Enhancing Boron Uptake in Brain Glioma by a Boron-Polymer/Microbubble Complex with Focused Ultrasound

Boron neutron capture therapy (BNCT) is a promising radiotherapy for treating glioblastoma multiforme (GBM). However, the penetration of drugs (e.g., sodium borocaptate and BSH) for BNCT into brain tumors is limited by cerebral vesicular protective structures, the blood brain barrier, and the blood brain tumor barrier (BTB). Although BSH has been reported to be selectively taken up by tumors, it is rapidly excreted from the body and cannot achieve a high tumor-to normal brain ratio (T/N ratio) and tumor-to-blood ratio (T/B ratio). Despite the development of large-molecular weight boron compounds, such as polymers and nanoparticles, to enhance the permeation and retention effect, their effects remain insufficient for clinical use. To improve the efficiency of boron delivery to the tumor site, we propose combinations of self assembled boron-containing polyanion [polyethylene glycol-b-poly((closo-dodecaboranyl)thiomethylstyrene) (PEG-bPMBSH)] nanoparticles (295 +/- 2.3 nm in aqueous media) coupled with cationic microbubble (B-MB)-assisted focused ultrasound (FUS) treatment. Upon FUS sonication (frequency = 1 MHz, pressure = 0.3-0.7 MPa, duty cycle = 0.5%, sonication = 1 min), B-MBs can simultaneously achieve safe BTB opening and boron drug delivery into tumor tissue. Compared with the MBs of the PEG-b-PMBSH mixture group (B + MBs), B-MBs showed 3- and 2.3-fold improvements in the T/N (4.4 +/- 1.4 vs 1.3 +/- 0.1) and T/B ratios (1.4 +/- 6 vs 0.1 +/- 0.1), respectively, after 4 min of FUS sonication. The spatial distribution of PEG-b-PMBSH was also improved by the complex of PEG-b-PMBSH with MBs. The findings presented herein, in combination with the expanding clinical application of FUS, may improve BNCT and treatment of GBM.