The Synthesis And Characterization Of Acid-sensitive Polyethylene Oxide - Graft - Doxorubicin Prodrug

In this paper, anionic ring-opening polymerization was used to synthesize functional PEO with multiple pendant double bonds (PEO-g-allyl). pH-sensitive macromolecular drugs, PEO-g-DOX, were obtained by transforming the pendant allyl groups to hydrazine groups followed by conjugation with doxorubicin (DOX). The vitro release experiments showed that drug release rates were highly pH-dependant. These PEO-g-DOX prodrugs following uptaken by cells effectively released DOX into the cytosol and cell nuclei, achieving high drug efficacy. The biodistribution studies showed that these prodrugs had much longer circulation time and higher accumulation in the tumor tissue as compared to free DOX.(1). We have synthesized a series of functional PEO with multiple pendant double bonds (PEO-g-allyl). Random copolymers of ethylene oxide (EO) and allyl glycidyl ether (AGE), referred to as PEO-g-allyl, were synthesized with controlled molecular weights, low polydispersities and controlled functionality by ring-opening copolymerization of EO and AGE using ethylene glycol/potassium naphthalene as an initiator. Polymer PEO-g-allyl like PEO had good water solubility and was non-toxic.(2). pH-sensitive PEO-g-DOX prodrugs were prepared by derivatizing PEO-g-allyl into hydrazine groups followed by conjugation with DOX via hydrazone bonds. These PEO-g-DOX prodrugs were stable under physiological conditions (pH 7.4). However, at mildly acidic pH of 5-6, DOX would be rapidly released. These PEO-g-DOX prodrugs following uptaken by cells effectively released DOX into cell nuclei, achieving high drug efficacy. The biodistribution studies showed that these prodrugs had much longer circulation time and higher accumulation in the tumor tissue as compared to free DOX.