Abstract C062: The use of nanoparticles to improve tumour radiosensitivity

Abstract

Fractionated radiotherapy, administered by high energy external beam X-rays, is the mainstay of several cancer treatment regimens. However, treatment is often required for several weeks, with cure rates limited by radio-resistant hypoxic areas within the tumour, patient compliance due to the frequency of required treatments and cumulatively high total radiation dose that can cause adjacent tissue toxicity. Radiosensitisers are being developed to improve efficacy, but most are still limited by tumour hypoxia. Titanium oxide is a well-known, non-toxic, photoactive material that generates hydroxyl free radicals by water splitting under ultraviolet light. Rare earth doped titanium oxide nanoparticles can be delivered to cancer cells and interact with X-rays and electrons, concentrating free radicals within the cells. Crucially, this response is also effective within hypoxic tumour regions. Proof of concept studies were performed in pancreatic tumour cells PANC-1 irradiated in vitro. Both cell number and clonogenicity were reduced following irradiation in the presence of nanoparticles compared to irradiation alone. This response was then further evaluated in subcutaneously xenografted tumours. Briefly, male CD-1 nude mice were inoculated with either the pancreatic carcinoma, MiaPaCa-2, or the head and neck squamous cell carcinoma, FaDU, cells. Tumours were allowed to grow until palpable and then irradiated with 2Gy daily for 5 days (Mon-Fri) for 1 or 2 weeks (or sham irradiated) to mimic the clinical protocol. Immediately prior to the first irradiation each week tumours were injected with 125μg nanoparticles or vehicle. Tumour growth was then monitored for up to 5 weeks. Injection of the nanoparticles alone had no effect on tumour growth rate, but when combined with irradiation there was up to 65-75% reduction in tumour volume 30 days after the start of treatment. Sections of Carnoy’s fixed tumours taken 3 days (Day 15) after the last irradiation were immunohistochemically labelled with the proliferation marker bromodeoxyuridine (BrdU). Whilst there was a clear radiation response there was little difference in proliferation following co-administration of nanoparticles at this early timepoint, suggesting either surviving radioresistant clones had evolved by two weeks or that the nanoparticle induced tumour growth delay was not simply the result of early cell death/cell cycle interruption but may have delayed effects. These preliminary studies show that titanium oxide nanoparticles are non-toxic and can enhance the efficacy of radiotherapy in pancreatic and head and neck tumour cell lines. Further work will quantify the level of tumour cell death in normal vs hypoxic tumour regions over time, in a range of tumour types with differing levels of radiosensitivity. Citation Format: Ben Reed, Gareth Wakefield, Matt Stock, Gregory Tudor. The use of nanoparticles to improve tumour radiosensitivity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C062. doi:10.1158/1535-7163.TARG-19-C062