Gadolinium-based nanoparticles to improve the hadrontherapy performances Erika Porcel, PhD a , Olivier Tillement, PhD b , François Lux, PhD b , Pierre Mowat, PhD b , Noriko Usami, PhD c , Katsumi Kobayashi, PhD c , Yoshiya Furusawa, PhD d , Claude Le Sech, MD, PhD a , Sha Li a , Sandrine Lacombe, PhD a, ⁎ a Institut des Sciences Moléculaires d’Orsay, Université Paris Sud, CNRS, Orsay, France b Institut Lumière Matière, Université Claude Bernard Lyon 1, CNRS, Villeurbanne, France c Photon Factory, Institute of Material Science, High Energy Accelerator Research Organization, Oho 1, Tsukuba, Ibaraki, Japan d Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Japan Received 29 October 2013; accepted 12 May 2014 Abstract Nanomedicine is proposed as a novel strategy to improve the performance of radiotherapy. High-Z nanoparticles are known to enhance the effects of ionizing radiation. Recently, multimodal nanoparticles such as gadolinium-based nanoagents were proposed to amplify the effects of x-rays and g-rays and to improve MRI diagnosis. For tumors sited in sensitive tissues, childhood cases and radioresistant cancers, hadrontherapy is considered superior to x-rays and g-rays. Hadrontherapy, based on fast ion radiation, has the advantage of avoiding damage to the tissues behind the tumor; however, the damage caused in front of the tumor is its major limitation. Here, we demonstrate that multimodal gadolinium-based nanoparticles amplify cell death with fast ions used as radiation. Molecular scale experiments give insights into the mechanisms underlying the amplification of radiation effects. This proof-of-concept opens up novel perspectives for multimodal nanomedicine in hadrontherapy, ultimately reducing negative radiation effects in healthy tissues in front of the tumor. © 2014 Elsevier Inc. All rights reserved. Key words: Nanomedicine; Gadolinium; Nano-sensitisation; Hadrontherapy; Theranostics Background Nanodrugs for cancer-therapy is a rapidly developing field of investigation, where new drug delivery vehicles, contrast agents and therapeutics are being processed with the goal of improving medical protocols. 1–3 Recently, the use of nanomaterials was proposed as a promising way to enhance the performance of radiation therapies. Indeed, the limitation of conventional radiotherapy comes from the damage induced in the healthy tissues surrounding the tumour. In 2004, it was shown that the effects of X-rays can be amplified in tumours when gold nanoparticles are present. 4 The in vivo study demonstrated the high potential of using tumour-targeted nanomaterials to improve radiotherapies. Other studies performed on DNA and mammalian cells confirmed the properties of high-Z nanoparti- cles to amplify radiation effects. 5,6 On the other hand, fast ion-based radiation therapies (hadronther- apy and protontherapy) are considered superior approaches for the treatment of tumours located in highly sensitive tissues (brain, neck, eyes), paediatric cancers, and also tumours that are resistant to radiotherapy. 7 The advantage of ions compared to photons stems from their property to induce maximum damage at the end of the track (called the Bragg peak). In operating conditions, the beam is tuned such that the Bragg peak is spread out and the maximum of the radiation effects coincides with the total volume of the tumour (mode of spread out Bragg peak). As a result, the damage induced behind the tumour is close to zero and the healthy tissues are preserved. 8 Hence, hadrontherapy and protontherapy represent strong advances in cancer therapies. The major limitation of these techniques stems from the radiation effects that remain significant in front of the tumour (at the entrance of the track). It is thus a challenge to diminish the dose given to the patient and to enhance the biological effect of the treatment in the tumour. The use of tumour-targeted nanopar- ticles to amplify the radiation-effect of heavy ions in the tumour is a novel strategy, which has never been explored before. Nanomedicine: Nanotechnology, Biology, and Medicine xx (2014) xxx – xxx nanomedjournal.com ⁎ Corresponding author at: Institut des Sciences Moléculaires d'Orsay, Université Paris Sud, CNRS, 91405 Orsay CEDEX, France. E-mail address: sandrine.lacombe@u-psud.fr (S. Lacombe). Please cite this article as: Porcel E., et al., Gadolinium-based nanoparticles to improve the hadrontherapy performances. Nanomedicine: NBM 2014;xx:1-8, http://dx.doi.org/10.1016/j.nano.2014.05.005 http://dx.doi.org/10.1016/j.nano.2014.05.005 1549-9634/© 2014 Elsevier Inc. All rights reserved.