Diruthenium complexes as pH-responsive delivery systems: a quantitative assessment?

Inorganic Chemistry Frontiers Pub Date: 2023-05-18 DOI: 10.1039/D3QI00399J

Abstract

The controlled release of biologically active species from diruthenium compounds is crucial for the development of selective drug delivery systems based on such complexes, which in addition display antineoplastic properties by themselves. In the present work, we analyse in detail the kinetics of the pH-triggered release of the auxin-related hormones 2,4-D (2,4-dichlorophenoxyacetate) and NAA (1-naphthaleneacetate) from the metal–metal bonded tris(formamidinato) Ru25+ complexes [Ru2Cl(μ-DPhF)3(μ-2,4-D)] (Ru2,4-D), [Ru2Cl(μ-DPhF)3(μ-NAA)] (RuNAA), [Ru2Cl(μ-DAniF)3(μ-2,4-D)] (Ru′2,4-D) and [Ru2Cl(μ-DAniF)3(μ-NAA)] (Ru′NAA) (DPhF = N,N′-diphenylformamidinate, DAniF = N,N′-bis(p-methoxy)phenylformamidinate). Moreover, the synthesis and complete characterisation of [Ru2Cl(μ-DAniF)3(μ-IAA)] (Ru′IAA, IAA = indole-3-acetate), Ru′2,4-D and Ru′NAA, including the crystal structure of the two latter ones, is reported. The release of auxins is studied through a fluorimetric quantitative assay, which allows determining the influence of different formamidinate ancillary ligands and the nature of the outgoing auxin ligand in the release process. Chemometrics is employed to evaluate the statistical significance of the variables. The release of auxins is slower at physiological pH and occurs faster at slightly acidic pH values. Compounds containing DPhF ancillary ligands and NAA outgoing ligand present a slower dissociation of the auxin, which is not complete in the first 24 h. The release rate is also correlated with the bond distance O1(auxin)–Ru1(hexacoordinated). A mechanism of the substitution reaction is tentatively proposed based on these findings. Overall, these results pave the way towards new systems for the controlled delivery of antineoplastic drugs under mild-acidic conditions like those surrounding solid tumours.

Graphical abstract: Diruthenium complexes as pH-responsive delivery systems: a quantitative assessment
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