Abstract
Purpose. Implantation of biodegradable polymers provides a powerfulmethod to deliver high, sustained concentrations of chemotherapeuticsto brain tumors. The present studies examined the ability of injectablepolymeric microspheres, formulated to release carboplatin or BCNUfor 2–3 weeks, to enhance survival in a rodent model ofsurgically-resected glioma.
Methods. Rat glioma (RG2) cells were implanted into the cortex ofrats and allowed to grow for 10 days prior to surgical resection. Ratswere given either surgical resection only, bolus injection (100 μg) ormicrospheres containing 10, 50, or 100 μg of carboplatin or BCNU.The microspheres were implanted, via hypodermic injection, eitherdirectly into the surgical cavity or into the tissue along the perimeterof the cavity.
Results. The order of survival among treatment groups was: noresection < resection only < bolus chemotherapy < sustained releasechemotherapy. Carboplatin and BCNU did not differ in this respectand in each case, the enhanced survival achieved with sustained releasewas dose-related. However, the enhanced survival achieved withcarboplatin was substantially greater when the microspheres wereimplanted into the perimeter wall of the resection cavity, compared toimplantation into the cavity itself. The enhanced survival produced bycarboplatin implants along the resection perimeter was associated witha significant attenuation of regrowth of the tumor. Finally, in a separatestudy in non-tumor brain, atomic absorption spectrophotometryrevealed that while the microspheres produced significantly prolongedtissue levels of carboplatin relative to a bolus injection, carboplatindiffusion was limited to brain tissue extending primarily 0.5 mm fromthe injection site.
Conclusions. These data demonstrate: (1) that sustained delivery ofchemotherapy is superior to equipotent bolus doses following tumorresection, and (2) that direct injection of sustained release microspheresinto the tissue surrounding a growing tumor mass may provide superioreffects over injections into the surgical cavity. They also suggest thatsuccessful implementation of this approach in humans may requiremeasures or circumstances that improve upon the limited spatial drugdiffusion from the implantation site.
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Emerich, D.F., Winn, S.R., Hu, Y. et al. Injectable Chemotherapeutic Microspheres and Glioma I: Enhanced Survival Following Implantation into the Cavity Wall of Debulked Tumors. Pharm Res 17, 767–775 (2000). https://doi.org/10.1023/A:1007576405039
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DOI: https://doi.org/10.1023/A:1007576405039