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Over the last decade, a growing interest in the improvement of radiation therapies has led to the development of gold-based nanomaterials as radiosensitizer. Although the radiosensitization effect was initially attributed to a dose enhancement mechanism, an increasing number of studies challenge this mechanistic hypothesis and evidence the importance of chemical and biological contributions. Despite extensive experimental validation, the debate regarding the mechanism(s) of gold nanoparticle radiosensitization is limiting its clinical translation. This article reviews the current state of knowledge by addressing how gold nanoparticles exert their radiosensitizing effects from a transdisciplinary perspective. We also discuss the current and future challenges to go towards a successful clinical translation of this promising therapeutic approach.

Protontherapy (PT) is a fast-growing cancer therapy modality thanks to much-improved normal tissue sparing granted by the charged particles’ inverted dose-depth profile. Protons, however, exhibit a low biological effectiveness at clinically relevant energies. To enhance PT efficacy and counteract cancer radioresistance, Proton–Boron Capture Therapy (PBCT) was recently proposed. PBCT exploits the highly DNA-damaging α-particles generated by the p + 11B→3α (pB) nuclear reaction, whose cross-section peaks for proton energies of 675 keV. Although a significant enhancement of proton biological effectiveness by PBCT has been demonstrated for high-energy proton beams, validation of the PBCT rationale using monochromatic proton beams having energy close to the reaction cross-section maximum is still lacking. To this end, we implemented a novel setup for radiobiology experiments at a 3-MV tandem accelerator; using a scattering chamber equipped with an Au foil scatterer for beam diffusion on the biological sample, uniformity in energy and fluence with uncertainties of 2% and 5%, respectively, was achieved. Human cancer cells were irradiated at this beamline for the first time with 685-keV protons. The measured enhancement in cancer cell killing due to the 11B carrier BSH was the highest among those thus far observed, thereby corroborating the mechanistic bases of PBCT.

This study aimed at developing antibody-functionalized gold nanoparticles (AuNPs) to selectively target cancer cells and probing their potential radiosensitizing effects under proton irradiation. AuNPs were conjugated with cetuximab (Ctxb-AuNPs). Ctxb-AuNP uptake was evaluated by transmission electron microscopy and atomic absorption spectroscopy. Radioenhancing effect was assessed using conventional clonogenic assay. Ctxb-AuNPs specifically bound to and accumulated in EGFR-overexpressing A431 cells, compared with EGFR-negative MDA-MB-453 cells. Ctxb-AuNPs enhanced the effect of proton irradiation in A431 cells but not in MDA-MB-453 cells. These data indicate, for the first time, that combining enhanced uptake by specific targeting and radioenhancing effect, using conjugated AuNPs, is a promising strategy to increase cell killing by protontherapy.

Background Proton therapy (PRT) is an innovative radiotherapeutic modality for the treatment of cancer with unique ballistic properties. The depth-dose distribution of a proton beam reduces exposure of healthy tissues to radiations, compared with photon-therapy (XRT). To date, only few indications for proton-therapy, like pediatric cancers, chordomas, or intra-ocular neoplasms, are reimbursed by Health systems. There is no published or recruiting prospective study evaluating the impact of proton-therapy or conventional irradiation on neurocognitive function for meningioma patients. Notably, long-term cognitive or ocular impact of these modern irradiation schemes remains poorly known. Yet, these patients had a long life-expectancy, and are at risk of developing long-term sequelae. Thus, according to its ballistic advantage, an improvement of patient functional outcomes and a reduction of neurocognitive long-term toxicity are expected if tissue sparing proton-therapy is used .Randomized trial seems crucial to further assess proton-therapy indication for patients with cavernous sinus meningioma.Methods COG-PROTON-01 is the first worldwide randomized phase III prospective study evaluating long-term toxicity of these two irradiation modalities (PRT and XRT)for the treatment of cavernous sinus meningioma. Primary objective is to compare long-term cognitive and/or functional (visual, hearing, neurological and/or endocrinological) deterioration between patients treated by fractionated proton-therapy (PRT) or photon radiotherapy (XRT), 5 years after the end of irradiation. The primary endpoint is based on the individual neurocognitive test scores (grouped into five cognitive domains: attention, executive functioning, verbal memory, working memory, information processing speed) and on visual, hearing, endocrinological and neurological evaluations, five years after radiotherapy. Eligible patients with low-grade cavernous sinus meningioma will be 1:1 randomised, with stratification on age, sex, MoCA score. Overall, the inclusion of 160 patients is planned (80 in each arm). To be considered as positive, asumming that 47% of patients will not develop long-term cognitive disabilities deficits after XRT radiotherapy, thus at least 70% of the patients treated with PRT should not develop functional impairment. First inclusions started on September 2023 (NCT05895344 ).Trial registration The study was registered on clinicaltrials.gov on June 8, 2023 with the following number: NCT05895344

The use of nanoparticles to enhance the effect of radiation-based cancer treatments is a growing field of study and recently, even nanoparticle-induced improvement of proton therapy performance has been investigated. Aiming at a clinical implementation of this approach, it is essential to characterize the mechanisms underlying the synergistic effects of nanoparticles combined with proton irradiation. In this study, we investigated the effect of platinum- and gadolinium-based nanoparticles on the nanoscale damage induced by a proton beam of therapeutically relevant energy (150 MeV) using plasmid DNA molecular probe. Two conditions of irradiation (0.44 and 3.6 keV/μm) were considered to mimic the beam properties at the entrance and at the end of the proton track. We demonstrate that the two metal-containing nanoparticles amplify, in particular, the induction of nanosize damages (>2 nm) which are most lethal for cells. More importantly, this effect is even more pronounced at the end of the proton track. This work gives a new insight into the underlying mechanisms on the nanoscale and indicates that the addition of metal-based nanoparticles is a promising strategy not only to increase the cell killing action of fast protons, but also to improve tumor targeting.

