Interstitial Chemotherapy of the 9L Gliosarcoma: Controlled Release Polymers for Drug Delivery in the Brain I

The administration of drugs directly into the central nervous system using polymers as drug carriers may improve the treatment of malignant brain tumors. In this study, the effect of the interstitial, localized delivery of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) incorporated into controlled release polymers implanted adjacent to the 9L gliosarcoma was assessed in s.c. and intracranial (i.c.) models. In the s.c. experiment, the 9L gliosarcoma was implanted in the flank of rats and subsequently treated w|th BCNU either (a) delivered in controlled release polymers inserted adjacent to the tumor or (b) administered systemically by i.p. injections or by controlled release polymers inserted at a site distant from the tumor. The interstitial release of BCNU adjacent to the tumor in the flank resulted in a significant tumor growth delay of 16.3 days, as compared to a growth delay of 9.3 and 11.2 days obtained with the systemic administration of BCNU. In the i.c. experiment, the 9L gliosarcoma was implanted in the brain of Fischer 344 rats and treated either (a) with controlled release polymers containing BCNU inserted into the brain or (b) with the systemic i.p. administration of BCNU. The interstitial release of BCNU in the brain resulted in a significant 5.4to 7.3-fold increased survival, compared with a 2.4-fold increased survival after the systemic administration of the same dose of BCNU. The two groups with i.c. tumors treated interstitially had 17 and 42% cures, but no long-term cures were obtained in the group treated with systemic therapy. The localized, controlled delivery of chemotherapeutic agents in the s.c. tissues and in the brain via polymeric carriers may be more effective than standard systemic chemotherapy. This approach could be used to deliver a wide variety of agents into the central nervous system to treat diverse neuropathological conditions which remain refractory to systemic therapy. I N T R O D U C T I O N Interstitial chemotherapy, the localized administration o f drugs using po lymer implants as vehicles for drug delivery, is an alternative to the systemic administration of chemotherapeut ic agents for the treatment of malignant brain tumors. Theoretically, polymeric devices implanted i.c. 3 could obviate the need for drugs to cross the bloodbrain barrier and deliver drugs directly to the site of pathology, hence minimizing the systemic toxicity associated with current systemic therapy. Consequently, neoplastic cells could be exposed to unprecedented high regional drug levels over a prolonged period, and higher concentrat ions of drug at the site of tumor growth would be expected to improve effectiveness of any given chemotherapeut ic regimen. In the present report, this hypothesis was tested by using controlled release polymers containing BCNU implanted in the f lank and in the brain at the site o f tumor growth to treat rats bearing the 9L gliosarcoma, a brain tumor syngeneic to the Fischer 344 rat (1-4). We have evaluated interstitial chemotherapy in terms of its effectiveness and toxicity as compared to standard systemic therapy. Received 8/4/92; accepted 11/25/92. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. l Supported by the Association for Brain Tumor Research Fellowship in memory of Steven Lowe, NIH Grant NS01058-01, National Cancer Institute Grant U01 CA52857, and a grant from Nova Pharmaceutical Company. z To whom requests for reprints should be addressed. 3 The abbreviations used are: i.c., intracranial; BCNU, 1,3-bis(2-chloroethyl)-l-nitrosourea; EVAc, ethylene-vinyl acetate copolymer; PCPP:SA, poly[bis(p-carboxyphenoxy)]propane-sebacic acid copolymer. Experimental Design s.c. Study. Ninety rats underwent implantation of the 9L gliosarcoma in the flank. On the fifth day after implantation, all the animals were again operated for the initiation of treatment of the established tumor. Treatment consisted of" (a) systemic administration of BCNU (15 mg/kg) as a single intraperitoneal injection; (b) interstitial delivery of BCNU (15 mg/kg) in the tumor flank from a controlled release polymer inserted adjacent to the tumor; or (c) prolonged systemic administration of BCNU (15 mg/kg) from a controlled release polymer inserted in the flank contralateral to the tumor (Table 1). The systemic administration of BCNU in a single dose is the best reported treatment protocol for the 9L gliosarcoma in rats (5, 6). In the s.c. experiment a nonbiodegradable controlled release polymer, EVAc (7, 8), was used. EVAc is the prototype of the diffusion-regulated, nondegradable, controlled release polymer (9). The tumors were followed with serial measurements until they reached a volume of about 24 cm 3, at which time the animals were sacrificed. The outcome of each treatment modality was evaluated by comparing the calculated time required for each tumor to reach 6000 mm 3, a 10-fold increase in tumor volume from the time treatment was initiated. i.c. Study. Ninety-six rats underwent a craniectomy. Sixty animals underwent implantation of the 9L gliosarcoma in the brain. The remaining 36 animals were assigned to three experimental groups to assess the toxicity of the i.c. and systemic administration of BCNU. The eight experimental groups are described in Table 2. On the fourth day after tumor implantation, all the animals were reoperated for initiation of treatment, which consisted of either systemic administration of BCNU (14 mg/kg) as a single i.p. injection or interstitial delivery of BCNU (14 mg/kg) in the brain via controlled release polymers implanted into the tumor. In the i.c. experiment two types of polymeric carriers were used: EVAc, as in the s.c. experiment, and the biodegradable polyanhydride PCPP:SA, an erosion-regulated controlled release polymer (10-12). The animals were examined twice daily for signs of chemotherapeutic toxicity or impending death. The long-term survivors were sacrificed 125 days after the initial operation. The effectiveness of each therapeutic intervention as well as the toxicity of either locally or systemically administered BCNU were assessed by comparing the survival of the animals in each group. Each animal underwent a full autopsy for determination of the cause of death.