| Autor: |
Kardashinsky, Mingyue Tang |
| Rok vydání: |
2017 |
| Předmět: |
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| Popis: |
Gadolinium photon activation therapy (GdPAT) is a binary cancer treatment for glioblastoma multiforme. It relies on the release of high linear energy transfer (LET) particles from excited gadolinium. Mitochondria is a critical cellular machinery which has been found to have an elevated membrane potential in tumours cells allowing for the selective accumulation of delocalised lipophilic cations such as tetraphenylphosphonium derivatives. Gadolinium complexes are highly stable molecules with low cytotoxicity. A small library of DO3A-Gd(III) complexes containing an arylphosphonium targeting moiety was synthesised to ascertain some structure-activity relationships (SARs) and assess their potential as GdPAT agents. Preliminary biological evaluation of the new Gd(III) complexes showed low cytotoxicity with preliminary IC50 values of greater than 1 mM for all complexes. Increasing lipophilicity increased Gd uptake into normal cells while having no effect on tumour cells. Increased proximity of Gd to phosphonium centre negatively impacted uptake into both cell lines. The para-tolyldiphenyl complex showed the most desirable overall statistic with low cytotoxicity (> 2mM), high uptake (6.6 ± 0.6 µg Gd/mg of protein) and the best tumour selectivity (T/N of 80:1 SE 12) of all complexes assessed. Synchrotron PAT experiments were performed to determine the PAT effect of three Gd complexes. The PAT effect is defined as the synergistic effect over and above any loss in cell viability resulting from the combined effects of drug and radiation. In addition to complex concentration and radiation does, post-treatment and media change both play a statistically significant role. The tolyldiphenyl complex was the most promising complex with selective cell kill (viability of ~69 % for T compared to ~77 % for N) and >20 % selective PAT effect supporting results from biological studies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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