2. Academic Validation
  3. 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

  • J Control Release. 2023 Apr 5;357:287-298. doi: 10.1016/j.jconrel.2023.03.058.
E 't Hart 1,  J Bianco 1,  M A C Bruin 2,  M Derieppe 1,  H C Besse 3,  K Berkhout 1,  L A Chin Joe Kie 1,  Y Su 1,  E W Hoving 1,  A D R Huitema 4,  M G Ries 3,  D G van Vuurden 5
Affiliations

Affiliations

  • 1 Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
  • 2 Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
  • 3 Center for Imaging Sciences, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
  • 4 Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
  • 5 Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 37019285 DOI: 10.1016/j.jconrel.2023.03.058
Abstract

Background and purpose: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Blood-brain barrier; Diffuse midline glioma H3K27-altered; Focused ultrasound; PARP1; Radiosensitisation.

Figures
Products