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The major goal of all radiotherapy is to maximise the therapeutic index by efficient killing of tumour cells whilst protecting normal tissues. It has long been thought that the development of nanomedicine approaches, using metal-based nanoparticles can contribute to this, by acting as radiosensitising agents alongside being used as imaging agents, so called theranostics. For many years, significant effort has been focussed on the development of particularly gold-based nanoparticles. Our radiation physics understanding of how gold nanoparticles sensitise cells to radiation has moved from an assumption that mass attenuation coefficients of metal NP effects are critical to also including the importance of localised auger electron cascades around the nanoparticle. This has important implications for nanoparticle selections and sensitisation effects seen with different types of clinical radiations including high energy photons and ion beams. In general, however there is still significant gaps in our knowledge around the optimal chemistry around nanoparticles, their uptake mechanisms, bioavailability and cellular/tissue distributions. Overall, in many experimental studies significant biological sensitisation is observed beyond that predicted by known physical enhancement mechanisms.
Despite our gaps in knowledge, a vast range of nanoparticle types have been assessed pre-clinically, including gold and iron-based nanoparticles but the most encouraging to date, which have reached clinical testing, are a hafnium oxide-based particle (NBTXR3) and a gadolinium-based nanoparticle (AGuIX). AGuIX is now in clinical trials for patients with multiple metastatic brain tumours showing good bioavailability and little toxicity. Crucially it appears to be effective even administered by systemic delivery, crossing the blood brain barrier and showing good tumour uptake and theranostic utility.
Recent preclinical work in glioma has highlighted the potential of combing nanoparticles with other therapeutics including DNA damage inhibitors such as PARPi or ATMi and also targeting patients with mutations in DNA repair pathways. These combinatorial approaches have significant potential if optimal scheduling can be defined. New opportunities may also exist with a greater appreciation of the role of immune responses and their potential targeting and activation with metal-based nanoparticle.
Despite the challenges, there is now significant opportunity for bespoke nanoparticle design based on an improved understanding of both physical and biological sensitisation mechanisms.