Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH 3) 2} 2μ-dpzm] 2+ and its implications for anticancer drug delivery

• Published in: Journal of inorganic biochemistry Vol. 103; no. 3; pp. 448 - 454
• Main Authors: Wheate, Nial J., Abbott, Grainne M., Tate, Rothwelle J., Clements, Carol J., Edrada-Ebel, RuAngelie, Johnston, Blair F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2009
• Subjects: Alamar blue; Anticarcinogenic Agents - administration & dosage; Anticarcinogenic Agents - chemistry; Calixarenes - administration & dosage; Calixarenes - chemistry; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin - administration & dosage; Cisplatin - chemistry; Cytotoxicity; Drug delivery; Drug Delivery Systems; Drug Design; Female; Humans; MTT; Multinuclear; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - chemistry; Ovarian cancer; Ovarian Neoplasms - metabolism; p-sulphonatocalixarene; Phenols - administration & dosage; Phenols - chemistry; Platinum; p-sulphonatocalixarene; Alamar blue; Platinum; Multinuclear; Cytotoxicity; Drug delivery; MTT; Ovarian cancer
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2008.12.011

The utility of
p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using
trans-[{PtCl(NH
3)
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-CX[4] 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-CX[4] cavity with binding further stabilised by ion–ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] 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-CX[4]. The cytotoxicity of free di-Pt and s-CX[4] 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 IC
50 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-CX[4] 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
×
10
4
M
−1) means the host–guest complex is mostly disassociated at biologically relevant concentrations.