Functionalized Gold Nanoparticles as Photocatalysts for the Activation of Pt(IV) Prodrugs

Gold nanoparticles (AuNPs) have emerged as promising carriers in therapeutic applications, particularly for delivering metal-based prodrugs such as platinum(IV) derivatives of cisplatin. Their unique optical properties and ability to facilitate light-driven reactions enhance their potential as “smart” transport vectors, enabling targeted and on-demand drug activation in response to specific stimuli, particularly light. The integration of photocatalytic properties into functionalized AuNPs may revolutionize how we approach drug activation and delivery, potentially minimizing side effects associated with conventional drug therapies while maximizing therapeutic efficacy. Despite advancements in using AuNPs in drug delivery, the intrinsic photocatalytic properties of these nanoparticles, particularly regarding the activation mechanisms of Pt(IV) prodrugs, are not yet fully understood. Previous studies indicated that cationic, monolayer-functionalized AuNPs could activate Pt(IV) complexes efficiently under blue light irradiation. However, the observation of substantial substrate conversion without additional photocatalysts raises important questions about the inherent capabilities of AuNPs and warrants further investigation. The primary aim of this thesis is to develop a robust and biocompatible Pt(IV) delivery system using functionalized AuNPs as photocatalysts for activating Pt(IV) prodrugs. This work seeks to provide insights into enhancing AuNP performance as drug delivery vehicles by exploring their photocatalytic properties and interactions with several substrates. To achieve these objectives, various methodologies were employed. Functionalized AuNPs were synthesized with distinct surface chemistries that allowed them to form supramolecular assemblies with Pt(IV) prodrugs through electrostatic and hydrogen-bonding interactions. This study leveraged the incorporation of thiols with cationic functional groups like cyclen and tacn to facilitate attractive interactions with negatively charged Pt(IV) complexes. The photocatalytic activities of these nanoparticles were systematically evaluated using different light sources and conditions. Additionally, the attachment of photosensitizers (PSs), such as 4-amino-1,8-naphthalimide (NMI-NH2) and rhodamine B (RhB), was explored to enhance the nanoparticles' light absorption capabilities. The experimental results confirmed that functionalized small-sized AuNPs efficiently activate Pt(IV) prodrugs, with only positively charged nanoparticles effectively reducing anionic Pt(IV) species to the more reactive Pt(II) form. Notably, cyclen-capped and tacn-functionalized AuNPs demonstrated superior reactivity compared to TMA-capped counterparts, underscoring the importance of surface chemistry in facilitating this catalytic performance. Regarding the photocatalytic behaviour of AuNPs towards the reduction of ferricyanide, they exhibited notable background catalytic activity, even in the absence of additional photocatalysts. This intrinsic photocatalytic behaviour was highlighted through the effective reduction of ferricyanide, wherein the reaction rate increased with light intensity and nanoparticle concentration, suggesting that the nanoparticles can sustain their photocatalytic activity under varying conditions. The successful functionalization of AuNPs with photosensitizers NMI and RhB significantly enhanced their light absorption and photocatalytic efficiency. The differential surface coverage of the two dyes resulted in NMI-functionalized AuNPs exhibiting a greater photocatalytic activity under visible light, reflecting the effectiveness of the PSs in promoting electron transfer processes. Collectively, these findings illustrate that functionalized AuNPs serve as versatile systems capable of efficiently activating Pt(IV) prodrugs and exhibiting intrinsic photocatalytic properties, thereby augmenting therapeutic applications.