Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model

Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model

Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but r...

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Bibliographic Details
Published in:Journal of controlled release Vol. 357; pp. 287 - 298
Main Authors: ’t Hart, E., Bianco, J., Bruin, M.A.C., Derieppe, M., Besse, H.C., Berkhout, K., Chin Joe Kie, L.A., Su, Y., Hoving, E.W., Huitema, A.D.R., Ries, M.G., van Vuurden, D.G.
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01-05-2023
Subjects:
Animals
Blood-brain barrier
Cell Line, Tumor
Chromatography, Liquid
Diffuse midline glioma H3K27-altered
Focused ultrasound
Glioma - drug therapy
Glioma - pathology
Humans
Mice
PARP1
Radiosensitisation
Tandem Mass Spectrometry
Focused ultrasound
PARP1
Blood-brain barrier
Radiosensitisation
Diffuse midline glioma H3K27-altered
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Summary:Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO). Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model. Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 μM in blood and 1.39 μM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model. Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models. [Display omitted] •PARP1 inhibition by olaparib and radiation cause radiosensitisation in DMG cells.•Focused ultrasound blood-brain barrier disruption enables drug delivery in pons.•In vivo found pharmacokinetics values of olaparib delay neurosphere growth in vitro.•Focused ultrasound with olaparib and radiotherapy induce tumour growth delay.
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ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2023.03.058