Microbeam Radiation Therapy Opens a Several Days' Vessel Permeability Window for Small Molecules in Brain Tumor Vessels.

Abstract

Synchrotron microbeam radiation therapy (MRT), based on an inhomogeneous geometric and microscopic irradiation pattern of the tissues with high-dose and high-dose-rate x-rays, enhances the permeability of brain tumor vessels. This study attempted to determine the time and size range of the permeability window induced by MRT in the blood-brain (tumor) barrier. Rats-bearing 9L gliomas were exposed to MRT, either unidirectional (tumor dose, 406 Gy) or bidirectional (crossfired) (2 × 203 Gy). We measured vessel permeability to molecules of 3 sizes (Gd-DOTA, Dotarem, 0.56 kDa; gadolinium-labeled albumin, ∼74 kDa; and gadolinium-labeled IgG, 160 kDa) by daily in vivo magnetic resonance imaging, from 1 day before to 10 days after irradiation. An equivalent tumor dose of bidirectional MRT delivered from 2 orthogonal directions increased tumor vessel permeability for the smallest molecule tested more effectively than unidirectional MRT. Bidirectional MRT also affected the permeability of normal contralateral vessels to a different extent than unidirectional MRT. Conversely, bidirectional MRT did not modify the permeability of normal or tumor vessels for both larger molecules (74 and 160 kDa). High-dose bidirectional (cross-fired) MRT induced a significant increase in tumor vessel permeability for small molecules between the first and the seventh day after irradiation, whereas permeability of vessels in normal brain tissue remained stable. Such a permeability window could facilitate an efficient and safe delivery of intravenous small molecules (≤0.56 kDa) to tumoral tissues. A permeability window was not achieved by molecules larger than gado-grafted albumin (74 kDa). Vascular permeability for molecules between these 2 sizes has not been determined.