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.