Platinum nanoparticles: a promising material for future cancer therapy?

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Platinum nanoparticles: a promising material for future cancer therapy?

This article has been downloaded from IOPscience. Please scroll down to see the full text article. 2010 Nanotechnology 21 085103 (http://iopscience.iop.org/0957-4484/21/8/085103) View the table of contents for this issue, or go to the journal homepage for more

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IOP PUBLISHING

NANOTECHNOLOGY

Nanotechnology 21 (2010) 085103 (7pp)

doi:10.1088/0957-4484/21/8/085103

Platinum nanoparticles: a promising material for future cancer therapy? Erika Porcel1 , Samuel Liehn1 , Hynd Remita2 , Noriko Usami3 , Katsumi Kobayashi3 , Yoshiya Furusawa4, Claude Le Sech1 and Sandrine Lacombe1 1

Laboratoire des Collisions Atomiques et Moléculaires (UMR 8625), Université Paris-Sud 11, CNRS, 91405 Orsay Cedex, France 2 Laboratoire de Chimie Physique (UMR 8000), Université Paris-Sud 11, CNRS, 91405 Orsay Cedex, France 3 Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization, Oho, Tsukuba, Ibaraki 305-0801, Japan 4 Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan E-mail: [email protected]

Received 18 November 2009, in final form 4 January 2010 Published 26 January 2010 Online at stacks.iop.org/Nano/21/085103 Abstract Recently, the use of gold nanoparticles as potential tumor selective radiosensitizers has been proposed as a breakthrough in radiotherapy. Experiments in living cells and in vivo have demonstrated the efficiency of the metal nanoparticles when combined with low energy x-ray radiations (below conventional 1 MeV Linac radiation). Further studies on DNA have been performed in order to better understand the fundamental processes of sensitization and to further improve the method. In this work, we propose a new strategy based on the combination of platinum nanoparticles with irradiation by fast ions effectively used in hadron therapy. It is observed in particular that nanoparticles enhance strongly lethal damage in DNA, with an efficiency factor close to 2 for double strand breaks. In order to disentangle the effect of the nano-design architecture, a comparison with the effects of dispersed metal atoms at the same concentration has been performed. It is thus shown that the sensitization in nanoparticles is enhanced due to auto-amplified electronic cascades inside the nanoparticles, which reinforces the energy deposition in the close vicinity of the metal. Finally, the combination of fast ion radiation (hadron therapy) with platinum nanoparticles should strongly improve cancer therapy protocols. (Some figures in this article are in colour only in the electronic version)

surrounding tissue. The implementation of such techniques is therefore limited by the tolerance of normal tissues. The challenge of future radiation therapies is to develop methods for targeting the dose deposition in tumors and to enhance biological effects. The addition of high- Z atom loaded compounds was proposed long ago as a method for enhancing the effect of ionizing radiations [2–5]. At a preclinical level, chemotherapy with cis-platinum associated to x-ray radiotherapy has shown encouraging results for the treatment of gliomas [6]. The effect of these compounds is well understood at the molecular level in terms of local dose amplification due to the electron emission

1. Introduction Nanotechnology has provided an essential breakthrough in the fight against cancer [1]. Recently, a combination of radiotherapy with nanoparticles has been proposed as a new alternative to improve protocols of treatment. Conventional radiotherapies based on x-ray and γ -ray radiations are the most widespread techniques in the world for the treatment of malignant diseases. These radiations present the advantage of penetrating tissues, which allows the treatment of deeply sited tumors. One major difficulty is the lack of selectivity between the tumor and the healthy 0957-4484/10/085103+07$30.00

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© 2010 IOP Publishing Ltd Printed in the UK

