Unraveling the cell-type dependent radiosensitizing effects of gold through the development of a multifunctional gold nanoparticle

Abstract

The radiosensitizing efficacy of gold is well established, however, there remain several significant barriers to the successful clinical translation of nano-sized gold particles (AuNPs). These barriers include: retaining stability in relevant biological sera, demonstrating effectiveness at clinically relevant AuNP concentrations and identifying the biological context where significant benefit is most likely to be achieved. Herein we have developed a AuNP preparation, stress-tested to provide effective protection from salt and serum mediated agglomeration. Furthermore, the core AuNP is co-functionalized with two biologically derived peptides designed to enhance endocytosis and promote endosomal escape, thus maximizing intracellular AuNP surface area. In summary, these investigations demonstrate restored AuNP internalization using the co-functionalized preparation that generated significant radiosensitization, in both in vitro and in vivo models, at clinically viable treatment concentrations. Furthermore, we have identified an underpinning biological mechanism in the inherent radical scavenging capacity that could be used to predict radiosensitizing efficacy.

Chemical Mechanisms of Nanoparticle Radiosensitization and Radioprotection: A Review of Structure-Function Relationships Influencing Reactive Oxygen Species

“…Polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyglycerol are nanoparticle capping agents that aid in stability and can operate as binding sites for additional conjugates [134,136]. PEG of different molecular weights are common and simple to functionalize onto the surface of metal nanoparticles, stabilizing their surface [114]. Although this stabilizes the nanoparticle, cell uptake is often decreased [139,151].…”

“…Surface functionalization can be utilized to promote cellular uptake and determine nanoparticle sub-cellular localization. Targeting ligand and peptide conjugation promotes nanoparticle uptake [153] and radiosensitization [4,114,136]. Other surface coatings can also enhance uptake.…”

Mechanisms of nanoparticle radiosensitization

“…Courtesy of Dylan Peukert convoluted. Cell traits are highly variable (Nicol et al, 2018). Nanoparticle uptake is cell dependant (Ivošev et al, 2020) and even localize differently between cell lines (X.…”

“…Biological mechanisms are many, varied, and highly convoluted. Cell traits are highly variable (Nicol et al, 2018). Nanoparticle uptake is cell dependant (Ivošev et al, 2020) and even localize differently between cell lines (X. Cai et al, 2011; Chen et al, 2011).…”

A synchrotron-based infrared microspectroscopy study on the cellular response induced by gold nanoparticles combined with X-ray irradiations on F98 and U87-MG glioma cell lines

“…The radiosensitization potential dependence as a function of the cell type has also been reported in previous studies using the same type of NP. 5,25,26,54 The distinct cellular responses of different cell lines are a key point for the study of radiosensitization effects of NP. Within this context, SR-FTIRM can provide new insights into the molecular and cellular levels for understanding the complex radiosensitization processes involving nanoparticles and radiotherapy, as shown in this work.…”