DEXTRAN RETENTION IN THE RAT-BRAIN FOLLOWING RELEASE FROM A POLYMER IMPLANT

Intracranial controlled release polymers may improve drug administration to the brain, where therapy is frequently limited due to the low permeability of brain capillaries to therapeutic agents. On the basis of drug transport and elimination rates, we proposed that high molecular weight, water-soluble molecules would be retained in the brain space following release from an intracranial implant. To test this hypothesis, solid particles of different molecular weight fractions of fluorescein isothiocyanate labeled dextran (FITC-dextran; 4 x 10(3) Da (4 kDa) < weight-averaged molecular weight (M(w)) < 150 kDa) or fluorescein were uniformly dispersed in matrices of a polyanhydride copolymer synthesized from a fatty acid dimer and sebacic acid in a 50:50 ratio, P(FAD: SA). When incubated in buffered saline, FITC-dextran fractions of 70 kDa M(w) were released from the polymer within 48 h; 4 kDa M(w) FITC-dextran and fluorescein were released more slowly. Following implantation of p(FAD:SA) matrices containing either 70 kDa M(w) FITC-dextran, 4 kDa M(w) FITC-dextran, or fluorescein into the brains of normal rats, fluorescent tracers were continuously released into the brain tissue for 30 days. Tracer concentrations within the brain were significantly higher for large molecular weight tracers (70 kDa M(w) FITC-dextran much greater than 4 kDa M(w) FITC-dextran > fluorescein). The rate of elimination, k(app), of each tracer from the brain was determined by comparing experimental data with a model describing tracer diffusion/elimination in the brain extracellular space; k(app) decreased with increasing molecular weight (fluorescein > 4 kDa M(w) FITC-dextran > 70 kDa M(w) FITC-dextran). 41364743