Dextrins as potential carriers for drug targeting: tailored rates of dextrin degradation by introduction of pendant groups

There is a recognised need to identify new biodegradable polymers suitable for development as targetable drug carriers, The aim of this study was to determine the rate of degradation of two dextrin fractions (Mw 15.5 and 51 KDa) by alpha -amylase and liver lysosomal enzymes (tritosomes). Also experiments were conducted to discover whether backbone modification by succinolyation (1 - 34 mol%) or pendant group incorporation (e.g. doxorubicin) could be used to tailor the rate of polymer degradation. Dextrin (alpha -1,4 polyglucose) is a natural polymer used clinically as a peritoneal dialysis solution and as a controlled drug delivery formulation. Size exclusion chromatography (SEC) showed that dextrin was degraded rapidly (within 20 min) by rat plasma and porcine pancreatic alpha -amylase. In contrast over 48 li no degradation was observed in the presence of tritosomes. The rate of alpha -amylase degradation of succinoylated dextrins (Mw similar to 51 KDa) was dependant on the degree of modification (dextrin > 1 > 5 > 15 > 34 mol% succinoylation). Dextrin-doxorubicin conjugates were prepared from the 15 and 34 mol% succinoylated intermediates to have a doxorubicin loading of 8 and 12 wt.%, respectively. These doxorubicin conjugates were more stable than their parent intermediates, and SEC showed an apparently higher molecular weight. The drug conjugates did however degrade slowly over 7 days to release oligosaccharide-doxorubicin species. This fundamental study demonstrates the possibility of controlling the rate of dextrin enzymolysis by backbone modification and thus affords the potential to rationally design dextrin-drug conjugates for specific applications as targetable carriers. (C) 2001 Elsevier Science B.V. All rights reserved.