Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin |
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Authors: | Kirkpatrick Gordon J Plumb Jane A Sutcliffe Oliver B Flint David J Wheate Nial J |
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Affiliation: | a Strathclyde Institute of Pharmacy and Biomedical Sciences, John Arbuthnott Building, 161 Cathedral Street, Glasgow G4 0RE, United Kingdomb Institute of Cancer Studies, College of Medical, Veterinary and Life Sciences, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow G61 1BD, United Kingdom |
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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 1H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH3)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 6 mg/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 8 mg/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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Keywords: | Cancer Platinum PAMAM dendrimer Cisplatin Cytotoxicity Diffusion NMR |
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