Nanotechnology 21 (2010) 085103

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in the surroundings of the high- Z atom. This phenomenon has been observed under different radiation conditions [3, 7, 8]. The bottleneck of this innovative protocol is the low tissue selectivity and the high cytotoxicity of the sensitizing agents. Improvements in tumor targeting and sensitizing efficiency are crucial. Noble metals, especially gold, have long been used in medicine [9]. Recent years have seen impressive advances in the applications of gold nanoparticles in particular. The surface chemistry of the nanoparticles opens perspectives for targeting and differentiating tissues by the adsorption of specific molecules. Optical properties in the infrared range encourage the development of new techniques such as photodiagnostic and photothermal therapy [10]. More recently, gold nanoparticles have been proposed as potential radiosensitizers for x-ray cancer therapy [11]. Gold nanoparticles coated with glucose in particular are good candidates to treat breast cancer [12]. A full understanding of the processes induced by nanoparticles in the genetic material is fundamental to further improve the sensitizing properties of these compounds. Hence, DNA is used as a model system to quantify the effects of ionizing radiations combined with nanoparticles in biological conditions [13, 14]. Most of the studies have been focused on the effect of gold nanoparticles combined with x-rays. However, it is worthwhile mentioning that these studies have been performed with laboratory x-rays of 200 keV and below, sources that are poorly relevant for medical applications [15–17]. In the perspective of future applications in cancer treatment, advanced medical sources must be considered. One of the most promising techniques in cancer therapy is hadron therapy (or proton therapy), where fast carbon (or proton) ions are used as an alternative to hard x-rays [18]. The advantage of these techniques stems from the unique ballistic effect of the ions, which differs strongly from electrons and photons [19]. In addition, due to their large cross section of interaction with matter, the ions are three times more efficient than conventional radiations. Finally, the treatment by fast ions opens new perspectives for an efficient and less traumatic eradication of cancers, including radio-resistant tumors seated in badly sensitive tissues difficult to access for surgery (brain, eyes, children’s tumors). This explains the fast expansion of hadron therapy and proton therapy centers in the world [18]. In order to improve efficiency and targeting of medical treatments, we propose a breakthrough in the development of protocols by combining metal nanoparticles and fast ion irradiation. The present study is focused on the damage induced by a medical carbon ion beam on DNA loaded with platinum nanoparticles. The analysis of DNA damage is used to characterize the effect of this combination. In order to disentangle the effect related to the nano-design architecture, a comparison with dispersed platinum atoms is also included. This allows us to underline new properties of nanoparticles that are relevant for radiation biology. It is finally shown that the addition of high- Z nanoparticles with fast ion irradiation is a very promising method for future advances in cancer therapy.

