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Intrathecal Chemotherapy with 1,3-Bis(2-chloroethyl)-1-nitrosourea Encapsulated into Hybrid Liposomes for Meningeal Gliomatosis: An Experimental Study¹

Department of Neurosurgery, Kumamoto University Medical School, 1-1-1 Honjo [I. K., M. K., J-i. K., Y. U.], and Graduate Course of Applied Chemistry, Kumamoto Institute of Technology, 4-22-1 Ikeda, [Y. M., R. U.], Kumamoto 860, Japan

1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), one of the chloroethyl nitrosoureas, is effective against malignant glioma. To develop its use in intrathecal chemotherapy, we encapsulated BCNU in hybrid liposomes composed of dimyristoylphosphatidylcholine and micellar surfactants (Tween 20) and dissolved it in artificial cerebrospinal fluid (lipo-BCNU). We then studied the toxicity of hybrid liposomes and cellular proliferation inhibition of lipo-BCNU in vitro. We found that 3 mM hybrid liposomes did not affect the viability of human endothelial cells and that lipo-BCNU inhibited the proliferation of human glioma cell lines U-105MG, U-251MG, and U-373MG, and rat glioma cell lines C6 and 9L in a concentration-dependent fashion. Wistar rats that were administered lipo-BCNU intracisternally showed no weight loss, neurological symptoms, or histological changes of the brain and spinal cord. A Wistar rat model of meningeal gliomatosis was established by intracisternal inoculation of 0.1 ml cell suspension containing 1 x 10⁶ or 5 x 10⁶ viable C6 glioma cells. Two days after inoculation, lipo-BCNU (BCNU, 2.5 mg/kg) was administered intracisternally. When 1 x 10⁶ glioma cells were inoculated (experiments 1 and 2), the median survival times were 24.5 and 26 days in the control groups and 32 and 45 days in the lipo-BCNU-treated groups, respectively. When 5 x 10⁶ glioma cells were inoculated (experiments 3–6), the median survival times were 17–29.5 days in the control groups and 23–44 days in the treated groups, respectively. Significantly prolonged survival was obtained in three of six experimental groups. After the administration of 1 ml lipo-BCNU (BCNU, 4.67 mM) or 1 ml BCNU solubilized with 5% dextrose/water (BCNU, 4.67 mM) into the cisterna magna of dogs, the cisterna magna cerebrospinal fluid was sampled, and the BCNU concentrations were assayed by high-performance liquid chromatography. The half-life of the lipo-BCNU was longer than that of BCNU solubilized with 5% dextrose/water. These results suggest that the intrathecal administration of lipo-BCNU may be possible for the treatment of meningeal gliomatosis.

¹ This work is supported in part by a Grant-in-Aid (05671172, 07808101) for Science Research from the Ministry of Education and the Science Research Promotion Fund from the Japan Private School Promotion Foundation.

² To whom requests for reprints should be addressed.

Received 3/22/96. Accepted 7/ 2/96.