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Dextrins as Carriers for Drug Targeting: Reproducible Succinoylation as a Means to Introduce Pendant Groups

Lisa German

Centre for Polymer Therapeutics, School of Pharmacy, University of London, London, WCIN 1AX, UK

Ruth Duncan

Centre for Polymer Therapeutics, School of Pharmacy, University of London, London, WCIN 1AX, UK; Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, Wales. DUNCANR{at}cf.ac.uk

Dextrin (a-1,4 polyglucose) is in clinical use as a peritoneal dialysis solution and controlled drug delivery formulation. As a biodegradable polymer, dextrin has considerable potential as a polymeric drug carrier. Succinoylation, using dimethylaminopyridine (DMAP) as a catalyst, was used to conjugate chemotherapeutic agents, probes to follow biodistribution and probes to monitor intracellular fate. The aims of this study were to optimize the reaction conditions for the succinoylation (in respect of temperature and reaction time), to assess the suitability of succinoylated-dextrin as an intermediate for conjugation of drugs and probes selected to monitor pharmacokinetics (doxorubicin, tyrosinamide and biotin). The optimum temperature for succinoylation was 50⁰C with a minimum of 8 h reaction time. Under these conditions succinoylation was reproducible with a coefficient of variation of < 10% and always gave a -50% yield. Different degrees of dextrin succinoylation (0.5-30 mol%) was achieved by variation of the reactants. Conjugation of doxorubicin to the succinoylated dextrin intermediate (15 or 34 mol%) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysulfosuccinimde (sulfo-NHS) reproducibly gave conjugates containing-9.0 wt% with < 1% of the total doxorubicin present as free drug. Tyrosinamide and biotin were bound to the succinoylated intermediate using carbodiimidazole (CDI). Dextrin-tyrosinamide conjugates were -1 mol% modified and the dextrin-biotin conjugates containing 6.8 wt% biotin. Succinoylation of dextrin is a non-polymer-disruptive method that can be used to reproducibly introduce pendant groups. The resultant conjugates are suitable for biological evaluation in in vitro and in vivo.

Journal of Bioactive and Compatible Polymers, Vol. 16, No. 5, 353-365 (2001)
DOI: 10.1106/QBKY-E3VM-19K4-3GA5


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