Local delivery of minocycline and systemic BCNU have synergistic activity in the treatment of intracranial glioma

Abstract

Minocycline, a tetracycline derivative, has been shown to inhibit tumor angiogenesis through inhibitory effects on matrix metalloproteinases. Previous studies have shown this agent to be effective against a rodent brain tumor model when delivered intracranially and to potentiate the efficacy of standard chemotherapeutic agents. In the present study, the in vivo efficacy of intracranial minocycline delivered by a biodegradable controlled-release polymer against rat intracranial 9L gliosarcoma was investigated to determine whether it potentiates the effects of systemic 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Minocycline was incorporated into the biodegradable polymer polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid] (pCPP:SA) at a ratio of 50:50 by weight. The release kinetics of minocycline from the polymer were assessed. For the efficacy studies, female Fischer 344 rats were implanted with 9L glioma. Treatment with minocycline delivered by the pCPP:SA polymer at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. Treatment with the minocycline-polymer 5 days after tumor implantation provided only modest increases in survival. The combination of intracranial minocycline and systemic BCNU extended median survival by 82% compared to BCNU alone (p < 0.0001) and 200% compared to no treatment (p < 0.004). We conclude that local intracranial delivery of minocycline from biodegradable controlled-release polymers inhibits tumor growth and may have clinical utility when combined with a chemotherapeutic agent.