Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH3)2}2μ-dpzm] and its implications for anticancer drug delivery |
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Authors: | Nial J Wheate Grainne M Abbott Carol J Clements Blair F Johnston |
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Institution: | a Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, United Kingdom b Strathclyde Innovations in Drug Research, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, United Kingdom |
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Abstract: | The utility of p-sulphonatocalix4]arene (s-CX4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-{PtCl(NH3)2}2μ-dpzm]2+ (di-Pt; where dpzm = 4,4′-dipyrazolylmethane) as a model complex, has been examined using 1H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5′-guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX4]. The cytotoxicity of free di-Pt and s-CX4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC50 of 100 and 60 μM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 μM, respectively). s-CX4] displays no cytotoxicity at concentrations up to 1.5 mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 × 104 M−1) means the host-guest complex is mostly disassociated at biologically relevant concentrations. |
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Keywords: | p-sulphonatocalix[4]arene Platinum Alamar blue MTT Drug delivery Multinuclear Cytotoxicity Ovarian cancer |
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