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|Title:||QUANTITATION OF HIGH MOLECULAR WEIGHT MOLECULES DELIVERY TO THE CNS
FOLLOWING OBBBD PROCEDURE USING DYNAMIC MRI|
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|Authors/Affiliations:||1 Marie Blanchette*; 1 Luc Tremblay; 1 Martin Lepage; 1 David Fortin; |
1 Universite de Sherbrooke, QC, Canada
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|Content:||Introduction: Prognosis in malignant astrocytoma patients remains poor despite recent advances in the standard treatment options. One of the major limitations of chemotherapy efficacy is the poor penetration of antineoplasic agents across the blood-brain barrier (BBB). Many |
strategies have been developed to circumvent this obstacle. One such approach, the osmotic blood-brain barrier disruption (OBBBD) increases significantly the delivery of therapeutic agents to the central nervous system (CNS). This method consist in the administration of an hyperosmolar solution in a cerebral arterial distribution to permeabilize the cerebral capillaries. Even though it is already used in the clinic, few data are available detailing its physiology. Our group has developed a technique using MRI scanner to image and characterize the dynamic process of the OBBBD. The aim of this study was thus to determinate the dynamic parameters in the delivery of a high molecular weight molecule, Gadomer (T1 contrast agent, 17 kDa), across the BBB following an OBBBD procedure.
Methods: Sixty-two Wistar healthy male rats were put under general anaesthesia by a caudal iv propofol infusion. Animals were then intubated and the external right carotid was canulated
in retrograde fashion with a polpropylene tubing (PE50). The canula containing the hyperosmolar solution (mannitol 25%) was heated to prevent its crystallization. The instrumented animal was then prepared and inserted in the MRI scanner. Vital signs were monitored during the scan. Image acquisition was initiated 2 min prior to the OBBBD
procedure, and the contrast agent was administered at 3 min after the OBBBD procedure. A second contrast infusion was performed at varying time in different animals (45 min ,1 hr, 3 hr, 6 hr or 12 hr) to study the window in the opening of the barrier.
Immediately after the first Gadomer injection, we observed an important signal
enhancement in the treated hemisphere. Gadomer rapidly reached its maximal
concentration in the CNS and was still present in the brain parenchyma at high
concentration as long as 2 hours after the procedure. The BBB remains opened 6 hours
after the procedure, as a second infusion of gadomer up to 6 hours produced a significant
and lasting increase in its concentration.
This data support the efficiency of the OBBBD procedure in increasing both the
concentration and time of exposition of the CNS to high molecular weight compounds.
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