Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain.
BACKGROUND
Convection-enhanced delivery (CED) of adenoviruses offers the potential of widespread virus distribution in the brain. In CED, the volume of distribution (Vd) should be related to the volume of infusion (Vi) and not to dose, but when using adenoviruses contrasting results have been reported. As the characteristics of the infused tissue can affect convective delivery, this study was performed to determine the effects of the gray and white matter on CED of adenoviruses and similar sized super paramagnetic iron oxide nanoparticles (SPIO).


RESULTS
We convected AdGFP, an adenovirus vector expressing Green Fluorescent Protein, a virus sized SPIO or trypan blue in the gray and white matter of the striatum and external capsule of Wistar rats and towards orthotopic infiltrative brain tumors. The resulting Vds were compared to Vi and transgene expression to SPIO distribution. Results show that in the striatum Vd is not determined by the Vi but by the infused virus dose, suggesting diffusion, active transport or receptor saturation rather than convection. Distribution of virus and SPIO in the white matter is partly volume dependent, which is probably caused by preferential fluid pathways from the external capsule to the surrounding gray matter, as demonstrated by co-infusing trypan blue. Distant tumors were reached using the white matter tracts but tumor penetration was limited.


CONCLUSIONS
CED of adenoviruses in the rat brain and towards infiltrative tumors is feasible when regional anatomical differences are taken into account while SPIO infusion could be considered to validate proper catheter positioning and predict adenoviral distribution.
Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands. s.idema@vumc.nl
Sander
S
Idema
Viola
V
Caretti
Martine L M
ML
Lamfers
Victor W
VW
van Beusechem
David P
DP
Noske
W Peter
WP
Vandertop
Clemens M F
CM
Dirven
D000256:Adenoviridae / Q000378:metabolism*; D000257:Adenoviridae Infections / Q000821:virology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000473:pathology; D018481:Convection; D003911:Dextrans / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D015870:Gene Expression; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D058185:Magnetite Nanoparticles; D053758:Nanoparticles / Q000737:chemistry; D009457:Neuroglia / Q000473:pathology / Q000821:virology; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014343:Trypan Blue / Q000378:metabolism
D003911:Dextrans; D058185:Magnetite Nanoparticles; D012709:Serum Albumin; D049452:Green Fluorescent Proteins; C065507:ferumoxides; D014343:Trypan Blue