STABILIZATION OF NERVE GROWTH-FACTOR IN CONTROLLED-RELEASE POLYMERS AND IN TISSUE

We have studied the release of nerve growth factor (NGF), a protein un der consideration for treatment of Alzheimer's Disease, from polymer m atrices and microspheres to characterize the stability of NGF, the dyn amics of NGF release, and the distribution of NGF within the brain int erstitium. Poly(ethylene-co-vinyl acetate) (EVAc) disks and poly(L-lac tic acid) (PLA) microspheres were formed by codispersing NGF with one of a variety of molecules. The mass of mouse NGF (mNGF) detected follo wing release from EVAc disks into buffered saline varied five-fold ove r the range of codispersants studied, with carboxymethyldextran provid ing optimal release, while the mass of recombinant human NGF (rhNGF) r eleased varied four-fold from both EVAc disks and PLA microspheres, wi th albumin and carboxymethyldextran providing optimal release. Variati on of the codispersant species significantly affected NGF release into buffered saline; it also had a noticeable, but small, effect of the a mount of NGF found in the brain tissue following implantation of a pol ymer device. To improve NGF retention in tissue, NGF was conjugated to 70000 molecular weight dextran and incorporated into a polymeric devi ce. The distribution of NGF was enhanced by conjugation; comparison of NGF concentrations in the brain to a mathematical model of diffusion and elimination suggested that the elimination rate of NGF-dextran con jugate in the tissue was over seven times slower than the elimination rate of NGF. These results indicate that variation of the properties o f the controlled release system may be useful in regulating the time c ourse of NGF delivery to tissue, and that modification of the NGF itse lf can improve penetration and retention in the brain.