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Getting new insights into the radio-sensitization effects of nanoparticles in photon and charged particle therapy

Periodic Reporting for period 1 - NANOCANCER (Getting new insights into the radio-sensitization effects of nanoparticles in photon and charged particle therapy)

Okres sprawozdawczy: 2017-10-30 do 2019-10-29

The use of nanoparticles (NP) as dose enhancers in conventional (photon) radiotherapy (RT) is a growing research field. Recently, the use of NP has been extended to charged particle RT in order to improve the performance in very radioresistant tumors. However, the biological mechanisms underlying the synergistic effects involved in NP-RT approaches are not clearly understood. In addition to the damage due to a possible local dose enhancement (physical effects), the interaction of NP with essential biological macromolecules could lead to changes in the cells (biochemical effects) leading to an amplified effect of the radiation.

Within this framework, we used the capabilities of synchrotron-based Fourier Transform Infrared Microspectroscopy (SR-FTIRM) as a bio-analytical tool to elucidate the NP-induced cellular damage at the molecular level and at a single-cell scale. Glioma cells doped with AuNP and GdNP were irradiated using several types of medical ion beams (photons, protons and heavier ions). Differences in cell composition were analyzed in the nucleic acids, protein and lipid spectral regions using Principal Component Analysis (PCA). Results provided new insights into the molecular changes in response to NP-based RT and highlighted the relevance of SR-FTIRM as a useful and precise technique for assessing cell response to innovative radiotherapy approaches. The knowledge of these biochemical features will help researchers to develop RT by taking full advantage of the underlying biology an enhance the therapeutic index of RT for diseases with poor prognosis, such as radioresistant cancers.
The main scientific objective of the project was to get deeper insights into the radiosensitization mechanisms underlying the amplification of radiation effects of (Au and Gd) NP in glioma cells. Specifically, the radiosensitization effects were evaluated under several type of radiations: megavoltage RT using photons and charged particle RT.

MEGAVOLTAGE RT

The main goal of this part was to provide new insights into the radiosensitization effects of glioma cells exposed to gadolinium and gold NP combined with clinical megavoltage beams and compare them with respect to kilovoltage RT (commonly used in combination with NP). For this purpose, we used SR-FTIRM to provide relevant information on the treatment-induced biochemical changes of the main cell biomolecules.

PCA revealed Gadolinium NP-dependent changes in megavoltage treated cells. However, PCA did not discriminate clearly between megavoltage and kilovoltage groups treated with NP, indicating that megavoltage radiosensitization effects might not differ significantly from those in kilovoltage RT.

Gold NP (AuNP) have become particularly popular due to their multiple advantages. Within this context, our research work also aimed to study the biochemical radiosensitization capacity of F98 and U87-MG glioma cell lines to AuNP combined with X-ray irradiations through SR-FTIRM. SR-FTIRM data revealed clear AuNP-induced changes in the DNA, protein and lipid spectral regions.

More scientific details can be found in the related Gold Open Access publications:

• Martínez-Rovira et al. Analyst 144, 5511-5520 (2019). DOI: 10.1039/C9AN00792J.

• Martínez-Rovira et al. Analyst 144, 6352-6364 (2019). DOI: 10.1039/C9AN01109A.

Our works constituted the first studies that evaluates cell radiosensitization to nanoparticles by using SR-FTIRM, providing the foundation for understanding the cell changes in response to NP-based RT treatments. Our studies also highlighted the relevance of SR-FTIRM as a useful and precise technique for assessing cell response to innovative RT approaches.

CHARGED PARTICLE RT

Recently, the use of NP has been extended to charged particle RT in order to improve the performance in very radioresistant tumors. However, the biological mechanisms underlying the synergistic effects involved in NP-RT approaches are not clearly understood. Within this context, we used the capabilities of SR-FTIRM as a bio-analytical tool to elucidate the NP-induced cellular damage at the molecular level and at a single-cell scale in charged particle RT.

F98 glioma cells doped with AuNP and GdNP were irradiated using several types of medical ion beams. Differences in cell composition were analyzed in the nucleic acids, protein and lipid spectral regions using PCA. Several NP-induced cellular modifications were detected, which seem to be correlated to the already shown enhancement both in the DNA damage response and in the reactive oxygen species (ROS) production by the NP, which causes cell damage in the form of protein, lipid, and/or DNA oxidations.

An article has been recently submitted for publication:

• Martínez-Rovira et al. "Charged particle therapy and nanoparticles: study of the F98 glioma cells radiosensitization mechanisms at the molecular level through synchrotron-based infrared microspectroscopy".

This study constituted the first work that evaluates cell radiosensitization to NP in charged particle RT by using SR-FTIRM, providing new insights into the understanding of the cell response to NP-based charged particle RT treatments.

DISSEMINATION ACTIVITIES

Dissemination activities took place in order to give the maximum visibility of the goals, outcome and expected impact of the project. The dissemination method to specialized public included scientific publications (described previously) and the participation in scientific conferences (PTCOG, IUPESM, etc.).

Results were also published in the ALBA website. They present a regular review of ALBA synchrotron news, updates and developments and will reach specialized and non-specialized audiences.

Finally, to create awareness of the importance of research to society, we were committed to celebrate outreach activities to non-specialized public related with this project. Among the possible activities that serve to disseminate the importance of this proposal to a larger audience, I focused on performing outreach research presentations to undergraduate students in order to promote science among young students.
Scientific impact. Our project shed light on the radiobiological features of NP-based RT strategies through innovative synchrotron-based analytical approaches. To the best of our knowledge, this is the first study that evaluates NP-induced effects in RT by using infrared synchrotron light. The multidisciplinary-based approach of this project, joining both academic/research and clinical partners at the international level, brought knowledge across different fields, bridging the gap between biomedical engineering, physics, biochemistry and biology. This was and will be essential to improve our understanding of cancer and cancer treatments.

Socio-economic impact. RT represents one of the most useful tools available to cure cancer, together with surgery and chemotherapy. Usually these therapeutic modalities are used in combination, with an overall 50-65% fraction of total diagnoses undergoing radiotherapy. Given the size of the population subject to radiotherapy, the development and understanding of new emerging radiotherapy approaches is essential. Moreover, from economics point of view, cancer is the main cause of premature death in developed countries. Therefore, any increase in tumour control will have a direct economic impact.
Overview of the NANOCANCER project