Platinum(II)−Dendrimer Conjugates: Synthesis and Investigations on Cytotoxicity, Cellular Distribution, Platinum Release, DNA, and Protein Binding

Kapp, Timo; Dullin, Anja; Gust, Ronald

doi:10.1021/bc900406m

Cited by 53 publications

(32 citation statements)

References 38 publications

(45 reference statements)

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“…Significant activity was only observed in vivo in L1210 murine leukaemia and B16 melanoma bearing mice. In another study, in vitro cytotoxicity was only observed when a platinum-dendrimer complex was incubated with cells for very long periods of time: 75 to 225 h [33]. Therefore our in vitro results do not necessarily imply that the drug-dendrimer complexes developed in this study are not active and different methods for determining cytotoxicity, including in vivo experiments, may be necessary for dendrimer-based delivery systems to be investigated properly.…”

Section: In Vivo Effectivenessmentioning

confidence: 68%

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

Plumb

Sutcliffe

et al. 2011

Journal of Inorganic Biochemistry

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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 Article Type: Regular Paper Keywords: cancer; platinum; PAMAM dendrimer; cisplatin; guanosine; cytotoxicity; diffusion NMR. 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 y 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 oC 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%. We have revised the manuscript taking into account all your listed corrections and stylistic requirements.As siDNA and PBS were used only once in the manuscript we have now written these in full and not used them as abbreviations.For simplicity, we have made figure 5 just black and white and have changed the figure caption to reflect this. 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 o 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 tu...

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Section: In Vivo Effectivenessmentioning

confidence: 68%

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

Plumb

Sutcliffe

et al. 2011

Journal of Inorganic Biochemistry

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“…Full generation PAMAM dendrimers have amine surface groups that can be used to irreversibly bind platinum, thus using the dendrimer as part of the structure of the drug rather than as a delivery vehicle (Kapp et al 2010). Half-generation PAMAM dendrimers have carboxylate surface groups and can bind cationic platin drugs via electrostatic interactions (Pisani et al 2009).…”

Section: Dendrimersmentioning

confidence: 99%

The state-of-play and future of platinum drugs

Apps

Choi

Wheate

2015

Endocrine-Related Cancer

230

142

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The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects.

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“…Instead of using the cellular Pt accumulation (ng of Pt per 10 6 cells), the accumulation ratio (AR), a concept similar to the "accumulation grade of factor" previously defined by Gust et al [53], was employed in the present paper. AR is the dimensionless ratio between the cellular Pt concentration (taking into account the experimentally measured cell volume) and the extracellular Pt concentration (i.e.…”

Section: Lipophilicity and Cellular Accumulation Of 1-4 Complexes On mentioning

confidence: 99%

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Ravera

Gabano

Zanellato

et al. 2015

Journal of Inorganic Biochemistry

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Platinum(II)−Dendrimer Conjugates: Synthesis and Investigations on Cytotoxicity, Cellular Distribution, Platinum Release, DNA, and Protein Binding

Cited by 53 publications

References 38 publications

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

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

The state-of-play and future of platinum drugs

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

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