Millimeter-scale positioning of a nerve-growth-factor source and biological activity in the brain

Toxicity prevents the systemic administration of many therapeutic proteins, and attempts at protein targeting via the circulatory system (i.e,, "magic bullets") have failed in all but a few special cases. Direct administratio n at the target site is a logical alternative, particularly in the central nervous system, but the limits of direct administration have not been defin ed clearly, Nerve growth factor (NGF) enhances survival of cholinergic neur ons and, therefore, has generated considerable interest for the treatment o f Alzheimer's disease. We tested the effectiveness of local delivery by imp lanting small polymer pellets that slowly released NGF into the central ner vous system of adult rats at controlled distances from a target site contai ning transplanted fetal cholinergic cells. NGF-releasing implants placed wi thin 1-2 mm of the treatment site enhanced the biological function of cellu lar targets, whereas identical implants placed approximate to 3 mm from the target site of treatment produced no beneficial effect. Effective NGF ther apy required millimeter-scale positioning of the NGF source, and efficacy c orrelated with the spatial distribution of NGF concentration in the tissue; this result suggests that NGF must be delivered within several millimeters of the target to be effective in treating Alzheimer's disease. Because the human brain is divided into functional regions that are typically several centimeters in diameter and often irregular in shape, new methods for sculp ting larger-scale drug fields are needed. We illustrate a concept, called p harmacotectonics, in which drug delivery systems are arranged spatially in tissues to shape concentration fields for potent agents.