Phosphonate and bisphosphonate - functionalized poly (B-amino ester)s and polyethylenimines for biomedical applications

Abstract

In the first part of this study, phosphonate/bisphosphonate end-modified poly(βamino ester)s (PBAEs) are synthesized and their pH sensitivity and drug delivery properties are investigated. Synthesis of the polymers involves two steps: i) preparation of acrylate-terminated polymers from reactions of poly(ethylene glycol) diacrylate (PEGDA, Mn=575) and 1,6-hexanediol diacrylate (HDDA) with propyl amine (PA) or 5-amino-1pentanol (HP) and ii) reaction of these polymers with a phosphonate or a bisphosphonatefunctionalized amine to give phosphonate/bisphosphonate end-modified PBAEs. The pH sensitivity of the polymers are determined, the pKb values ranging 4.90 to 7.50. Two of the micelle forming PBAEs were investigated for the delivery of the chemotherapy drug Doxorubicin (DOX). The micelles released DOX slowly at pH 7.4 (less than 20% in 120 hours). However, DOX release at pH 5.5 was fast (60% in 120 hours) because of the dissolution of the micelles at the acidic pH. Results of this study demonstrated the potential of the tested polymers as drug delivery systems. In the second part, phosphonate/bisphosphonate functionalized polyethylenimines (PEIs) (branched, Mn= 1.8 and 10 kDa) are synthesized for possible gene transfer applications. Synthesis of polymers involved Michael Addition reactions of diethyl vinylphosphonate (P1), tetraethyl vinylidene bisphosphonate (P2) and PEIs. Preliminary examinations showed some transfection efficiencies for P2 substituted PEIs. Moreover, P2 substitution decreased the toxicity of the polymers in vitro.