CPP are short sequences of amino-acids that facilitate trans-membrane transport through a variety of endocytic pathways, without the requirement of specific targeting receptors.

One strategy to overcome this limitation is to enhance the efficiency with which AuNPs are internalised using cell penetrating peptides (CPP). However, the clinical relevance of this result is confounded by the high nanoparticle concentration (2.7В g Au/kg) required to produce such a response. dose of AuNPs combined with a large 30В Gy dose fraction survived 1-year post treatment compared to only 20% of mice treated with RT alone. Eighty six percent of mice treated with a single i.v. For example, early in vivo studies demonstrated significant AuNP tumour accumulation and radiosensitisation using 1.9В nm AuNPs using a mammary tumour model.

Furthermore, many of the existing pre-clinical studies use nanoparticle concentrations which represent clinically unfeasible doses, both in terms of cost but more importantly posing an elevated risk of systemic toxicity. High-Z nanomaterials such as gadolinium (ZвЂ‰=вЂ‰64), and gold (ZвЂ‰=вЂ‰79) are proven radiosensitisers, but commercial development leading to widespread use in clinical practice has been hampered by issues that include short systemic circulation, endosomal entrapment and poor target cell uptake. As such, efficient radiosensitisers could help improve treatment outcomes, while concurrently limiting off-target radiation damage. RT can also contribute to significant off-target damage to neighbouring healthy tissue including the bladder and bowel, impacting patient quality-of-life. However, 20вЂ“40% of PCa patients experience treatment failure leading to disease progression. Radiotherapy (RT) is a standard-of-care treatment option for a number of localised cancers including prostate cancer (PCa), offering the best chance for curative intervention. This effect was achieved using RALA, providing functional evidence to support our previous imaging study indicating RALA-AuNP nuclear accumulation. This is the first study to demonstrate meaningful radiosensitisation using low microgram AuNP treatment concentrations. Mechanistic studies support RALA-AuNP nuclear accumulation resulting in increased DNA damage yields. Using clinical radiation energies (6 MV) RALA-AuNP also significantly augmented radiation sensitivity. This effect was greatest using the 25:1 RALA-AuNP formulation, producing a dose enhancement effect (DEF) of 1.54 in PC3 cells.

Importantly, all RALA-AuNP formulations significantly increased prostate cancer cell radiosensitivity. ICP-MS demonstrated that RALA enhanced AuNP internalisation by more than threefold in both PC-3 and DU145 prostate cancer cell models, without causing significant toxicity. Nano-complexes successfully formed at w:w ratios >вЂ‰20:1 (20В Вµg RALA:1В Вµg AuNP) yielding positively charged nanoparticles, sized <вЂ‰110В nm with PDI values <вЂ‰0.52. Physical nanoparticle characteristics were determined by UVвЂ“vis spectroscopy and dynamic light scattering. RALA/Au nanoparticles were formed by optimising the ratio of RALA to citrate capped AuNPs, with assembly occurring through electrostatic interactions. This work examines the potential of RALA, a short amphipathic peptide, to enhance the uptake efficiency of negatively charged AuNPs in tumour cells, detailing the subsequent impact of AuNP internalisation on tumour cell radiation sensitivity. Gold nanoparticles (AuNP) are effective radiosensitisers, however, successful clinical translation has been impeded by short systemic circulation times and poor internalisation efficiency.

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