Effect of stereotactic implantation of biodegradable 5-fluorouracil-loaded microspheres in healthy and C6 glioma-bearing rats.
OBJECTIVE
Poly(lactic acid-co-glycolic acid) (PLAGA) microspheres are promising systems for interstitial chemotherapy of brain tumors. They can be readily implanted by stereotaxy and are biocompatible with the brain, in which they are totally biodegraded within 2 months. 5-Fluorouracil (5-FU) was selected for encapsulation, because this hydrophilic and antimetabolic drug is not directly neurotoxic and does not readily cross the blood-brain barrier. Also, its anticancer activity may be improved by sustained administration. Furthermore, it is a potent radiosensitizer.


METHODS
To study their fate and toxicity, two types of 5-FU-loaded PLAGA microspheres were implanted in healthy rats by stereotaxy. One type presented a fast in vitro release profile (FR), and the second exhibited a slow in vitro release pattern (SR) (100% of the encapsulated 5-FU is released within 72 hours and 18 days, respectively). Periodically, rats were killed for microscopic examination. The efficacy of these microspheres on rat glioma was then evaluated. Seven days after stereotactic implantation of C6 malignant glioma cells in the brain, the rats were treated by intratumoral injection of 5-FU solution, blank microspheres, or 5-FU-loaded microspheres (FR and SR types). The mortality of these treated groups was compared by the log-rank test with that of an untreated group.


RESULTS
After implantation of two types of 5-FU-loaded PLAGA microspheres, no sign of clinical or histological toxicity was observed. Entrapped 5-FU crystals were observed until Days 12 and 20 postimplantation within FR and SR microspheres, respectively, which suggests a longer releasing period in vivo than in vitro. In the therapeutic evaluation, only intratumoral implantation of SR-type 5-FU-loaded microspheres significantly decreased the mortality (P = 0.017).


CONCLUSIONS
5-FU-loaded PLAGA microspheres were implanted in rat brains without evident toxicity. Histological examination suggested a longer sustained delivery period in vivo than in vitro. Intratumoral implantation of SR-type 5-FU-loaded microspheres decreased the mortality of C6 tumor-bearing rats. This effect can be related to the local and the sustained delivery of the drug, because 5-FU administered systemically is ineffective against brain tumors.
Menei
P
P
Service de Neurochirurgie, Centre Hospitalo-Universitaire, Angers, France.
Boisdron-Celle
M
M
Croué
A
A
Guy
G
G
Benoit
J P
JP
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D001673:Biodegradation, Environmental; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004343:Drug Implants; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008863:Microspheres; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013238:Stereotaxic Techniques; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004343:Drug Implants; D005472:Fluorouracil