Background Proton therapy (PT) is recognized as a superior treatment for head cancer (HC) due to its precision and minimal damage to surrounding healthy tissues, relying on computed tomography (CT) data for dose calculations. Adaptive proton therapy (APT) is crucial to address changes in patient anatomy during treatment and update dose accuracy. However, in‐room cone‐beam CT (CBCT) assistance is limited to assessing patient setup, with occasional constraints due to artifacts and/or lower image quality and resolution compared to a CT scan. Purpose Although deep learning (DL) techniques can successfully convert a CBCT into a synthetic CT (sCT), soft tissue delineation remains a challenging task. We hypothesized that, by including Magnetic Resonance Image (MRI) in CBCT‐based CT synthesis, the sCT generation could more closely approximate the CT ground truth while improving tissue definition and dose calculation in PT treatment planning. Methods We propose a Pix2Pix‐conditional generative adversarial network (cGAN) to synthesize a CT scan by combining two different input images: CBCT and T1‐weighted MRI. ResUnet and SwinUnet were evaluated as the cGAN generator. Additionally, a CBCT‐only‐based CycleGAN was tested. Results Model performance improved with the inclusion of MRI data, especially in recovering soft tissue details like eyes and ventricles, with ResUnet models outperforming SwinUnet models. Our cGAN outperformed both the self‐autoencoder approaches and the CycleGAN model. Pix2Pix‐ResUnet (MR‐based) significantly reduced average HU errors in volumes of interest and also enhanced the precision in dose values, as demonstrated in dose differences and profiles. ConclusionsWe demonstrated the promising contribution of MRI to CBCT‐based CT synthesis, enhancing sCT image quality and dose calculation accuracy. Future efforts should aim to collect a larger dataset and validate the integration of MRI in APT.

PurposeBrainstem radionecrosis is an important issue during the irradiation of tumors of the posterior fossa. The aim of the present study is to analyze postsurgical geometrical variations of tumor bed (TB) and brainstem (BS) and their impact on dosimetry.MethodsRetrospective collection of data from pediatric patients treated at a single institution. Availability of presurgical magnetic resonance imaging (MRI) was verified; availability of at least two postsurgical MRIs was considered a further inclusion criterion. The following metrics were analyzed: total volume, Dice similarity coefficient (DSC), and Haudsdorff distances (HD).ResultsFourteen patients were available for the quantification of major postsurgical geometrical variations of TB. DSC, HD max, and HD average values were 0.47 (range: 0.08;0.76), 11.3 mm (7.7;24.5), and 2.6 mm (0.7;6.7) between the first and the second postoperative MRI, respectively. Postsurgical geometrical variations of the BS were also observed. Coverage to the TB was reduced in one patient (D95: −2.9 Gy), while D2 to the BS was increased for the majority of patients. Overall, predictive factors for significant geometrical changes were presurgical gross tumor volume (GTV) > 33 mL, hydrocephaly at diagnosis, Luschka foramen involvement, and younger age (≤ 8 years).ConclusionMajor volume changes were observed in this cohort, with some dosimetric impact. The use of a recent co-registration MRI is advised. The 2–3 mm HD average observed should be considered in the planning target volume/planning organ at risk volume (PTV/PRV) margin and/or robust optimization planning. Results from wider efforts are needed to verify our findings.

CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) was the first Italian protontherapy facility dedicated to the treatment of ocular neoplastic pathologies. It is in operation at the LNS Laboratories of the Italian Institute for Nuclear Physics (INFN-LNS) and to date, 500 patients have been successfully treated. Even though proton therapy has demonstrated success in clinical settings, there is still a need for more accurate models because they are crucial for the estimation of clinically relevant RBE values. Since RBE can vary depending on several physical and biological parameters, there is a clear need for more experimental data to generate predictions. Establishing a database of cell survival experiments is therefore useful to accurately predict the effects of irradiations on both cancerous and normal tissue. The main aim of this work was to compare RBE values obtained from in-vitro experimental data with predictions made by the LEM II (Local Effect Model), Monte Carlo approaches, and semi-empirical models based on LET experimental measurements. For this purpose, the 92.1 uveal melanoma and ARPE-19 cells derived from normal retinal pigmented epithelium were selected and irradiated in the middle of clinical SOBP of the CATANA proton therapy facility. The remarkable results show the potentiality of using microdosimetric spectrum, Monte Carlo simulations and LEM model to predict not only the RBE but also the survival curves.

An evaluation of the improvement in radiotherapy obtained using gold nanoparticles embedded in the tumor tissues is presented for traditional treatments using X-rays and electrons and for innovative proton therapy. The possible nanoparticles’ preparation via physical, by laser ablation in liquids, and chemical techniques is presented. The use of functionalized gold nanoparticles is discussed and results from the study of uptake and decay from mice living systems are reported. The improvement obtainable in medical images and in the dose distribution enhancement in disease tissues with respect to healthy ones is investigated.

The sophistication of Hadron facilities led to major technical and conceptual advances in the treatment immobilization, reproducibility, planning and execution. Some of these developments have had a pivotal impact on conventional treatments, which can now approach the dose localization advantage of protons in the majority of clinical situations. While the biological advantages of neutrons may finally be combined with excellent dose localization in Heavy Ion Facilities, modern surgical or systemic treatment methods may reduce high LET advantages. Clinical trials still need to define the relative merits of these approaches in their most modern implementation. The advantage gap has certainly been narrowed by recent developments in conventional therapy.