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 administration at the target site is a logical alternative, particularly in the central nervous system, but the limits of direct administration have not been defined clearly.
Nerve growth factor (
NGF) enhances survival of cholinergic neurons and, therefore, has generated considerable interest for the treatment of
Alzheimer's disease. We tested the effectiveness of local delivery by implanting small
polymer pellets that slowly released
NGF into the central nervous system of adult rats at controlled distances from a target site containing transplanted fetal
cholinergic cells.
NGF-releasing implants placed within 1-2 mm of the treatment site enhanced the
biological function of cellular targets, whereas identical implants placed approximately 3 mm from the target site of treatment produced no beneficial effect. Effective
NGF therapy required millimeter-scale positioning of the
NGF source, and efficacy correlated 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 sculpting larger-scale
drug fields are needed. We illustrate a concept, called pharmacotectonics, in which drug-delivery systems are arranged spatially in tissues to shape concentration fields for potent agents.