Auranofin-Loaded Chitosan Nanoparticles Demonstrate Potency against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains a clinical challenge due to molecular, metabolic, and genetic heterogeneity as well as the lack of validated drug targets. Thus, therapies or delivery paradigms are needed. Gold-derived compounds including the FDA-approved drug, auranofin have shown promise as effective anticancer agents against several tumors. To improve the solubility and bioavailability of auranofin, we hypothesized that the nanodelivery of auranofin using biodegradable chitosan modified polyethylene glycol (PEG) nanoparticles (NPs) will enhance anticancer activity against TNBC by comparing the best nanoformulation with the free drug. The selection of the nanoformulation was based on synthesis of various chitosan PEG copolymers via formaldehyde-mediated engraftment of PEG onto chitosan to form [chitosan-g-PEG] copolymer. Furthermore, altered physiochemical properties of the copolymer was based on the formaldehyde ratio towards nanoparticles (CP 1-4 NPs). Following the recruitment of PEG onto the chitosan polymer surface, we explored how this process influenced the stiffness of the nanoparticle using atomic force microscopy (AFM), a factor crucial for in vitro and in vivo studies. Our objective was to ensure the full functionality and inherent properties of chitosan as the parent polymer was maintained without allowing PEG to overshadow chitosan's unique cationic properties while improving solubility in neutral pH. Hence, CP 2 NP was chosen. To demonstrate the efficacy of CP 2 NP as a good delivery carrier for auranofin, we administered a dose of 3 mg/kg of auranofin, in contrast to free auranofin, which was given at 5 mg/kg. In vivo studies revealed the potency of encapsulated auranofin against TNBC cells with a severe necrotic effect following treatment superior to that of free auranofin. In conclusion, chitosan-g-PEG nanoparticles have the potential to be an excellent delivery system for auranofin, increasing its effectiveness and potentially reducing its clinical limitations.

Circumventing Physicochemical Barriers of Cyclometalated Gold(III) Dithiocarbamate Complexes with Protein-Based Nanoparticle Delivery to Enhance Anticancer Activity.

Optimizing the bioavailability of drug candidates is crucial to successful drug development campaigns, especially for metal-derived chemotherapeutic agents. Nanoparticle delivery strategies can be deployed to overcome physicochemical limitations associated with drugs to improve bioavailability, pharmacokinetics, efficacy, and minimize toxicity. Biodegradable albumin nanoconstructs offer pragmatic solutions for drug delivery of metallodrugs with translational benefits in the clinic. In this work, we explored a logical approach to investigate and resolve the physicochemical drawbacks of gold(III) complexes with albumin nanoparticle delivery to improve solubility, enhance intracellular accumulation, circumvent premature deactivation, and enhance anticancer activity. We synthesized and characterized stable gold(III) dithiocarbamate complexes with a variable degree of cyclometalation such as phenylpyridine (C^N) or biphenyl (C^C) Au(III) framework and different alkyl chain lengths. We noted that extended alkyl chain lengths impaired the solubility of these complexes in biological media, thus adversely impacting potency. Encapsulation of these complexes in bovine serum albumin (BSA) reversed solubility limitations and improved cancer cytotoxicity by ∼25-fold. Further speciation and mechanism of action studies demonstrate the stability of the compounds and alteration of mitochondria bioenergetics, respectively. We postulate that this nanodelivery strategy is a relevant approach for translational small-molecule gold drug delivery.