Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation

Abstract

Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Methods: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. Results: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the “permeability window”. Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. Conclusions: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc.

Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy

“…This indicates, as expected, a size-dependent transpermeability following MRT. It was possible to conclude from this study that the transient vascular permeability induced by MRT can be a strategy to improve the delivery of nanocarriers to the tumor site [123].…”

Divide and conquer: spatially fractionated radiation therapy

“…64), as a primer for drug delivery thanks to a transient vascular permeability in the tumour induced by MRT (Ref. 65) or to alleviate the symptoms of neurological conditions. In this context, MRT could be used to deliberately transect key neuronal pathways or ablate highly localised regions of the brain in order to modulate or suppress the networks responsible for abnormal movement as well as to treat epilepsy (Refs 66-69).…”

A matter of space: how the spatial heterogeneity in energy deposition determines the biological outcome of radiation exposure

“…While the high peak doses kill almost all cells, the level of the valley dose will determine cell survival and, indeed, many studies show the dependence of normal tissue effects on the valley dose and show that the valley dose is important for biological effects in vitro (Steel et al 2021) and in vivo (Serduc et al 2009, Smyth et al 2018. Nonetheless, processes originating from tissue parts within the radiation peaks are likely to cause the (Sabatasso et al 2021) differential effect and there are several hypothesized mechanisms involving the microenvironment of normal tissue and tumour. Probably, a combination of mechanisms leads to the observed differential effect.…”

“…( a , b from Bartzsch et al 2020 ) c ) H&E stained tissue section the rat spinal cord after treatment with microbeams (Laissue et al 2013 ). d ) Normal chicken chorioallantoic membrane after microbeam exposure showing localized leakage of the vasculature (Sabatasso et al 2021 ) …”