Shining a Light on Cancer: Gold Nanoclusters for Photodynamic Therapy

Metal nanoparticles have developed as an exciting class of nanomaterials for biomedical applications, including bioimaging, drug delivery, and photodynamic treatment (PDT). Small gold nanoclusters (∼2 nm) are of great interest due to their unusual physical and chemical features, including strong chemical and photostability. Furthermore, due of their small size, these nanoclusters excrete moderately from the body, resulting in a reasonable balance between accumulation at pathogenic targets and biocompatibility. The superficial synthesis of these particles employing thiols with linking groups like azido, amino, and carboxy has resulted in substantial study into mono-functionalized gold nanoparticles that contain medicines, fluorescent dyes, proteins, and DNAs. As the importance of multimodality in precision medicine develops, the development of nanomaterials with various functionalities has sparked substantial attention. 

Metal nanoparticles having two or more distinct connecting groups (CGs) are useful intermediates for manufacturing multifunctional nanomaterials. However, this technique creates issues in ensuring consistent synthesis of gold nanoclusters, as CGs are randomly injected in varying places and quantities. Given the importance of material uniformity in maintaining quality, particularly for medical applications, there is an urgent need for a practical technology that allows for the controlled introduction of diverse functions into gold nanoparticles. Gold nanoclusters homogeneously modified with thiol units having an equal quantity of azido and amino groups, which are suited for click and amidation reactions, could be used to construct multifunctionalized nanomaterials. 

Gold nanoparticles synthesised by (A) random method (B) synthesised by gold nano particles with thiol group 

While various synthesises of gold nanoclusters containing azido groups have been reported, their inclusion has proven difficult due to their instability under standard synthesis conditions and establishing homogeneity necessitates converting all amino groups to azido groups, making it impossible to produce equal and uniform amounts of azido and amino groups with this method. the tiny gold nanocluster (2 nm) coated with homogenous tripeptides containing azido and amino groups, allowing for easy multifunctionalization. The gold nanoclusters synthesised without destroying the azido group by reducing tetrachloroauric(III) acid with sodium phenoxide in the presence of the cysteine-containing tripeptide. This clickable bisreactive nanocluster as a versatile platform to create multifunctional gold nanomaterials. The resultant nanoclusters were modified with an anticancer chemical linked to an indolizine moiety for photoinduced uncaging, a photodynamic therapy agent that acts as a photosensitizer for uncaging, and a cyclic RGD peptide. 

The cytotoxicity of multifunctionalized gold nanoclusters was demonstrated by irradiating human lung cancer-derived A549 cells with the produced nanomaterials under red light.  The cells' considerable cytotoxicity demonstrates the method's potential utility in advanced cancer therapy. Homogeneous peptide modification may open up new avenues for producing diverse multifunctional nanomaterials for biomedical purposes. To increase their utility, now construction of uniform tri- or more multiple functionalized nanoclusters is now under development.

Reference:

Watanabe K, Mao Q, Zhang Z, Hata M, Kodera M, Kitagishi H, Niwa T, Hosoya T. Clickable bisreactive small gold nanoclusters for preparing multifunctionalized nanomaterials: application to photouncaging of an anticancer molecule. Chemical Science. 2024;15(4):1402-8.

Image Source:

Cover image: https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcTN4oAlfcgNRycuLvh_wUQg4SEnTNYT5iS08w&s

Chemical Science: https://pubs.rsc.org/image/article/2024/sc/d3sc04365g/d3sc04365g-f1_hi-res.gif