Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models

Abstract

Convection-enhanced delivery (CED) is a local infusion technique, which delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED distribution is significantly increased if the infusate is hydrophilic. This study evaluated the safety and efficacy of CED of nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), a hydrophilic nitrosourea, in rat 9 L: brain tumor models. The local neurotoxicity of ACNU delivered via CED was examined in normal rat brains, and the maximum tolerated dose (MTD) was estimated at 0.02 mg/rat. CED of ACNU at the MTD produced significantly longer survival time than systemic administration (P < 0.05, log-rank test). Long-term survival (80 days) and eradication of the tumor occurred only in the CED-treated rats. The tissue concentration of ACNU was measured by high-performance liquid chromatography, which revealed that CED of ACNU at the dose of 100-fold less total drug than intravenous injection carried almost equivalent concentrations of ACNU into rat brain tissue. CED of hydrophilic ACNU is a promising strategy for treating brain tumors.