Advanced Non-Invasive Strategies: Cell-Penetrating Peptides as Smart Carriers for Theranostic Innovations

About the Project

The brain contains trillions of glial cells that communicate with each other, respond to infections, and support learning and memory. These cells are essential for brain function, making protein- or peptide-based shuttles targeting glial cells of particular interest. However, these compounds must first overcome two significant barriers: the blood-brain barrier (BBB), which blocks most large molecules, and the cell membrane of the glial cells themselves.

Cell-penetrating peptides (CPPs) are highly promising for delivering proteins or peptides into glial cells due to their natural ability to traverse cell membranes while carrying various payloads, such as therapeutic and/or imaging agents. These short amino acid sequences (up to 30 residues) can be harnessed to transport compounds into glial cells, aiding their survival or enabling the restoration from traumatic brain injury or neuronal damage. Notably, peptides generally possess a tolerable safety profile, making them a valuable tool in theranostic applications.

Focused ultrasound (FUS) combined with microbubbles offers a non-invasive method to deliver agents across the BBB. Ultrasound is focused on the target brain region, and clinically approved microbubbles (0.5-10 µm in diameter) are injected intravenously along with the smart theranostic agents. The microbubbles oscillate in the targeted area, temporarily opening the BBB to facilitate delivery. This technique, currently in clinical trials, offers a safe and efficient approach to brain-targeted delivery.

The inherent penetrability of CPPs, combined with FUS and microbubbles to temporarily open the BBB, will offer a synergistic effect, allowing CPPs to effectively reach and localise at the targeted brain site, along with their conjugated payloads, such as drugs and/or imaging agents.

The supervisors have previously reported the successful synthesis of a CPP specifically targeting glial cells. The student will engineer and synthesise analogues with enhanced stability and internalisation by incorporating strategic amino acid mutations and tagging them with gold nanoparticles to improve penetration. Using the technology developed and patented by the lead supervisor, the student will create first-in-class CPPs. Performance evaluation of these analogues will be conducted using techniques in the supervisors' laboratories. Additionally, the student will assess patient tolerability and acceptability through a scoping review and focus groups with key stakeholders.

We invite applications for a cutting-edge project focused on developing a theranostic cell-penetrating peptide (CPP) capable of crossing the blood-brain barrier (BBB) to selectively target glial cells, enabling advanced brain interventions.

Project Overview

• Objective: Engineer and deliver a novel CPP that selectively targets glial cells in vivo.
• Innovation: Incorporate a non-proteinogenic amino acid into the peptide structure to enhance stability, increase half-life, and resist enzymatic degradation.
• Theranostic capabilities: Tag the CPP with a fluorophore for ex vivo tracking and encapsulate it with gold nanoparticles for efficient BBB transduction.
• Patient tolerability and acceptability: The student will also perform a scoping review to explore the patient tolerability and acceptability during our proposed project through a scoping review and a focus group with key stakeholders'.

Key Methodologies

• Peptide synthesis: Creating and optimising a stable, glia-targeting CPP.
• Delivery techniques: (a) Employing focused ultrasound and microbubbles for safe, localised peptide delivery into the murine brain; (b) Utilising gold nanoparticle encapsulation to facilitate BBB penetration.
• Ex vivo analysis: Monitoring and tracing CPP behaviour with fluorophore tagging.
• Scoping review: Perform a scoping review aligning to PRISMA ScR standards. Conduct qualitative data collection through focus groups to explore stakeholder perspectives on the use of focused ultrasound (FUS) combined with microbubbles as a delivery method.

Supervisory Team

• Dr Othman Almusaimi, Newcastle University
• Dr Sreejith Raveendran, Teesside University
• Dr Sophie V. Morse, Imperial College London
• Dr Clare Tolley, Newcastle University

References

• Al Musaimi O, Morse SV, Lombardi L, Serban S, Basso A, Williams DR. Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin. J Pept Sci. 2023;29(2):e3448.
• Al Musaimi O.; Williams DR. Methods of Chemical Synthesis of Peptides; I.P. Office, Ed.; Imperial College Innovations Limited: London, WO2024261319A1, UK, 2024
• Raveendran S, Giram A, Elmi M, Ray S, Ireson C, Alavijeh M, Savina IN. Combinatorial therapy: targeting CD133+ glioma stem-like cells with a polysaccharide-prodrug complex functionalised gold nanocages. Biomedicines. 2024;12(5):934.
• Morse SV, Pouliopoulos AN, Chan TG, Copping MJ, Lin J, Long NJ, Choi JJ. Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption. Radiology. 2019;291(2):459-466.
• Wilson S, Tolley C, Mc Ardle R, Beswick E, Slight SP. Key considerations when developing and implementing digital technology for early detection of dementia-causing diseases among health care professionals: qualitative study. J Med Internet Res. 2023;25:e46711.

Funding Notes

This project is suitable for self-funded students or students with third-party sponsorship. There is no dedicated funding from the university for this project. The student will be expected to provide funding for tuition fees and living expenses. UK students may be able to apply for a Doctoral Loan from Student Finance for financial support. Some students may be eligible to apply for supplemental funding.

Details about the tuition fees and a supplemental funding search tool are available on our website: View Website