INCREASING VOLUME OF DISTRIBUTION TO THE BRAIN WITH INTERSTITIAL INFUSION - DOSE, RATHER THAN CONVECTION, MIGHT BE THE MOST IMPORTANT FACTOR

THE VOLUME OF distribution in tissue (V-t) that can be achieved by dir ect interstitial infusion of therapeutic agents into brain is limited. The maintenance of a pressure gradient during interstitial infusion t o establish fluid convection has been shown to increase the V-t of sma ll, medium, and large molecules. We have used monocrystalline iron oxi de nanocompounds, superparamagnetic particles of sizes the same order of magnitude as virions, to investigate the effect of dose, the volume of infusate, and the time of infusion on the distribution of large mo lecules in rodent brain. Our initial study in rats (n = 6) replicated the results of a previously described report of convection-enhanced de livery in cats. At a constant rate and concentration, the V-t increase d in a linear fashion, proportional to the increases in time, volume, and dose. When using a constant rate and a constant concentration, how ever, it is unclear which variable or variables (dose, volume, infusio n time) have the greatest influence on this effect. Therefore, we asse ssed each variable independently (n = 12). When the iron dose was incr eased from 5.3 to 26.5 mu g, there was a three- to fivefold increase i n the V-t, depending on the volume and time of infusion (2 mu l/20 min , 24 mu l/20 min, or 24 mu l/120 min) (P < 0.001). When the volume of infusate was increased from 2 to 24 mu l, at an infusion time of 20 mi nutes and a dose of either 5.3 or 26.5 mu g, there was a 43 or 52% dec line in the V-t, respectively (P = 0.018). When the time for the infus ion of 24 mu l was increased from 20 to 120 minutes, there was a 79% i ncrease in the V-t at a dose of 26.5 mu g but no change in the V-t at a dose of 5.3 mu g. The effect associated with infusion time was not s ignificant (P = 0.113). Magnetic resonance imaging was performed to do cument the distribution of monocrystalline iron oxide nanocompounds in vivo, and histochemical staining for iron was used to document the di stribution of monocrystalline iron oxide nanocompounds in tissue secti ons. The V-t for both methods was calculated by computer image analysi s, and the correlation between magnetic resonance and histological vol umes was determined (r(2) = 0.93). On the basis of this model, we sugg est that dose, rather than convection, might be the most important var iable in maximizing the V-t and improved distribution might be achieve d by administering an increased concentration of agent.