Modulated release of IdUrd from poly (D,L-lactide-co-glycolide) microspheres by addition of poly (D,L-lactide) oligomers

This paper reports the release characteristics of a radiosensitizer, 5-iodo -2'-deoxyuridine (IdUrd), from poly (D,L-lactide-co-glycolide) 50: 50 (PLGA ) microparticles obtained by a phase separation technique. Poly (D,L-lactid e) oligomers (D,L-PLA) were incorporated into the PLGA matrix in order to a ccelerate the overall drug release rate and regulate the triphasic release profile exhibited by the standard PLGA microparticles. For D,L-PLA (800), t he burst effect was large and the IdUrd release was complete between 28 and 35 days. These results were attributed to rapid pore formation on the peri phery of the microspheres in the early stages of incubation, due to hydroso lubility of the smallest oligomers (D,L-PLA (800)). In the case of D,L-PLA (1,100), drug release occurred over a six week period, the standard time co urse of conventional radiation therapy. The period during which the radiose nsitizer was incorporated in human brain tumor cell nuclei after its entrap ment in biodegradable microspheres was determined by using an organotypical tissue culture. The presence of radiosensitizer in the DNA of tumor cell n uclei was detected by immunohistochemical labelling of tumor fragments. IdU rd release from standard microspheres (7 +/- 0.5 weeks) was longer than fro m oligomer-containing batches. For D,L-PLA (800)-containing microspheres, t he radiosensitizer was entirely released within 4.5 +/- 0.5 weeks. The micr ospheres containing D,L-PLA (1,100) allowed an IdUrd release over a 5 to 6 week period. The ex vivo data were consistent with the in vitro findings in terms of release duration. (C) 1999 Elsevier Science B.V. All rights reser ved.