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

Adedamola S. Arojojoye, Breyanna Walker, James C. Dawahare, Maame Abena O. Afrifa, Sean Parkin, Samuel G. Awuah

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)43607-43620
Number of pages14
JournalACS Applied Materials and Interfaces
Volume15
Issue number37
DOIs
StatePublished - Sep 20 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

  • bovine serum albumin
  • cyclometalation
  • dithiocarbamate
  • encapsulation
  • gold(III)
  • nanoparticles
  • stability

ASJC Scopus subject areas

  • General Materials Science

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