Osmotic disruption of the blood brain barrier (BBB) by intraarterial mannitol injection is sometimes the key step for the delivery of chemotherapeutic drugs to brain tissue. BBB disruption (BBBD) with mannitol, however, can be highly variable and could impact local drug deposition. We use optical pharmacokinetics, which is based on diffuse reflectance spectroscopy, to track in vivo brain tissue concentrations of indocyanine green (ICG), an optical reporter used to monitor BBBD, and mitoxantrone (MTX), a chemotherapy agent that does not deposit in brain tissue without BBBD, in anesthetized New Zealand white rabbits. Results show a significant increase in the tissue ICG concentrations with BBBD, and our method is able to track the animal-to-animal variation in tissue ICG and MTX concentrations after BBBD. The tissue concentrations of MTX increase with barrier disruption and are found to be correlated to the degree of disruption, as assessed by the ICG prior to the injection of the drug. These findings should encourage the development of tracers and optical methods capable of quantifying the degree of BBBD, with the goal of improving drug delivery.
Preliminary studies have shown that there is great variability in the degree of disruption of blood-brain barrier (BBBD)
after the intraarterial injection of mannitol in rabbit models. The disruption of blood-brain barrier (BBB) is affected by a
number of factors, and the variations could have a profound impact on regional delivery of chemotherapeutics. Optically
measured brain tissue concentrations of indocyanine green (ICG) and Evan's blue (EB) enable the quantification of
BBBD after intraarterial administration of mannitol. Using the optical pharmacokinetics technique, a variation of diffuse
reflectance spectroscopy, we are able to track in vivo brain tissue concentrations of ICG and EB in rabbits, before and
after barrier disruption. This study shows the feasibility of optical monitoring of BBBD, a method that can help improve
intraarterial delivery of chemotherapeutic drugs.
We describe an optical tissue phantom that enables the simulation of drug extravasation from microvessels and validates
computational compartmental models of drug delivery. The phantom consists of a microdialysis tubing bundle to
simulate the permeable blood vessels, immersed in either an aqueous suspension of titanium dioxide (TiO2) or a TiO2
mixed agarose scattering medium. Drug administration is represented by a dye circulated through this porous
microdialysis tubing bundle. Optical pharmacokinetic (OP) methods are used to measure changes in the absorption
coefficient of the scattering medium due to the arrival and diffusion of the dye. We have established particle sizedependent
concentration profiles over time of phantom drug delivery by intravenous (IV) and intra-arterial (IA) routes.
Additionally, pharmacokinetic compartmental models are implemented in computer simulations for the conditions
studied within the phantom. The simulated concentration-time profiles agree well with measurements from the phantom.
The results are encouraging for future optical pharmacokinetic method development, both physical and computational, to
understand drug extravasation under various physiological conditions.