Study On PEGylation Of Dasatinib

Dasatinib is the second generation of tyrosine kinase inhibitors after Imatinib,used to treat chronic granulocyte and Philadeplhia chromosome positive acute lymphoblastic leukemia with advantages of low effective concentration,well tolerance,good efficacy and high safety.But there are still shortcomings existing in Dasatinib,for instance,low water-solubility,short half-time and low bioavailability.According to the theory of prodrug,the purpose of this paper is to choose the polyethylene glycol(PEG)as the suitable carrier to modify Dasatinib to form the prodrug of Dasatinib through a specific group.The prodrug of Dasatnib is expected to increase the stability,prolong the half-life and improve the bioavailability of Dasatinib drug,while the PEGylated Dasatinib also is expected having the ability of controlled-release.PEG was used as the carrier and reacted with succinyl anhydride to give a PEG derivative with the active carboxylic terminal.The derivative can be further activated with N-hydroxysuccinimide to afford the active ester.The active ester further reacted with Dasatinib to prepare the prodrug of Dasatinib.The structure of prepared PEG-Dasatinib prodrug was characterized by IR,~1H-NMR,X-ray diffraction(XRD)and differential scanning calorimetry(DSC).Reaction steps of PEG-Dasatinib prodrug were optimized,and the loading rate and water solubility of prepared PEG-Dasatinib prodrug were also measured by Ultraviolet spectrum(UV)and high performance liquid chromatography(HPLC).The stability and external release experiments of PEG-Dasatinib prodrug were studied and the content of PEG-Dasatinib was measured by HPLC.The results showed that the prepared Dasatinib prodrug has owned better stability,the water solubility of Dasatinib drug was greatly improved and the prodrug has ability of controlled-release.