TY - JOUR
T1 - Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH3)2}2μ-dpzm]2+ and its implications for anticancer drug delivery
AU - Wheate, Nial J.
AU - Abbott, Grainne M.
AU - Tate, Rothwelle J.
AU - Clements, Carol J.
AU - Edrada-Ebel, Ru Angelie
AU - Johnston, Blair F.
PY - 2009/3
Y1 - 2009/3
N2 - The utility of p-sulphonatocalix[4]arene (s-CX[4]) 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-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 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-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 × 104 M-1) means the host-guest complex is mostly disassociated at biologically relevant concentrations.
AB - The utility of p-sulphonatocalix[4]arene (s-CX[4]) 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-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 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-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 × 104 M-1) means the host-guest complex is mostly disassociated at biologically relevant concentrations.
KW - Alamar blue
KW - Cytotoxicity
KW - Drug delivery
KW - MTT
KW - Multinuclear
KW - Ovarian cancer
KW - p-sulphonatocalix[4]arene
KW - Platinum
UR - http://www.scopus.com/inward/record.url?scp=59649103369&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2008.12.011
DO - 10.1016/j.jinorgbio.2008.12.011
M3 - Article
C2 - 19171382
AN - SCOPUS:59649103369
SN - 0162-0134
VL - 103
SP - 448
EP - 454
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
IS - 3
ER -