2. Experimental section 2.1. Preparation of the samples For simple and rapid quantification of simple and complex damage, plasmid DNA pBR322 (Euromedex) is used for our study. It consists of a supercoiled double-stranded DNA of 4361 base pairs (2.83 × 106 Da) diluted in TE buffer (10 mmol l−1 Tris-HCl (pH = 7.6) and 1 mmol l−1 ethylenediaminetetraacetic acid (EDTA)). Plasmid DNA presents the advantage of having three conformations, namely supercoiled, circular, and linear conformations when, respectively, no break, one break in one strand, two breaks in two strands (separated with less than ten base pairs) are produced in the DNA molecule. The three conformations are separated by migration in agarose gel electrophoresis submitted to an electric field (10 V cm−1 , 70 mA). Prior to irradiation, DNA samples contain more than 95% supercoiled, 5% circular, and no linear forms. The platinum chloro 2,2 :6 ,2 terpyridine (PtTC) is a commercial product (Sigma Aldrich Chemie Gmbh, Schnelldorf, Germany). It was diluted in pure water, at a concentration of 4.23 × 10−5 mol l−1 determined by absorption spectroscopy (ε = 25 100 mol cm−2 at λ = 278 nm, 1.06 OD). The solution was used without any further purification. Platinum nanoparticles (PtNP) coated with polyacrylic acid (PAA) (Sigma Aldrich) were synthesized by radiolytic reduction of platinum complexes (Pt(NH3 )4 Cl2 ·H2 O) (Sigma Aldrich) (10−4 mol l−1 ) in aqueous solution containing or not containing PAA (10−2 mol l−1 ). The solutions were deaerated prior to the irradiation by bubbling with nitrogen. The irradiation was carried out in a panoramic source (60 Co source), at a dose rate of 2.2 kGy h−1 (1 Gy = 1 J kg−1 ). The irradiation dose was close to 1000 Gy. The irradiated solutions were protected from light and stored at 4 ◦ C. Transmission electron microscopy (TEM) observations were performed on a JEOL JEM 100 CXII transmission electron microscope at an accelerating voltage of 100 kV. The solutions were finally diluted down to a concentration in metallic atoms of 4.23 × 10−5 mol l−1 , similar to the concentration reached with PtTC. The nanoparticles were finally kept in a buffer consisting of chlorine and ammonium ions at 4.23 × 10−5 mol l−1 . It is a crucial aspect to take into account in such an experiment because ions such as chlorine anions modify strongly the effects of radiation and sensitization in biological systems. In this work, the concentration of ions remaining in the samples after addition in DNA solutions are much lower than the concentrations of ions in the Tris EDTA buffer of DNA, and should therefore not induce any artifact. The samples of DNA–radiosensitizer complexes were prepared as follows. 18 μl aliquots contained each 500 ng of DNA (1 μl). In order to keep constant the concentrations in counter ions, 12.3 μl of TE buffer was added to each sample. Radiosensitizers were added to the samples, so that the concentrations of platinum atoms remain constant when PtTC and PtNPs were used (2.4 μl). The final volume was adjusted to 18 μl with pure water. The DNA was incubated with radiosensitizer for 1 h prior to irradiation. 2


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Figure 1. Schemes of (a) PtTC bound to DNA; (b) nanoparticles bound to DNA.

It is commonly admitted that positively charged PtTC is electrostatically bound to DNA (negatively charged) [20]. Additional studies have shown that for such a quantity of PtTC, a negligible fraction of PtTC remains free in solution and a complete binding of PtTC to DNA has been observed [2]. Platinum nanoparticles are prepared from precursors which contain ammonia groups. We may expect that ammonia groups stick to metallic nanoparticles. It thus gives to the clusters a positive charge that allows possible binding to DNA as proposed in figure 1. The complexes are prepared so that they contain on average one platinum atom per seven–eight base pairs on average (one platinum atom per 15 phosphate atoms, 500 platinum atoms per plasmid), as used elsewhere [3, 8]. Nanoparticles are added to DNA with the same number of platinum atoms per plasmid, which corresponds to a final PtNP:DNA ratio close to one nanoparticle per two plasmids (3 nm diameter, 1000 atoms per PtNP). The addition of any of the radiosensitizers had no deleterious effects on DNA, as shown systematically with controls.

2.3. Analysis The 18 μl samples were divided into two aliquots in order to preserve half of the product in case of artifacts in the analysis. The 9 μl samples were loaded with 1 μl 6× loading dye solution. The electrophoresis was performed in a 1.7% agarose gel, in an electric field of 10 V cm−1 , at 4 ◦ C for 3.5 h. After migration, the gel was stained with ethidium bromide (1 μg ml−1 ), and the DNA lines were revealed under ultraviolet (UV) light (302 nm) and recorded by a CCD camera. Image analysis software (Image Quant) was used to quantify the intensity of DNA lines of the different DNA conformations. The supercoiled plasmids ( S ) bind 1.47 times less ethidium bromide than relaxed ( R ) and linear ( L ) conformations. The yield of DNA damage was determined as follows: Total = 1.47 × S + R + L

S = 1.47 × S/total

R = R/total L = L/total.

