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. 2025 Mar 31:noaf093.
doi: 10.1093/neuonc/noaf093. Online ahead of print.

The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic GBM tumors

Wenjuan Zhang  1 , Michael P Grams  2 , Rajneet K Oberoi  1 , Ju-Hee Oh  1 , Paul A Decker  2 , Terence T Sio  2 , Surabhi Talele  1 , Zac C Wilson  2 , Margaret A Connors  2 , Katrina K Bakken  2 , Brett L Carlson  2 , Lauren L Ott  2 , Danielle M Burgenske  2 , Erik J Tryggestad  2 , Jeanette E Eckel Passow  2 , William F Elmquist  1 , Jann N Sarkaria  2
Affiliations

The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic GBM tumors

Wenjuan Zhang et al. Neuro Oncol. .

Abstract

Background: Most oncology therapeutics have limited distribution into the brain, and developing strategies to overcome this limitation would be clinically impactful. While therapeutic radiation is often cited as a strategy accomplish this, there are no published studies demonstrating the effect of radiation on drug distribution into the brain or brain tumors.

Methods: Mice were treated with brain radiation (6 Gy × 5, 4 Gy × 10; 40 Gy × 1) and dosed with drugs (levetiracetam, cefazolin, nedisertib, brigimadlin, apitolisib, or GNE-317) at times ranging from just prior to months after radiation. Plasma and tissue drug concentrations were measured by LC-MS/MS.

Results: Radiation did not significantly enhance drug delivery into brain tissue for levetiracetam, cefazolin, GNE-317, apitolisib, or nedisertib at any times post-radiation. Even a single, supra-therapeutic dose of radiation (40 Gy) did not significantly affect brain distribution of GNE-317 or apitolisib (P ≥ 0.07) from 16 to 160 hours post-radiation. For brigimadlin, radiation (6 Gy × 5) was associated with a modest but significant increase on drug accumulation only at 72 hours post-radiation (brain-to-plasma ratio 0.014±0.006 vs. 0.025±0.010, respectively; P = 0.04), but not at any other timepoint (24 hr, 15, 28, 94, 133, 183 days; P > 0.05). Similarly, radiation (6 Gy × 5) of orthotopic tumors did not increase levels of brigimadlin in GBM10 or GBM108 or nedisertib in GBM108 (P > 0.05).

Conclusions: Radiation had no meaningful impact of drug delivery into brain or brain tumors for the drugs tested.

Keywords: BBB permeability; Radiation therapy; brain tumor models; drug delivery.

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Conflict of interest statement

Conflict of interest statement

All authors have no conflict of interest to disclose.

Comment in

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