For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) minimal diffusion in the brain severely limits drug distribution after direct drug administration into the brain. We previously investigated convection, molecular transport with bulk flow of fluid, to enhance the distribution of large and small molecules in the brain. By using convection to supplement simple diffusion, greatly enhanced distribution of large and small molecules can be achieved in the brain while achieving drug exposure orders of magnitude greater than systemic exposure. Convection-enhanced distribution was shown to be an effective technique to homogeneously deliver large and small molecules in the gray matter of rats and non-human primates. The infusion of molecules selectively toxic to certain subsets of neurons is now being investigated as a potential new therapeutic strategy for Parkinson's disease and for seizures. Continuous perfusion of most of the cerebral hemisphere of monkeys with transferrin was achieved for several days with an implanted controllable pump. We also have shown that this delivery technique can be used to deliver and distribute macromolecules in the spinal cord and peripheral nerves. Because of the inability to deliver macromolecules in effective concentrations over appropriate volumes across the blood-spinal cord barrier, the use of numerous therapeutic compounds that may have potential for treating spinal cord disorders is limited. Regional convective delivery provides reproducible, safe, regional-specific, and homogeneous distribution of macromolecules over large longitudinal segments of spinal cord. This delivery method overcomes obstacles associated with current delivery techniques and provides for research of new treatments of various conditions of the spinal cord. To determine the feasibility and utility of convective delivery in a common experimental model of spinal cord injury, we delivered macromolecules using convection in traumatized and non-traumatized rat spinal cords. Histologic analysis confirmed that the infusion was limited to the dorsal columns in nontraumatized animals, but was distributed in white and gray matter after trauma. The concentration across Vd was homogeneous in the nontraumatized and traumatized cords. Nontraumatized animals observed after infusion had no deficits. Thus, direct convective delivery reliably delivers macromolecules into normal and traumatized rat spinal cord. This technique should prove useful for investigation of new therapeutic approaches for spinal cord injury. Many macromolecules have treatment potential for peripheral nerve disease. Clinical use of many of these agents has not been possible due to limitations of delivery including systemic toxicity, heterogeneous dispersion, and inadequate distribution. In an effort to overcome these obstacles, we examined the use of convection to deliver and distribute macromolecules in peripheral nerves. Concentration across the infusion region was homogeneous. The infusate, which was limited circumferentially by the epineurium, followed the parallel arrangement of axonal fibers, filling long segments of nerve (up to 3.5 cm). No neurological deficits arose from infusion. Convective delivery of macromolecules to peripheral nerve is safe and reliable. It overcomes the obstacles of current delivery methods and allows selective regional delivery of putative therapeutic agents to long sections of nerve. This technique now permits research into new treatments of various peripheral nerve lesions.
NIH ExPorter
NIH ExPorter