Study On The Synthesis And Toxicity Of Liver-targeted Dendrimer Prodrug With PH-sensitive Doxorubicin Release Profile

Several novel PEG-block-polyamide-imides(PEG-b-PAMAM) were synthesized from the PEG-amine derivatives(HO-PEG-NH₂,NH₂-PEG-NH₂,mPEG-NH₂),which were obtained from PEG or mPEG.HO-PEG-NH₂ and NH₂-PEG-NH₂ were galactosylated to get targeted groups.PEG-b-PAMAM-Dox prodrug was fabricated by conjugation of doxorubicin and PEG-b-PAMAM block copolymer via an acid-labile hydrazone bond,and characterized by FT IR,¹H NMR,UV-Vis,and anthrone colorimetry.Their in vitro drug release behavior was evaluated in different pH buffer media,while the cytotoxicity study towards liver cells was studied by MTT and fluorescence microscope.Targeting to live of PEG-b-PAMAM galactosylated derivative was investigated by MRI.In vivo antitumor activity was performed by animal experiments.It was found that PEG-b-PAMAM-Dox prodrug showed a pH-sensitive drug release manner due to the acid-liable hydrazone bond between Dox and PEG-b-PAMAM,and its drug release rate in acid buffer was sharply higher than that in neutral or alkaline buffer. Then the in vitro cytotoxicity of PEG-b-PAMAM-DOXn was lower than that of DOX with the same Dox dosage within a certain period of time due to its slow release nature of the prodrug.It also showed that the in vitro cytotoxicity of galactosylated prodrug against hepatoma cells was enhanced.Gal-CONH-PEG-b-PAMAM-Gd showed a clear effect of contrast-enhanced in MRI and had a longer residence time in the liver.It was found that galactosylated prodrug had a better tumor inhibition via in vivo study,as well as shown excellent targeting property via MRI,which might lead to greater potential applications for targeting therapy of liver cancer.