and return to it at any time convenient to you.

A link to the online application form and comprehensive guidance notes can be found at www.port.ac.uk/pgapply.

When applying, please quote project code: PHBM3810918.

Interview date: TBC

Start date: October 2018.

Funding notes

The fully-funded, full-time three-year studentship provides a stipend that is in line with that offered by Research Councils UK of £14,553 per annum.

The above applies for Home/EU students only.

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