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 h no degradation was observed in the presence of tritosomes. The rate of alpha-amylase degradation of succinoylated dextrins (Mw approximately 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.
Hreczuk-Hirst
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D
Centre for Polymer Therapeutics, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Chicco
D
D
German
L
L
Duncan
R
R
D000818:Animals; D002240:Carbohydrate Sequence; D003912:Dextrins / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers; D016503:Drug Delivery Systems; D066298:In Vitro Techniques; D019344:Lactic Acid; D008099:Liver / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010179:Pancreas / Q000201:enzymology; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D013386:Succinates / Q000378:metabolism; D013552:Swine; D000516:alpha-Amylases / Q000737:chemistry
D003912:Dextrins; D004337:Drug Carriers; D011108:Polymers; D013386:Succinates; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000516:alpha-Amylases