Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Gordon J Kirkpatrick, Jane A Plumb, Oliver B Sutcliffe, David J Flint, Nial J Wheate

Research output: Contribution to journalArticle

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Abstract

Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60°C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%.
LanguageEnglish
Pages1115-1122
Number of pages8
JournalJournal of Inorganic Biochemistry
Volume105
Issue number9
Early online date27 Sep 2011
DOIs
Publication statusPublished - Sep 2011

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Dendrimers
Cisplatin
Pharmaceutical Preparations
Tumors
Cytotoxicity
Poly(amidoamine)
Guanosine Monophosphate
Neoplasms
Maximum Tolerated Dose
Centrifuges
Tumor Burden
Heterografts
Ovarian Neoplasms
Assays
Binding Sites
Cells
Nuclear magnetic resonance

Keywords

  • cancer
  • platinum
  • pamam dendrimers
  • cisplatin
  • cytotoxicity
  • diffusion NMR

Cite this

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title = "Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin",
abstract = "Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37{\%}, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60°C for over a week (percentage of drug released 18, 30, 35 and 63{\%}, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6mg/kg, reduced tumour size by 33{\%} compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32{\%}, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45{\%}.",
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Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin. / Kirkpatrick, Gordon J; Plumb, Jane A; Sutcliffe, Oliver B; Flint, David J; Wheate, Nial J.

In: Journal of Inorganic Biochemistry, Vol. 105, No. 9, 09.2011, p. 1115-1122.

Research output: Contribution to journalArticle

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AU - Kirkpatrick, Gordon J

AU - Plumb, Jane A

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AU - Wheate, Nial J

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