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

doi:10.1021/acsami.3c10025

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 journal › Article › peer-review

10 Scopus citations

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 language	English
Pages (from-to)	43607-43620
Number of pages	14
Journal	ACS Applied Materials and Interfaces
Volume	15
Issue number	37
DOIs	https://doi.org/10.1021/acsami.3c10025
State	Published - Sep 20 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

Funding

This work was supported by grant R01CA258421-01 (S.G.A.) from the National Cancer Institute (NCI) and a National Science Foundation Chemistry of Life Processes (NSF-CLP) grant for S.G.A. (Award CHE-2203559). The following research centers and facilities at the University of Kentucky aided in completing the studies described in this publication. The UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). We would like to thank Tomoko Sengoku PhD and Michael Alstott for the support with our mitostress experiments, these experiments were carried out by support from the shared resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). We also thank Dr. Pat Sullivan’s laboratory for access to their Seahorse XF96 and Dr. Hemendra Vekaria for running some of the mito stress experiments. For the scanning electron microscopy (SEM) characterization assistance was provided by the Electron Microscopy Center at the University of Kentucky, member of the KY INBRE (Kentucky IDeA Networks of Biomedical Research Excellence), which is funded by the National Institutes of Health (NIH) National Institute of General Medical Science (IDeA Grant P20GM103436). We would also like to acknowledge BioRender.com for TOC image.

Funders	Funder number
OK-INBRE
National Science Foundation Chemistry of Life Processes	CHE-2203559
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	CHE-997738, CHE-1625732
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute
National Institute of General Medical Sciences	P20GM103436
National Institute of General Medical Sciences
University of Kentucky
University of Kentucky Markey Cancer Center	P30CA177558
University of Kentucky Markey Cancer Center

Keywords

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

ASJC Scopus subject areas

General Materials Science

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsami.3c10025

Cite this

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

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\textasciicircum{}N) or biphenyl (C\textasciicircum{}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.",

keywords = "bovine serum albumin, cyclometalation, dithiocarbamate, encapsulation, gold(III), nanoparticles, stability",

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year = "2023",

month = sep,

day = "20",

doi = "10.1021/acsami.3c10025",

language = "English",

volume = "15",

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Circumventing Physicochemical Barriers of Cyclometalated Gold(III) Dithiocarbamate Complexes with Protein-Based Nanoparticle Delivery to Enhance Anticancer Activity. / Arojojoye, Adedamola S.; Walker, Breyanna; Dawahare, James C. et al.
In: ACS Applied Materials and Interfaces, Vol. 15, No. 37, 20.09.2023, p. 43607-43620.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Circumventing Physicochemical Barriers of Cyclometalated Gold(III) Dithiocarbamate Complexes with Protein-Based Nanoparticle Delivery to Enhance Anticancer Activity

AU - Arojojoye, Adedamola S.

AU - Walker, Breyanna

AU - Dawahare, James C.

AU - Afrifa, Maame Abena O.

AU - Parkin, Sean

AU - Awuah, Samuel G.

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KW - bovine serum albumin

KW - cyclometalation

KW - dithiocarbamate

KW - encapsulation

KW - gold(III)

KW - nanoparticles

KW - stability

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VL - 15

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EP - 43620

JO - ACS Applied Materials and Interfaces

JF - ACS Applied Materials and Interfaces

IS - 37

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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