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 d etermine the rate of degradation of two dextrin fractions (Mw 15.5 and 51 K Da) by alpha -amylase and liver lysosomal enzymes (tritosomes). Also experi ments were conducted to discover whether backbone modification by succinoly ation (1 - 34 mol%) or pendant group incorporation (e.g. doxorubicin) could be used to tailor the rate of polymer degradation. Dextrin (alpha -1,4 pol yglucose) is a natural polymer used clinically as a peritoneal dialysis sol ution and as a controlled drug delivery formulation. Size exclusion chromat ography (SEC) showed that dextrin was degraded rapidly (within 20 min) by r at 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 de pendant on the degree of modification (dextrin > 1 > 5 > 15 > 34 mol% succi noylation). 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 the ir parent intermediates, and SEC showed an apparently higher molecular weig ht. The drug conjugates did however degrade slowly over 7 days to release o ligosaccharide-doxorubicin species. This fundamental study demonstrates the possibility of controlling the rate of dextrin enzymolysis by backbone mod ification and thus affords the potential to rationally design dextrin-drug conjugates for specific applications as targetable carriers. (C) 2001 Elsev ier Science B.V. All rights reserved.