posted on 2023-09-11, 17:34authored byAdedamola
S. Arojojoye, Breyanna Walker, James C. Dawahare, Maame Abena O. Afrifa, Sean Parkin, Samuel G. Awuah
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.