Metal nanoparticles for photobiomodulation localised therapy of brain injury

Background Traumatic

Brain Injury is a significant global health problem with no disease modifying treatment shown to improve outcomes. The pathophysiological mechanisms include factors such as raised intracranial pressure and cerebral h ypoxia, but also mitochondrial dysfunction, neuroinflammation, and oxidative stress. Pharmacological therapeutics typically target discrete pathways or mechanisms, but have thus far failed to demonstrate clear benefit in the context of this multi-faceted pathology. Photobiomodulation (PBM) is an optical therapy gaining recent attention based on the delivery of red or near-infrared wavelength light (600-1000 nm) for a therapeutic effect. A proposed mechanism of action is based on the chromophore activity of cytochrome c oxidase, which influences mitochondrial function that averts the overproduction of reactive oxygen, reducing local oxidative stress. Via modulation of apoptotic pathways, cell survival is increased. PBM has also been demonstrated to reduce microglia activation after traumatic brain injury and ameliorate the local inflammatory response. Currently, its translational potential is severely limited due to current approaches which use transcranial (non-invasive) application that restricts light delivery and optimal energy dose at the injurious target site and cellular level.Nanoparticles have emerged with attractive properties for crossing the Brain Blood Barrier, making them good candidates for non-invasive therapy approaches. Gold nanoparticles are attractive probes with photothermal effect due to their surface plasmon resonance and provide possibilities for down and upconversion of light with functionalisation to allow localised light delivery on the cellular level. Recent results of modified nanoparticles show therapeutic action by light excitation.

Aims and Hypothesis

The project will develop a novel class of gold nanoparticles which will target mitochondria at the injury site. Nanoparticles will be modified with photoactivatable probes to down convert to either 660 nm or 810 nm to enable precise photobiomodulation at the cellular level. This approach will improve the therapeutic efficiency of PBM by directly stimulating mitochondrial activity, leading to increased ATP production, reduced oxidative stress, and enhanced cellular repair, thereby offering new possibilities for treating conditions involving mitochondrial dysfunction.

Methods

Synthesis and characterisation of metal complexes and gold nanoparticles to tune the photophysical properties which will be employed in photobiomodulation experiments. 2D mixed co-cultures of human neural cell lines and animal astrocytes will be established in cell culture plates. Electrophysiological recordings and morphological analysis will be performed and cellular uptake and mitochondrial localisation will be studied together with mitochondrial function.: Light delivered to the cell culture plates and at mitochondrial levels will be determined.

Funding notes:

https://www.birmingham.ac.uk/research/activity/mibtp

References:

[1] Yang B, Xu J, Li Y, Dong Y, Li Y, Tucker L, et al. J Biophotonics 2020;13. https://doi.org/10.1002/JBIO.201960117.

[2] Stevens AR, Hadis M, Milward MR, Ahmed Z, Belli A, Palin WM, et al. Https://HomeLiebertpubCom/Neu 2022. https://doi.org/10.1089/NEU.2022.0140.

[3] Zha S, Wong, K. L Homayoun All, A, ACS Nano 2024, 18, 1820–1845.

https://pubs.acs.org/doi/10.1021/acsnano.3c10674?ref=recommended

[4] L. S. Watson, J. Hughes, S. T. Rafik, S.T., A. R. Muguruza, P. M. Girio, G. Rochford, G, A. J. MacRobert, N. J. Hodges, E. Yaghini, Z. Pikramenou Nanoscale, 2024, 16, 16500–16509. https://doi.org/10.1039/D4NR01901F