Vladimir S. Trubetskoy

Injectable nanoparticulate carriers have important potential applications such as site-specific drug delivery or medical imaging. Conventional carriers, however, cannot generally be used because they are eliminated by the reticulo-endothelial system within seconds or minutes after intravenous injection. To address these limitations, monodisperse biodegradable nanospheres were developed from amphiphilic copolymers composed of two biocompatible blocks. The nanospheres exhibited dramatically increased blood circulation times and reduced liver accumulation in mice. Furthermore, they entrapped up to 45 percent by weight of the drug in the dense core in a one-step procedure and could be freeze-dried and easily redispersed without additives in aqueous solutions.

Basic fibroblast growth factor (bFGF) is a polypeptide that supports the survival of brain cells (including neurons, glia, and endothelia) and protects neurons against a number of toxins and insults in vitro. This factor is also a potent dilator of cerebral pial arterioles in vivo. In previous studies, we found that intraventricularly administered bFGF reduced infarct volume in a model of focal cerebral ischemia in rats. In the current study, bFGF (45 micrograms/kg/h) in vehicle, or vehicle alone, was infused intravenously for 3 h, beginning at 30 min after permanent middle cerebral artery occlusion by intraluminal suture in mature Sprague-Dawley rats. After 24 h, neurological deficit (as assessed by a 0- to 5-point scale, with 5 = most severe) was 2.6 +/- 1.0 in vehicle-treated and 1.5 +/- 1.3 in bFGF-treated rats (mean +/- SD; N = 12 vs. 11; p = 0.009). Infarct volume was 297 +/- 65 mm3 in vehicle- and 143 +/- 135 mm3 in bFGF-treated animals (p = 0.002). During infusion, there was a modest decrease in mean arterial blood pressure but no changes in arterial blood gases or core or brain temperature in bFGF-treated rats. Autoradiography following intravenous administration of 111In-labeled bFGF showed that labeled bFGF crossed the damaged blood-brain barrier to enter the ischemic (but not the nonischemic) hemisphere. Whether the infarct-reducing effects of bFGF depend on intraparenchymal or intravascular mechanisms requires further study.