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Details of Grant 

EPSRC Reference: EP/W035049/1
Title: Next-Generation Biomimetic Nanomedicines
Principal Investigator: Itzhaki, Professor L
Other Investigators:
Fruk, Dr L
Researcher Co-Investigators:
Dr P Chaturbedy
Project Partners:
Department: Pharmacology
Organisation: University of Cambridge
Scheme: Standard Research
Starts: 01 July 2022 Ends: 30 June 2025 Value (£): 475,026
EPSRC Research Topic Classifications:
Biological & Medicinal Chem. Drug Formulation & Delivery
Structural biology
EPSRC Industrial Sector Classifications:
Healthcare
Related Grants:
Panel History:
Panel DatePanel NameOutcome
18 May 2022 Healthcare Technologies Investigator Led Panel May 2022 Announced
Summary on Grant Application Form
Cancer and neurodegenerative diseases are major global health problems, and it is estimated that by 2025 nearly 20 million and 10 million new cases of cancer and dementia (caused by neurodegenerative diseases), respectively, will be diagnosed each year. Current targeted therapeutic approaches include small molecules and antibodies that act by inhibiting the function of specific disease-promoting proteins. These drugs are often of limited use because of low bioavailability (the ability to reach the required site of action) and off-target effects that cause toxicity. Moreover, disease cells commonly develop resistance to such drugs by acquiring mutations in the target protein that allow them to escape the inhibitor's action. Nanoparticle formulations of drugs, referred to as "nanotherapeutics", can help to improve bioavailability and reduce toxicity. However, they have not been extensively used in the clinic to date because of the limited therapeutic improvements relative to the high cost of their formulation.

Here we will address these challenges by combining our expertise in protein engineering and bionanotechnology to build "nanoparticle-based target eliminators" (NTEs) designed to safely and effectively destroy pathological target proteins. Target degradation is irreversible and should therefore be more effective and longer lasting than target inhibition. The NTEs will be built by functionalizing the surface of nanoparticles with two classes of ligands, one to bind a pathological target protein of interest and one to bind to degradation effectors to co-opt the cell's quality control machineries - the ubiquitin-proteasome system and the autophagy-lysosome system - and drive target destruction. By condensing targets and degradation effectors within a small volume in these nanoparticle "reactors" we should dramatically accelerate the reaction between them. A key strength of the NTE platform is that it will be able to utilise a variety of different binding ligands (small molecules, peptides, oligonucleotides) and can thereby be applied to potentially any target and can harness many different degradation pathways. Many disease drivers are hard to drug by conventional means because they are not enzymes or receptors whose activities can be straightforwardly blocked with a small-molecule ligand; these drivers will be amenable to our NTE platform. We will also develop stimuli-responsive NTEs that can be activated remotely and in a site-specific manner, making the therapy safer.

This work is necessarily interdisciplinary. Through interaction between the Investigators and our collaborators, the project will bring together expertise in nano-biotechnology, chemistry, biochemistry and cell and cancer biology, with the longer-term goal of translating the work in an efficient and relevant manner. The results will provide new insights into the basic molecular mechanisms underpinning the quality control pathways of the cell and will deliver a new way to target proteins for destruction. We will focus here on cancer and neurodegenerative disease targets, but the NTE platform could be applied very widely to many other disease areas. The results will also provide proof of concept for the broader exploitation of these next-generation biomimetic nanomedicines as proximity-inducing drugs with diverse activities beyond targeted protein degradation.
Key Findings
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Organisation Website: http://www.cam.ac.uk