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

Abstract

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.

Get full access to this article

View all access options for this article.

References

1. Vasey, P. , Twelves, C. , Kaye, S. , Wilson, P. , Morrison, R. , Duncan, R. , Thomson, A. , Hilditch, T. , Murray, T. , Burtles, S. and Cassidy, J. (1999). Clin. Cancer Res., 5: 83-83.

2. Brocchini, S. and Duncan, R. (1999). In: Mathiowitz, E. (Ed.), The Encyclopedia of Controlled Drug Delivery. New York: John Wiley and Sons. p. 786-786.

3. Li, C. , Yu, D. , Inoue, T. , Yang, D. , Milas, L. , Hunter, N. , Kim, E. and Wallace, S. (1996). Anticancer Drugs, 7: 642-642.

4. Vercauteren, R. , Bruneel, D. , Schacht, E. and Duncan, R. (1990). J. Bioact. Compat. Polym., 5: 4-4.

5. Alsop, R.M. (1994). Perit. Dial. Int., 14: 85-85.

6. Kerr, D.J. , Young, A.M. , Neoptolemos, J.P. , Sherman, M. , VanGeene, P. , Stanley, A. , Ferry, D. , Dobbie, J.W. , Vincke, B. , Gilbert, J. , ElEini, D. , Dombros, N. and Fountzilas, G. (1996). Brit. J. Cancer, 74: 2032-2032.

7. Bruneel, D. and Schacht, E. (1993). Polymer, 34: 2628-2628.

8. Hermanson, G.T. , Mallia, A.K. and Smith, P.K. (1991). In: Immobilised Affinity Techniques. London: Academic Press. p. 63-63.

9. Bruneel, D. and Schacht, E. (1993). Polymer, 34: 2633-2633.

10.

10. Bruneel, D. and Schacht, E. (1994). Polymer, 36: 2656-2656.

11.

11. Danauser-Reidl, S. , Hausmann, E. , Schick Bender, H.R. , Dietzfelbinger, H. , Rastetter, J. and Hanauske, A. (1993). Investigational New Drugs, 11: 187-187.

12.

12. Hreczuk-Hirst, D.H. , German, L. and Duncan, R. (1999). In: Proc. Intl. Symp. on Cont. Rel. Bioact. Master, 26: 1086-1086.

13.

13. German, L. , Hirst, D. and Duncan, R. (1999). In: Proc. of the 9th Intl. Symp. on Recent Adv. in Drug Delivery Systems. USA: Salt Lake City. p. 212-212.

14.

14. Fraier, D. , Frigerio, E. , Pianezzola, E. , Strolin Benedetti, M. , Cassidy, J. and Vasey, P. (1995). J. Pharma Biomed. Anal., 13: 625-625.

15.

15. Hermanson, G.T. (1996). Bioconjugate Techniques. London: Academic Press. p. 592-592.

16.

16. Arranz, F. , Sanchez-Chaves, M. and Ramirez, J.C. (1992). Angewandte Chemie., 194: 79-79.

17.

17. Bruneel, D. and Schacht, E. (1995). J. Bioact. Compat. Polym., 10: 299-299.