The number of single strand breaks and double strand breaks per plasmid were thus determined by the following respective equations: 1 − L SSB yield (breaks per plasmid) = ln S L DSB yield (breaks per plasmid) = . 1 − L

2.2. Irradiations Irradiations by C6+ ions were performed at the Heavy Ion Medical Accelerator (HIMAC, Chiba, Japan), one of the most advanced hadron therapy centers in the world. The beam was set at an energy of 276 MeV amu−1 , which corresponds to a linear energy transfer (LET) in the medium of 13.4 keV μm−1 at the sample location, with a dose rate of approximately 4 Gy min−1 . The DNA solutions were placed in Eppendorfs vessels. The thickness of the irradiated samples was 1.5 mm, ensuring a constant dose deposition along the track through the sample. The irradiation was performed under atmospheric conditions at room temperature. The doses ranged from 0 up to 360 Gy, which corresponds to a maximum irradiation time of the order of 50 min.

No significant artifacts due to the binding of PtTC or NP to DNA were found in the electrophoresis. The presence of radiosensitizers does not change the conformation of DNA, as shown also by TEM images in the case of DNA–PtTC complexes (not shown here). This result agrees with the hypothesis that the radiosensitizers proposed here bind to DNA by electrostatic interaction and not covalently.

3. Results 3.1. Synthesis and characterization of platinum nanoparticles The synthesis of platinum nanoparticles was mediated by γ -ray water radiolysis. The hydrated electrons and the 3


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Figure 4. Average number of double strand breaks (DSBs) per plasmid versus the dose for pure DNA (), DNA in the presence of PtTC () and DNA in the presence of PtNP coated with PAA ( ), and the same as the latter case with DMSO added in the solution ( ). The samples were irradiated by ions C6+ 276 MeV amu−1 (LET = 13.4 keV μm−1 ).

Figure 2. TEM of platinum nanoparticles coated with PAA and synthesized by radiolysis, at 2.2 kGy h−1 .

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Table 1. Yields of SSB and DSB (slopes m ) induced by C6+ 276 MeV amu−1 in pure DNA plasmids and plasmids loaded with PtTC or with PtNP coated with PAA.

m(SSB) (breaks m(DSB) (breaks Sensitizing factor Gy−1 Da−1 ) Gy−1 Da−1 ) (×10−10 ) (×10−11 ) SSB DSB Pure DNA 19(±1) DNA + PtTC 31(±1) DNA + PtNPs 26(±3)

1.63 1.63 1.37 2.17

by carbon ions of 276 MeV amu−1 (energy deposition of 13 keV μm−1 ), are presented in figures 3 and 4 for a dose of irradiation ranging from 0 up to 200 Gy. The effect of platinum nanoparticles is compared to the effect of platinum atoms (PtTC) at the same concentration in atoms, well known from previous studies [7]. Pure DNA is used as a reference. The experiments performed with pure DNA, DNA loaded with PtTC and with PtNP show that the number of DNA breaks increases linearly with the dose. When platinum compounds are added to DNA—nanoparticles or atoms—the radiation effects are strongly amplified. The results obtained with PtTC are in good agreement with previous works [8]. The yields of SSBs and DSBs are defined as the number of breaks induced per gray and per dalton. They correspond to the slopes of the dose–response curves divided by the molecular weight of the plasmid (2.83 × 106 Da per plasmid for pBr322). The slopes (m ) are reported in table 1. The values of SSB and DSB yields illustrate the amplification effect induced by platinum compounds when carbon ions are used as ionizing radiation. These results confirm the sensitizing properties of metal nanoparticles [13, 14]. Considering the SSB, the amplification effect of PtNP is similar to the effects observed by other groups [13, 14]. In particular, the SSB yield of DNA loaded with PtNP (26×10−10 breaks per gray and per dalton) is of the same order of magnitude as that obtained by Butterworth et al when 5 nm diameter gold nanoparticles

Figure 3. Average number of single strand breaks (SSBs) per plasmid versus the dose for pure DNA (), DNA in the presence of PtTC (), DNA in the presence of PtNP coated with PAA ( ), and the same as the latter case with DMSO added in the solution ( ). The samples were irradiated by ions C6+ 276 MeV amu−1 (LET = 13.4 keV μm−1 ).

