Development of implantable antitumor devices based on polyphosphazenes

Abstract

AbstractPolyphosphazenes containing amino acid ester substituents are of considerable interest as bioerodible matrix systems for controlled release of drugs. In order to develop locally acting antitumor devices, a model anticancer agent, melphalan, was physically incorporated in three different polyphosphazene polymers. For studying the release rate of melphalan from the three polymers and the extent of degradation of melphalan during this sustained release process, a flow through‐system was used. This system is characterized by low flow rates, in order to approximate the in vivo implantation situation. Eluents were used, with pH 7.0 and 5.0, showing a melphalan degradation half time (respectively 2.0 and 1.9 hours) comparable with those observed in vitro in human plasma. Polymer 1 (poly[bis(glycine ethyl ester)phosphazene]) released after one week 35% and 42% unhydrolyzed melphalan, at pH 7.0 and pH 5.0 respectively, in a gradual manner. Considerable lower release rates were observed using polymers 2 and 3. Polymer 2 (50% substituted with glutamic acid diethyl ester, 50% with glycine ethyl ester) showed release percentages of 10 and 14%, polymer 3 (50% substituted with phenylalanine ethyl ester, 50% with glycine ethyl ester) 12 and 14% after one week at pH 7.0 and 5.0, respectively. Melphalan concentrations were measured by applying a High Pressure Liquid Chromatography method with fluorescence detection. By this method also the two degradation products mono‐ and dihydroxy‐melphalan could be measured.Considering the release profiles of these degradation products, the conclusion may be drawn that either melphalan is stabilized in the three polymers, or that melphalan is less exposed to the aqueous environment than is the case when used as a solution. These results justify expectations that it should be possible to develop locally acting tumor devices, being able to release an unstable anticancer agent in a gradual manner for several weeks or months and resulting in locally effective drug concentrations during this period.