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Controlled Delivery of 1,3-Bis(2-chloroethyl)-1-nitrosourea from Ethylene-Vinyl Acetate Copolymer¹

Departments of Neurological Surgery [M. B. Y., R. J. T., H. B.], Opthalmology [H. B.], and Oncology [H. B.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) has been found to be an effective chemotherapeutic agent against brain tumors. However, because it has a very short half-life in plasma, the exposure of neoplastic cells to BCNU is very brief. The delivery of BCNU may be enhanced by using controlled release polymers. We measured the release of BCNU from ethylene-vinyl acetate copolymer (EVAc) into blood, phosphate buffer, and brain tissue. BCNU-EVAc cylinders that weighed 60 mg were implanted in the peritoneum of rats, and BCNU was detected in blood for 6 days. Studies carried out in vitro showed that BCNU was released from EVAc at a decreasing rate for 195 h. BCNU-EVAc cylinders that weighed 15 mg were implanted either intracranially (i.c.) or i.p. in Fischer 344 rats. Controlled release of BCNU from the i.c. BCNU-EVAc implants was observed over 9 days, with peak drug levels of 49.6 µg/g of brain tissue in the implanted hemisphere. The BCNU levels in the contralateral hemisphere and the peripheral circulation were much lower and were detectable for only 1 day. By contrast, peak BCNU levels in the brain from the i.p. BCNU-EVAc implants were 2.7–3.0 µg/g for only 12 h, accompanied by peak BCNU levels in blood of 1.0 µg/ml tapering over 1 day. These results demonstrate the controlled release of intact BCNU from EVAc in vitro and in vivo. Furthermore, the i.c. implants resulted in localized, prolonged, high levels of the drug in the implanted hemisphere. Hence, the i.c. controlled delivery of BCNU may be more efficacious for the treatment of localized brain tumors.

¹ This investigation was supported in part by an Association for Brain Tumor Research Fellowship in Memory of Steven Lowe, NIH Grant NS01058-01, American Cancer Society Grant IN-11W, and an Andrew W. Mellon Foundation Johns Hopkins University Faculty Development Award.

² To whom requests for reprints should be addressed, at the Department of Neurological Surgery, Meyer 7-113, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205.

Received 6/30/88. Revised 1/ 5/89. Revised 6/ 2/89. Accepted 6/13/89.

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