Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain

Leslie L. Muldoon, Gajanan Nilaver, Robert A. Kroll, Michael A. Pagel, Xandra O. Breakefield, E. Antonio Chiocca, Beverly L. Davidson, Ralph Weissleder, Edward A. Neuwelt

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Abstract

Delivery of adenovirus, herpes simplex virus (HSV), and paramagnetic monocrystalline iron oxide nanoparticles (MION) to rat brain (n = 64) was assessed after intracerebral inoculation or osmotic disruption of the blood- brain barrier (BBB). After intracerebral inoculation, the area of distribution was 7.93 ± 0.43 mm2 (n = 9) for MION and 9.17 ± 1.27 mm2 (n = 9) for replication-defective adenovirus. The replication-compromised HSV RH105 spread to 14.00 ± 0.87 mm2 (n = 8), but also had a large necrotic center (3.54 ± 0.47 mm2). No infection was detected when virus was administered intra-arterially without hyperosmotic mannitol. After osmotic BBB disruption, delivery of the viruses and MIONs was detected throughout the disrupted cerebral cortex. Positive staining was found in 4 to 845 cells/100 μm thick coronal brain section (n = 7) after adenovirus administration, and in 13 to 197 cells/section (n = 8) after HSV administration. Cells of glial morphology were more frequently stained after administration of adenovirus, whereas neuronal cells were preferentially stained after delivery of both HSV vectors and MION. In a preliminary test of vector delivery in the feline, MION was detected throughout the white matter tracts after inoculation into normal cat brain. This MION may be a tool for use in vivo, to monitor the delivery of virus to the central nervous system. Additionally, BBB disruption may be an effective method to globally deliver recombinant viruses to the CNS.

Original languageEnglish (US)
Pages (from-to)1840-1851
Number of pages12
JournalAmerican Journal of Pathology
Volume147
Issue number6
StatePublished - Dec 1 1995

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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