BIODEGRADABLE POLYMERS FOR CONTROLLED DELIVERY OF CHEMOTHERAPY WITH AND WITHOUT RADIATION-THERAPY IN THE MONKEY BRAIN

Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue conce ntrations over extended periods of time. lt has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemic ally administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydr ide copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and s ebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combi ning interstitial BCNU with radiation therapy was also evaluated. Eigh teen male cynomologus monkeys were randomly assigned to one of four gr oups: a control group; a group with implantation of empty polymer; a g roup with implantation of BCNU-loaded polymer; and a group with implan tation of empty polymer in the right hemisphere and BCNU-loaded polyme r in the left hemisphere, followed by irradiation. The effects were ev aluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiogr aphically on postoperative Day 14 and had resolved by Day 72. Histolog ically, a subacute cellular inflammatory response was seen on postoper ative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisp here bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implanta tion site was normal. No neurological or general deleterious effects w ere seen in any of the animals. lt is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the p rimate brain and that concomitant radiation therapy did not lead to an y adverse effects. These experimental findings are important to an und erstanding of the clinical effects of PCPP:SA implants in treating bra in diseases.