Preparation And Performance Of PH And Reduction Dual-responsive Galactose Modified Gelatin-poly(β-amino Ester) Microspheres With Property Of Liver Targeting

Gelatin microsphere has been widely researched as antitumor drug delivery system combined with transarterial chemoembolization, however, releasing of drug loaded in the gelatin microsphere suffers inferior controllability for it is mainly determined by slow vector hydrolysis. Even when they are administrated in the transarterial chemoembolization, which means the more difficultly microspheres are degraded, the better embolization would be obtained, the chemotherapeutic effects would be disappointing with slow drug relase for antitumor drugs which need high concentrations to maintain therapeutic effects and reduce drug resistance. So it is significant to improve pharmacokinetics of traditional gelatin microspheres.Gelatin bears abundant groups in the structure such as amino, hydroxyl and carboxyl. These groups are highly reactive and can be used to connect functional molecules to gelatin to endow microsphers made of the modified gelatin active targeting. Asialoglycoprotein receptor (ASGR), existing only at the surface of mammal hepatocyte, can specifically recognize glycoprotein containing galactose or N-acetyl galactose at the end. For improving liver aggregation of gelatin microspheres mediated by ASGR, gelatin was modified by galactose through2-imino-2-methoxyethyl1-thioglycosides (IME-thioglycosides). What’s more, according to the fact that tumor tissues show lower pH and higher concentration of reduced glutathione (GSH) compared with normal tissues, galactose modified gelatin (galG) and linear poly(p-amino ester)(PBAE) synthesized by Michael addition polymerization between N,N’-dimethylethylenediamine and bis(acryloyxyethyl) disulfide and bearing disulfide bonds in each unit and secondary amino at both ends, were considered as monomers to construct a novel hybrid microspheres.Then such a novel pH and reduction dual-responsive hybrid microsphere (galG-PBAE microsphere) with liver targeting was prepared by emulsion cross-linking method. Doxorubicin hydrochloride (DOX·HC1) was loaded as antitumor drug model. The DOX-loaded galG-PBAE microspheres were prepared in spherical morphology with66.08%of drug loading efficiency (DLE%) and6.61%of drug loading content (DLC%) and passive targeting to liver could be obtained in size distribution of3-30μm. The in vitro drug release was greatly accelerated by reducing the pH or by adding a reducing agent, dithiothreitol (DTT). Active targeting of DOX loaded galG-PBAE microspheres was demonstrated by incubated with HepG2cells (with ASGR) and Hela cells (without ASGR).So, the proposed galG-PBAE microsphere has been proved as a pH and reduction dual-responsive novel drug delivery system in chemotherapy with property of liver targeting and could improve pharmacokinetics of gelatin microspheres.