Evaluating metal nanoparticle radiosensitisers with DNA repair inhibitors

: a novel theranostic approach in primary glioblastoma

Abstract

Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis of approximately 12 months following standard of care treatment with surgery, radiotherapy (RT), and temozolomide. RT drug combinations have the potential to improve patient outcomes, with high atomic number metal nanoparticles (NPs) and targeted DNA damage response inhibitors (DDRIs) demonstrating significant preclinical and clinical potential as novel radiosensitizers in brain tumours due to increased production of complex DNA lesions and diminished repair capacity. In this study, we aimed to evaluate the radiosensitizing potential of several metal NP formulations and combine radiosensitizing candidates with DDRIs to develop an optimised multimodal treatment approach.

The radiation response to metal NPs and DDRIs as monotherapies and in combination was evaluated in vitro by assessing clonogenic cell survival, cytotoxicity, DNA damage, and cell cycle modulation. Inhibitor IC30 values were determined by clonogenic survival assays for combination studies. Finally, the novel impact of differentially PEGylated gold NPs and radiation on GBM cell immune modulation was determined by cytokine arrays.

We found that AGuIX and ID11 in U-87 MG cells, and AGuIX, ID11, and ID12 in U-251 MG cells, potentiated the radiation response by enhancing DNA double-strand break (DSB) induction. Combination studies with these NPs and DDRIs (Olaparib, AZD0156, and AZD6738) identified four optimised NP-DDRI combinations with synergistic effects on GBM cell survival. The combinations include AGuIX and AZD6738 in U-87 MG cells, and ID11 and AZD0156, AGuIX and Olaparib, and ID12 and Olaparib in U-251 MG cells. Persistent DSBs were elucidated as an underlying mechanism of enhanced radiosensitization. The observed synergy provides valuable insight into the types of DNA lesions generated by each NP and the preferential mechanisms of repair. Our data demonstrate the synergistic potential of metal NPs and DDRIs that could improve the efficacy of RT in preclinical GBM models.

Cytokine expression changes in response to the differentially PEGylated GNPs and RT showed ID11 (PEG = 4) caused the greatest boost in RT immunogenicity. This desirable immune modulation highlights the therapeutic potential of GNP-RT combinations for greater tumour control in GBM patients in the future.

Date of Award	Jul 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Brainwaves NI
Supervisor	Karl Butterworth (Supervisor) & Kevin Prise (Supervisor)