Narrowing of glioma vascular caliber via chronic VEGFR2 blockade improves the uniformity of focused ultrasound-mediated small molecule drug delivery

Glioblastoma (GBM) is a devastating disease, with standard-of-care therapies still yielding dismal survival outcomes. GBM cells are protected by the blood-brain and blood-tumor barriers, which severely limit therapeutic agent delivery from the bloodstream. Focused ultrasound (FUS), in combination with microbubbles (MBs), addresses this challenge by enhancing drug delivery. However, dilated and tortuous brain tumor vasculature disrupts MB flux and oscillation, which may limit FUS-mediated delivery. Here, we evaluated whether normalizing tumor vasculature via chronic neoadjuvant VEGFR2 inhibition (aVEGFR2, DC101) improves subsequent FUS-mediated small molecule drug delivery. After aVEGFR2 administration had pre-normalized GL261 glioma vasculature through reduced permeability and vascular caliber, T1 mapping MRI of FUS-delivered Multihance (MH) contrast agent, a model small molecule drug, yielded no change in total delivery. However, radiomic analysis of the T1 maps indicated that FUS-mediated model drug penetration into otherwise poorly accessible tumor regions was improved with aVEGFR2 pre-treatment. This improvement was accompanied by acoustic signatures suggestive of more stable MB oscillation. These results were then compared to those achieved with acute aVEGF pre-treatment, a regimen that copied the permeability reduction of chronic aVEGFR2 without reducing vascular caliber. This comparison identified reduced vascular caliber as the probable mechanism of improved delivery uniformity, perhaps acting through a shift in MB oscillation towards more stable regimes. Our results indicate that neoadjuvant aVEGFR2 cooperates with FUS-mediated small molecule drug delivery through a unique biophysical mechanism. This mechanism may be leveraged to further augment the efficacy of combination therapies against GBM that entail blocking VEGF signaling.