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| As a proof of concept,a non-polar amino acid (valine) was attached to the C20position of SN38 via an ester bond to generate Val-SN38 (Fig. 6B). The exact solubility of the Val-SN38 in lipids was not reported. It was categorised as a lipophilic prodrug given the non-polarity of the attached valine moiety. Val-SN38 improved intracellular accumulation in MCF7 cells by more than 5-fold in comparison to SN38, without inducing significant multiple-drug resistance. Improved accumulation of ValSN38 has been suggested to be due to augmented uptakeviavarious amino acid transporters. The prodrug, however, showed poor stability and readily converted to the inactive carboxylate form in PBS, MCF 7 cell lines and plasma. Further optimisation of the prodrug to better control the conversion rate to the carboxylate form may result in more potent prodrugs. Alternatively, the prodrug may be incorporated into lipid-based formulations to stabilise the lactone form. |
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gundnir: 金币+50, 翻译EPI+1 2014-02-26 01:07:11
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