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Russell R. Lonser, Malisa Sarntinoranont, Paul F. Morrison and Edward H. Oldfield

has been used to distribute proteins, virus and/or virus-sized particles, liposomes, and nanoparticles. 24 , 33 , 42 , 106 While small- and most large-molecular-weight compounds will distribute by convective flow in a similar manner, viruses, virus-sized particles, and nanoparticles have restricted flow (tissue distribution volume to infusion volume ratio of 2:1 to 3:1). 13 , 42 , 106 This reduction in delivery efficiency is attributed to limits in the size of the extracellular space in the CNS, which has been estimated to be on the order of 100 nm, 75 , 108 and

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Michael Y. Chen, Alan Hoffer, Paul F. Morrison, John F. Hamilton, Jeffrey Hughes, Kurt S. Schlageter, Jeongwu Lee, Brandon R. Kelly and Edward H. Oldfield

Object. Achieving distribution of gene-carrying vectors is a major barrier to the clinical application of gene therapy. Because of the blood—brain barrier, the distribution of genetic vectors to the central nervous system (CNS) is even more challenging than delivery to other tissues. Direct intraparenchymal microinfusion, a minimally invasive technique, uses bulk flow (convection) to distribute suspensions of macromolecules widely through the extracellular space (convection-enhanced delivery [CED]). Although acute injection into solid tissue is often used for delivery of oligonucleotides, viruses, and liposomes, and there is preliminary evidence that certain of these large particles can spread through the interstitial space of the brain by the use of convection, the use of CED for distribution of viruses in the brain has not been systematically examined. That is the goal of this study.

Methods. Investigators used a rodent model to examine the influence of size, osmolarity of buffering solutions, and surface coating on the volumetric distribution of virus-sized nanoparticles and viruses (adeno-associated viruses and adenoviruses) in the gray matter of the brain. The results demonstrate that channels in the extracellular space of gray matter in the brain are large enough to accommodate virus-sized particles and that the surface characteristics are critical determinants for distribution of viruses in the brain by convection.

Conclusions. These results indicate that convective distribution can be used to distribute therapeutic viral vectors in the CNS.

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Nicholas J. Szerlip, Stuart Walbridge, Linda Yang, Paul F. Morrison, Jeffrey W. Degen, S. Taylor Jarrell, Joshua Kouri, P. Benjamin Kerr, Robert Kotin, Edward H. Oldfield and Russell R. Lonser

, Oldfield EH : Direct convective delivery of macromolecules to peripheral nerves . J Neurosurg 89 : 610 – 615 , 1998 25 Lum JT , Nguyen T , Felpel LP : Drug distribution in solid tissue of the brain following chronic local perfusion utilizing implanted osmotic minipumps . J Pharmacol Methods 12 : 141 – 147 , 1984 26 Mamot C , Nguyen JB , Pourdehnad M , Hadaczek P , Saito R , Bringas JR , : Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery . J Neurooncol 68 : 1 – 9