Thermotherapeutic enhancement of infusate distribution during convection enhanced delivery in the brain using fiber-optic microneedle devices

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and has a median survival of 13.4 months. Convection enhanced delivery (CED) has shown promise for the treatment of GBM by allowing intratumoral delivery of therapeutics, bypassing the blood brain barrier. A fiberoptic microneedle device (FMD) CED catheter enables simultaneous delivery of laser energy and therapeutic. The laser allows for heating of tissue in the region of infusion, called thermotherapy. Thermotherapy offers the advantages of increasing the volume of distribution (Vd) of the infusate, as well as facilitating intracellular penetration of the therapeutic. We hypothesize that heating of brain tissue will increase infusate Vd in ex vivo CED brain infusions.

Methods: Formalin fixed mouse brains were infused by FMD-CED with Evans blue for 1 hour at 0.1 μl/min, at 22°C, 37°C and 42°C (n=4 brains/group). The Vd was determined and compared using one-way ANOVA.

Results: FMD-CED performed at 42°C resulted in significantly higher mean Vd (4.90+2.2mm3; p =0.03) than those at 22°C (1.49+0.4 mm3), although no differences in Vd were observed between the other temperature groups. 42°C brains demonstrated interstitial and intracellular distribution, while rare intracellular distribution was noted in the other groups.

Discussion: The Vd of FMD-CED infusions is facilitated by sub-lethal thermotherapy. This study indicates that thermotherapeutic enhancement of infusate Vd does not occur exclusively via vascular mechanisms. Thermotherapy facilitates advective-diffusion by decreasing interstitial fluid pressure and increasing transcellular fluid transport. These results were validated in a companion in vivo FMD-CED study in the rodent brain.