Treatment of malignant gliomas with mitoxantrone-loaded poly (lactide-co-glycolide) microspheres.
OBJECTIVE
Mitoxantrone (MTZ) has potent in vitro activity against malignant glioma cell lines, but it cannot be used effectively as a systemic agent for the treatment of brain tumors because of its poor central nervous system penetration. However, MTZ-loaded poly(lactide-co-glycolide) (PLGA) microspheres may be injected into the peritumoral area and into tumor tissue to provide effective and sustained local drug concentrations without causing systemic side effects.


METHODS
Fisher rats were randomized into three groups. The first group (n = 9) was concomitantly implanted with rat glioma (RG2) cells and blank PLGA microspheres. The second group (n = 6) was implanted with RG2 cells and MTZ-loaded PLGA microspheres. The third group (n = 9) was implanted with RG2 cells, and MTZ-loaded PLGA microspheres were injected into the same area after 7 days. Animals were sacrificed on Day 15 or 35. Tumor volumes were measured after hematoxylin and eosin staining. Distribution kinetics of MTZ in the brain was determined by high-performance liquid chromatography in nine rats injected with MTZ-loaded microspheres.


RESULTS
The tumor volumes were 76 +/- 11 and 107 +/- 11 mm (mean +/- standard error) on Days 15 (n = 6) and 35 (n = 3), respectively, in the control group. In rats treated with MTZ-loaded microspheres on Day 7, tumor volumes were significantly reduced to 17 +/- 4 and 23 +/- 2 mm on Days 15 (n = 6) and 35 (n = 3), respectively. No tumor formation was observed when glioma cells and MTZ-loaded PLGA microspheres were implanted concomitantly (n = 6). No systemic side effects or parenchymal inflammatory infiltration were observed in either group of rats. Brain MTZ concentration was highest at the injection site and declined with time and distance from the injection site and with time.


CONCLUSIONS
These data demonstrate that MTZ-loaded PLGA microspheres can deliver therapeutic concentrations of drug to the tumor and prevent glioma growth without causing side effects. This treatment method may increase the efficiency of antineoplastic therapy and positively impact survival.
Yemisci
Muge
M
Department of Neurology, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
Bozdag
Sibel
S
Cetin
Meltem
M
Söylemezoglu
Figen
F
Capan
Yilmaz
Y
Dalkara
Turgay
T
Vural
Imran
I
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D008081:Liposomes / Q000737:chemistry; D008297:Male; D008863:Microspheres; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000737:chemistry; D011098:Polyglactin 910 / Q000737:chemistry*; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D011098:Polyglactin 910; D008942:Mitoxantrone