Abstract
The FDA-approved purine analog 6-thioguanine (6-TG) has shown unsatisfactory therapeutic effects in solid cancers due to poor solubility and bioavailability. In this study, an efficient thiol-based drug delivery platform is developed by conjugating 6-TG to BSA stabilized gold nanocluster (AuNC@BSA-TG) in a facile one-pot synthesis approach by fine-tuning of 6-TG to albumin concentration for maximum drug loading but without compromising the inherent fluorescent properties of gold nanoclusters. AuNC@BSA-TG nanoconjugate has a size of ∼3.3 ± 0.76 nm and exhibits ∼60 % 6-TG conjugation efficiency. The release of 6-TG depends on cellular thiols, with ∼90 % release within 24 h in the presence of 10 mM GSH at pH 7.4, mimicking the cytosol-reducing environment in cancer cells. The nanoconjugate also exhibits synergistic amplification of oxidative stress through GSH depletion and peroxidase mimetic (POD-mimetic) activity. Cytotoxicity analysis reveals an approximately 50 % reduction in IC50 values for AuNC@BSA-TG compared to free 6-TG for HCT116 and A549 cells exhibiting KRAS mutation. Interestingly, KRAS wild-type HEK293T cells showed minimal toxicity to AuNC@BSA-TG under similar conditions. This combinatorial approach subsequently produces overwhelming oxidative stress due to simultaneous intracellular GSH depletion and POD-mimetic activity to generate high ROS levels, which subsequently initiates DNA breakdown and activation of the Caspase 3/7 cascade, leading to apoptotic cell death, thereby potentiating the chemotherapeutic efficacy of 6-TG. Notably, to the best of our knowledge, this is the first attempt to develop a protein-stabilized fluorescent theranostic nanosystem for synergistic oxidative stress amplification and 6-TG-based chemotherapy in treating and managing challenging KRAS-mutated cancers.
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