Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by biodegradable polymer implants

Intracranial tumors, such as glioblastoma multiforme and astrocytomas, are among the most aggressive and difficult to cure. In the present study, we evaluated the intracranial distribution of released agents during the first 3 days after implantation. Polymer implants containing [³H]-1,3-bis(2- chloroethyl)-1-nitrosourea (BCNU), [³H]dextran (MW 70,000) or [¹⁴C]iodoantipyrene (IAP) were implanted into the brains of rabbits; autoradiography was used to measure the distribution of radiolabels within the brain at 6, 24 and 72 hr after implantation. For all of the agents studied, the majority of the radioactivity was found within the region 1 to 2 mm from the surface of the polymer. Dextran, however, penetrated farther into the brain than either IAP or BCNU. The distribution of radiolabel on an anteroposterior axis was determined by examining serial coronal images: after 72 hr, significant radioactivity (<2 S.D. above background) extended > 17 mm in animals with [³H]dextran implants and ~6 mm in animals receiving [³H]BCNU or [¹⁴C]IAP. Concentration profiles were also measured on coronal images obtained at the implant site: radioactivity dropped to a 10% maximum value 1.7 mm from the surface of the pellet in [³H]dextran-treated animals and < 1.2 mm in [³H]BCNU or [¹⁴C]IAP-treated animals. Measured concentration profiles near the polymer were compared to mathematical models of drug diffusion and elimination. These results demonstrate that the majority of agents delivered into the brain by intracranially implanted polymers accumulates in the tissue within 1 to 2 mm of the implant, but that the size of the treated region depends on physicochemical properties of the agents. Good experimental agreement with the mathematical models suggest their usefulness in predicting the effectiveness of new chemotherapeutic agents.