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AI-enabled nanoparticle surface engineering for cancer therapy: balancing targeting efficiency and blood circulation

Lead supervisor: Professor Dame Molly M. Stevens

Co-supervisor: Dr Adam Creamer

Commercial partner: Nanograb

 

 The holy grail of nanomedicine is for the injected nanomaterial to accumulate only at the region of interest (e.g. tumour, target organ, cell subtype) to maximise efficacy and avoid side effects (Veiga et al. Journal of Controlled Release, 2023). Getting close to this goal requires a delicate balance of passivation agents (typically poly(ethylene glycol)) and targeting ligands (e.g. antibodies, peptides) to improve target specificity. However, there is not currently enough understanding of the influence the nanoparticle surface on their targeting efficiency (Kappel et al. ACS nano, 2021). As a result, we are far away from achieving a true targeted nanomedicine.

 

One barrier to achieving targeted nanomedicine, is the poor circulation efficiency of most nanoparticles i.e. they are rapidly removed from the blood (via multiple mechanisms) and cannot reach the site of interest. In recently published work (Creamer et al. Advanced Materials, 2023) the Stevens Group illustrated fluorescent nanoparticles form a negligible protein corona and exhibit excellent circulation efficiency in their naked form. However, upon the functionalisation with cancer-targeting ligands, they did successfully target cancer cells in vivo, but with a far reduced circulation efficiency.

 

Here, this work will be continued with a systematic study of the effect of nanoparticle surface chemistry on the biological properties. Nanoparticles will be decorated first with HER2-targeting peptides, designed in silico with the assistance of commercial partner Nanograb. Peptide-coated nanoparticles will then be compared for cancer cell targeting efficiency (flow cytometry and confocal imaging), toxicity (MTT assay), protein corona formation (FCS, proteomics) and circulation efficiency (zebrafish injection studies). The top performer(s) from this study will then be further optimised by combining the ligands with passivation agents (e.g. PEG, zwitterions) to find the ‘Goldilocks region’ of maximal cancer targeting and minimal unwanted biofouling. Molecular dynamic simulations of the nanoparticle surface will then be modelled to better understand these structure-property relationships and influence the design of better nanomedicine. 

 

Apply using course: DPhil in Physiology, Anatomy and Genetics

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