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

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Abstract

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.
LanguageEnglish
Pages448-454
Number of pages6
JournalJournal of Inorganic Biochemistry
Volume103
Issue number3
DOIs
Publication statusPublished - Mar 2009

Fingerprint

Coordination Complexes
Platinum
Drug delivery
Cytotoxicity
Pharmaceutical Preparations
Assays
Cells
Ions
Guanosine Monophosphate
Cell Line
Electrospray ionization
Molecular modeling
Electrospray Ionization Mass Spectrometry
Guanosine
Hydrogen Bonding
Growth
Encapsulation
Antineoplastic Agents
Ovarian Neoplasms
Cisplatin

Keywords

  • p-sulphonatocalix[4]arene
  • platinum
  • alamar blue
  • MTT
  • drug delivery
  • multinuclear
  • cytotoxicity
  • ovarian cancer
  • pharmacology

Cite this

@article{7b038e4ba92b47fe93233e858f582040,
title = "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",
abstract = "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.",
keywords = "p-sulphonatocalix[4]arene, platinum, alamar blue, MTT, drug delivery, multinuclear, cytotoxicity, ovarian cancer, pharmacology",
author = "N.J. Wheate and Abbott, {Grainne M.} and Tate, {Rothwelle J.} and Clements, {Caorl J.} and RuAngelie Edrada-Ebel and B.F. Johnston",
year = "2009",
month = "3",
doi = "10.1016/j.jinorgbio.2008.12.011",
language = "English",
volume = "103",
pages = "448--454",
journal = "Journal of Inorganic Biochemistry",
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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, N.J.

AU - Abbott, Grainne M.

AU - Tate, Rothwelle J.

AU - Clements, Caorl J.

AU - Edrada-Ebel, RuAngelie

AU - Johnston, B.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 - p-sulphonatocalix[4]arene

KW - platinum

KW - alamar blue

KW - MTT

KW - drug delivery

KW - multinuclear

KW - cytotoxicity

KW - ovarian cancer

KW - pharmacology

UR - http://dx.doi.org/10.1016/j.jinorgbio.2008.12.011

U2 - 10.1016/j.jinorgbio.2008.12.011

DO - 10.1016/j.jinorgbio.2008.12.011

M3 - Article

VL - 103

SP - 448

EP - 454

JO - Journal of Inorganic Biochemistry

T2 - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

SN - 0162-0134

IS - 3

ER -