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ACOUSTIC MARKERS FOR ENHANCED REMOTE SENSING OF RADIATION DOSES

Periodic Reporting for period 2 - AMPHORA (ACOUSTIC MARKERS FOR ENHANCED REMOTE SENSING OF RADIATION DOSES)

Reporting period: 2018-11-01 to 2020-04-30

Approximately 50% of all cancer patients receive radiation therapy as part of their treatment. The aim is hereby to maximise tumor irradiation and to minimize healthy tissue irradiation. This implies a need for appropriate dosimetry strategies that can effectively measure the actual radiation dose imparted on the tumor. However, state-of-the-art dosimetry cannot quantify the dose distribution in (and around) the tumor, hereby inhibiting the full potential of radiotherapy.

AMPHORA aims to develop a non-invasive in-situ dosimetry system for radiation therapy with the potential of on-line dose assessment by casting ultrasound contrast agents (UCAs) into dose sensing theranostic devices. UCAs will be upgraded to injectable dose-sensitive and targeted devices that gather in tumor tissue and translate imparted radiation dosage into a modulation of their acoustic response upon ultrasound interrogation. Tailored ultrasound imaging and advanced signal processing algorithms will be developed to extract the (change in) acoustic signature of UCAs from backscatter data and to translate this information into a 2D or 3D dose distribution map. The specific objectives of this project are the design, development and pre-clinical validation of the aforementioned UCA based dosimetry system and a customised ultrasound read-out technology.

Upon successful completion, AMPHORA will have enabled the assessment of the effective radiation dose distribution in (and around) the tumor, offering an advanced and objective means to compare and evaluate treatment efficacy of different radiotherapy modalities. Such novel technology would revolutionize quality assurance and treatment follow up in radiotherapy, which also unmistakably will lead to increased patient safety and improved treatment protocols. Moreover, AMPHORA is expected to trigger an avalanche of novel technologies for radiation therapy delivery and to pave the way for other in-vivo UCA based distributed sensing applications.
To date, two main sensing technologies (i.e. UCA’s) have been developed and (partially) characterized: i) hyperthermal nanodroplets and ii) lipidic microbubbles by two of AMPHORA’s partners (i.e. UNITOV and IMEC respectively). Their respective working mechanism as a radiation-sensing device is distinct. Indeed, the ambition is to have the former change phase upon irradiation thereby changing its volume by several orders of magnitude and showing as an ‘off/on switch’ for ultrasound. The lipidic microbubble on the other hand will always be ‘visible’ by ultrasound but has the ambition to change its interaction with these waves upon irradiation thereby encoding its irradiation state in the backscattered signal. Importantly, to facilitate decoding the irradiation state from the captured echo signals, microfluidic manufacturing techniques are being used as to create a population of bubbles with very narrow size distribution thereby limiting the complexity of the ‘code’. To date, both agents have been well characterized in terms of their physico-chemical and functional characteristics and – more recently – their acoustic behaviour. For the latter, a dedicated measurement setup has been designed and built that allows extensive acoustic measurements (i.e. through-transmission, 90-degrees scattering as well as backscatter recording) not only pre- and post-irradiation but also during irradiation. Hereto, the setup was designed in such a way that it is compatible with (clinically used) radiation sources. As such, initial experiments towards the response of the developed UCA’s to differing radiation sources has recently started. In addition, proof-of-concept data shows that functionalization (i.e. targeting to specific cell ligands) of the developed nanodroplets is feasible. Finally, a rodent prostate-tumour model has been identified for in-vivo testing of the UCA’s developed and methodologies (i.e. 19F MRI) towards assessing bio-distribution of the devices developed have already been tested. Overall, the development of radiation-sensitive devices is on-going and moves forward according to plan.

The ultrasound read-out technology is based on the quantitative assessment of local acoustic properties of the (ultrasound) medium. Hereto, a prior-art algorithm to estimate local acoustic attenuation was further developed in order to make it more performing. Experimental data shows that the proposed solution is indeed faster as well as more accurate and precise than the original approach and allows estimating ultrasound wave attenuation in real-time. This combined with the fact that pre-AMPHORA pilot data showed lipidic UCA’s to change their attenuation characteristics upon irradiation is very promising towards reaching the final goal of AMPHORA. Importantly, the read-out technology developed remains generic in that it can be generalized to simultaneously estimate backscatter and non-linear characteristics of the propagating medium. This is the topic of going work and might be important in case the newly developed UCA’s behave different in their acoustic response to radiation than the pre-AMPHORA commercial agent tested. Finally, in order to translate this read-out technology to a clinical setting, a customized ultrasound system is required. During the first reporting period, systems specifications have been defined based on interaction with the Clinical Advisory Board (CAB) of AMPHORA. As such, the design and development of a 1024-channel ultrasound platform to be equipped with a 32x32 custom-made matrix array transducer has started. For the latter, simulation studies have been carried out (and are still on-going) as for optimal transducer design before its effective (expensive) fabrication starts. Overall, development of the ultrasound read-out technology is thus moving forward according to plan.
The scientific breakthroughs pursued are casting ultrasound contrast agents (UCAs) into the unprecedented role of dose sensing theranostic devices and tailoring ultrasound imaging and signal processing algorithms to extract the (change in) acoustic signature of UCAs from backscatter data and to translate this information into a 2D or 3D dose map.

Pursuing potential means to assess the radiation dose distribution in (and around) the tumor, this project intends to grant radiation therapists and physicists access to the currently unmeasurable very essence of their treatment. Successful completion of this project would therefore revolutionize quality assurance and treatment follow up, unmistakably leading to increased patient safety and offering advanced and objective means to compare and evaluate treatment efficacy of different radiotherapy modalities. This could potentially even further improve treatment protocols. Moreover, emergence of in-situ dose information is expected to trigger an avalanche of technological advances exploiting this new source of information to herald a new era in adaptive radiotherapy further focusing on treatment delivery specificity and tumor conformity. In addition, as ultrasound contrast agents provide a highly flexible platform, successful completion of this project is expected to pave the way for other in-vivo UCA
based distributed sensing applications (e.g. temperature, acidity, etc.). As such, the potential impact of AMPHORA ranges well beyond the field of radiotherapy.
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Amphora conceptual