What is the image-guided radiotherapy (IGR)?
The combination of medical imaging and radiotherapy constitutes an important research field, for the group “NCM” of UTINAM Institute (Université de Franche Comté, Besançon, France). Our studies aims at rendering radiotherapy more specific by concentrating the dose deposition of the radiation in the tumour while sparing the healthy tissues. For achieving this goal, multifunctional gold nanoparticles are in the heart of our research activities since these nanoparticles exhibit a great potential for radiosensitization and medical imaging. Their presence in the tumor will increase the deleterious effect of the radiation in order to specifically eradicate the cancerous cells. The cells appear therefore more sensitive to the therapeutic radiation. Indeed the preferential absorption of the ionizing radiation (X- or γ-rays) by the gold nanoparticles will produce a shower of highly reactive radicals which will seriously alter the tumor. Owing to the combination of medical imaging and therapy, the most opportune moment (high content of nanoparticles in tumour and low content in healthy tissues) can be determined for activating the therapeutic effect of gold nanoparticles. In other words, the radiotherapy is guided by imaging. The treatment by radiotherapy was based on MRT (Microbeam Radiation Therapy). MRT is a non-conventional irradiation technique performed at the ESRF (European Synchrotron Radiation Facility, Grenoble, France). The therapeutic radiation is constituted by an array of parallel microbeams.
Why we use gold nanoparticles for the IGR?
Owing to their large range of properties which can be accurately tuned by the chemical composition, the shape and the dimensions, multifunctional nanoparticles appear as promising candidates for image-guided therapy. Under the supervision of Stéphane Roux, who has strong background in this subject, we developed the synthesis of gold nanoparticles which are designed for combining multimodal imaging (magnetic resonance imaging (MRI), scintigraphy (SPECT), ultrasound imaging (echography) and X-ray imaging) and radiotherapy. Gold nanoparticles were synthesized by a simple protocol that allows the formation of gold nanoparticles embedded in a shell of organic molecules. These nanoparticles have a diameter of about 6-8 nanometres with an ultrasmall gold core size (~ 2.5 nm). Since their size does not exceed 10 nm, these gold nanoparticles can be removed through renal pathway which constitutes a prerequisite for the in vivo use of non-biodegradable nanoparticles.
The organic shell was designed for entrapping ions of interest for the medical imaging like gadolinium (for MRI) or radioelements like 111In or 99mTc (for scintigraphy, a nuclear imaging using radioactive elements). When one of these ions is present in the nanoparticles we can follow up them after injection in the body. Besides, the gold core of the nanoparticles provides a strong X-ray absorption that permits to better focalize the radiation.
Conclusion of the in vivo test: Chelate-coated gold nanoparticles exhibit a real potential for IGR
After intravenous injection to healthy and to tumour bearing mice and rats, the biodistribution of these nanoparticles was monitored by different kinds of medical imaging. The results show that the gold nanoparticles freely circulate in bloodstream without undesirable accumulation in healthy tissue and are efficiently cleared by renal elimination. However a passive accumulation in tumour zone can be observed in the case of rats bearing a brain tumor (9L gliosarcoma). This was exploited for radiotherapy. The possibility to follow up the nanoparticles by MRI is very interesting since the delay between the intravenous injection of the gold nanoparticles and the irradiation can be determined from the data collected by MRI. The combination of microbeam radiation therapy (MRT) performed in the beamline ID17 at the European Synchrotron Radiation Facility (ESRF) and gold nanoparticles led to the increase in lifespan of the diseased animals in comparison to non treated animals and animals treated only by MRT.
Finally, this study demonstrated that gold nanoparticles containing gadolinium in their shell exhibit a real potential for image-guided radiotherapy.
We wish to thank the “Agence Nationale de la Recherche” for the financial support (ANR 2011 NANO 017), the region Franche-Comté for the doctoral grant (GJS) and the ESRF Biomedical Beamline.
1 – Alric, C. et al. Gadolinium Chelate Coated Gold Nanoparticles As Contrast Agents for Both X-ray Computed Tomography and Magnetic Resonance Imaging. J. Am. Chem. Soc. 130, 5908–5915 (2008).
2 – Alric, C. et al. The biodistribution of gold nanoparticles designed for renal clearance. Nanoscale 5, 5930–5939 (2013).
3 – Miladi, I. et al. The In Vivo Radiosensitizing Effect of Gold Nanoparticles Based MRI Contrast Agents. Small 10, 1116–1124 (2014).
Gloria Jiménez Sanchez has a degree in Biochemistry from Universidad de Granada (Spain) as well as Master degrees in «Structural and Functional Biochemistry» from the Université Claude Bernard Lyon 1 (France). She is currently a PhD student at UTINAM Institute in France where she works on the functionalization of nanoparticles for a better targeting to the tumour, under the supervision of Stéphane Roux and Rana Bazzi.