TY - JOUR
T1 - Quantitative three-dimensional analysis and diffusion modeling of oligonucleotide concentrations after direct intraparenchymal brain infusion
AU - Haar, Peter J.
AU - Stewart, John E.
AU - Gillies, George T.
AU - Prabhu, Sujit S.
AU - Broaddus, William C.
N1 - Funding Information:
Manuscript received June 27, 2000; revised January 8, 2001. This work was supported in part by the Jeffress Memorial Trust, the Kopf Foundation, the National Institutes of Health (NIH) under Grants NS01766 and CA72955-01A10004, and the Cullather and Hord Funds of the MCV Foundation. Asterisk indicates corresponding author.
PY - 2001
Y1 - 2001
N2 - We compared quantitative experimental results on the diffusion of 35S-labeled phosphorothioate oligonucleotide (PS-ODN) after intraparenchymal infusion in rat brain, with the distributions predicted by Fick's second law of diffusion. Fischer 344 rats underwent identical intracerebral infusions of 35S-PS-ODN. After 0, 5, 11, 23, and 47 h, groups of animals were sacrificed and sequential brain cryosections subjected to autoradiography. The resulting experimental data were compared to the predicted distributions, for estimation of the apparent free diffusion coefficient, D*. Volumes of distribution and total content of 35S-PS-ODN in the parenchyma were also computed, to monitor loss of total material. The values for D* were within the expected range for the 21-mer PS-ODN used, but a progressive decrease in D* over time was noted. The model requires D* to remain constant and, thus, does not adequately explain the spread of 35S-PS-ODN following infusion. The progressive slowing of spread over time suggests that at later time points, 35S-PS-ODN may be fixed by tissue binding or cellular uptake in the brain. Loss of material via vascular and CSF clearance may also contribute to the lack of fit. Our results highlight issues to be addressed in the modeling and experimental design of the intraparenchymal infusion process.
AB - We compared quantitative experimental results on the diffusion of 35S-labeled phosphorothioate oligonucleotide (PS-ODN) after intraparenchymal infusion in rat brain, with the distributions predicted by Fick's second law of diffusion. Fischer 344 rats underwent identical intracerebral infusions of 35S-PS-ODN. After 0, 5, 11, 23, and 47 h, groups of animals were sacrificed and sequential brain cryosections subjected to autoradiography. The resulting experimental data were compared to the predicted distributions, for estimation of the apparent free diffusion coefficient, D*. Volumes of distribution and total content of 35S-PS-ODN in the parenchyma were also computed, to monitor loss of total material. The values for D* were within the expected range for the 21-mer PS-ODN used, but a progressive decrease in D* over time was noted. The model requires D* to remain constant and, thus, does not adequately explain the spread of 35S-PS-ODN following infusion. The progressive slowing of spread over time suggests that at later time points, 35S-PS-ODN may be fixed by tissue binding or cellular uptake in the brain. Loss of material via vascular and CSF clearance may also contribute to the lack of fit. Our results highlight issues to be addressed in the modeling and experimental design of the intraparenchymal infusion process.
KW - Antisense oligodeoxynucleotide
KW - Fick's second law
KW - High-flow microinfusion
KW - Mathematical diffusion modeling
KW - Three-dimensional diffusion
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U2 - 10.1109/10.918595
DO - 10.1109/10.918595
M3 - Article
C2 - 11341530
AN - SCOPUS:0035040331
SN - 0018-9294
VL - 48
SP - 560
EP - 569
JO - IEEE Transactions on Biomedical Engineering
JF - IEEE Transactions on Biomedical Engineering
IS - 5
ER -