Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH3)2}2mu-dpzm]2+ and its implications for anticancer drug delivery.
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)}(2)mu-dpzm](2+) (di-Pt; where dpzm=4,4'-dipyrazolylmethane) as a model complex, has been examined using (1)H 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 microM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 microM, respectively). s-CX[4] displays no cytotoxicity at concentrations up to 1.5mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 x 10(4)M(-1)) means the host-guest complex is mostly disassociated at biologically relevant concentrations.
Wheate
Nial J
NJ
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, United Kingdom. nial.wheate@strath.ac.uk
Abbott
Grainne M
GM
Tate
Rothwelle J
RJ
Clements
Carol J
CJ
Edrada-Ebel
Ruangelie
R
Johnston
Blair F
BF
D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000737:chemistry; D047250:Calixarenes / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D015195:Drug Design; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage / Q000737:chemistry*
D016588:Anticarcinogenic Agents; D009944:Organoplatinum Compounds; D010636:Phenols; C539778:bis(diamminechloroplatinum)-mu-4,4'-dipyrazolylmethane; C121325:calix(4)arene; D047250:Calixarenes; D002945:Cisplatin