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3.0(±0.5) 4.9(±0.6) 6.5(±0.8)

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reducing radicals (H·) produced during water radiolysis induce homogeneous reduction and nucleation [21]. The main advantage of this method is to produce nanoparticles in a solvent whose final chemical composition (mostly NaCl) is compatible with the use of biological systems and the study of radiation effects (alcohols for instance must be prohibited due to their radical scavenging properties). The platinum nanoparticles stabilized by PAA are 3 nm diameters on average (figure 2), which corresponds approximately to 1000 platinum atoms in a particle. TEM measurements show that coated nanoparticles stored eight days in a dark room at 4 ◦ C remain stable. 3.2. Radiation induced DNA damage The effect of platinum is characterized by the quantification of DNA damage, single strand breaks (SSBs), and double strand breaks (DSBs), induced by irradiation. The results obtained with DNA loaded with platinum nanoparticles and irradiated 4


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Figure 5. Fast processes (t < 10−12 s) involved in platinum nanoparticles excited by ionizing radiations.

were combined with x-rays [14]. However, the effect on complex damage (DSB) is clearly higher in the present experiment. More interestingly, at the same concentration in platinum, the ratio of SSB to DSB yields is lower in the presence of nanoparticles (43) than with dispersed atoms (63). Breaks are thus more complex with nanoparticles. Therefore, the amplification but also the quality of radiation damage is strongly related to the nano-design of the sensitizers. In particular, the addition of platinum nanoparticles enhances strongly the lethality of damage and thus the biological efficiency of radiations. A simple characterization of the sensitizers is provided by the sensitizing factors, defined as the ratio of the SSB (respectively DSB) yield in DNA loaded with platinum compound on the SSB (respectively DSB) yield obtained in pure DNA (see table 1 —last column). The sensitizing factor of PtTC is close to 1.6 for SSBs and DSBs. For PtNP, the respective sensitizing factors are 1.4 for the SSB induction and close to 2.1 for the DSB induction. In the work of Butterworth et al with gold nanoparticles combined with xrays, an amplification factor of 2 is reported for SSBs and only 1.2 for DSBs. Finally, the protocol consisting of the combination of 3 nm diameter platinum nanoparticles with fast ion irradiation is, so far, the most efficient way to induce lethal damage in DNA.

As a result, inhomogeneous distribution of electrons (blubs and spurs) appears along the track. Prior to salvation, low and high energy electrons interact with their environment and may further ionize water or biological molecules. In the presence of metallic compounds, additional ionizations take place because of the high ionization cross section of high- Z atoms [22]. Incident ionizing particles (like ions) and secondary electrons produced along the track may efficiently excite inner and outer shells of the metal. Ionizations in inner shells in particular are followed by Auger de-excitation processes, which result in the amplification of the electron emission by the metal. Approximately ten Auger electrons are emitted after ionization of the platinum L-shell. Stated briefly, the presence of high- Z atoms in the medium amplifies locally the density of ionization and the dose deposition. When DNA is loaded with platinum, Auger electrons may interact with DNA directly and induce breaks in the strands (direct effect). They otherwise interact with surrounding water molecules to produce clusters of radicals that may further damage DNA (indirect effect). The role of water radicals is investigated by adding a radical scavenger (dimethyl sulfoxide) in some of the experiments (see section 2). In the case of pure DNA as well as in DNA loaded with platinum compounds, the induction of SSBs and DSBs is strongly shut down (see figures 3 and 4). This result confirms that the induction of DNA damage and, more interestingly, the amplification of radiation effects due to the metal are mostly related to the production of water radicals close to the metal [7, 14]. Direct processes (not mediated by solvent molecules) such as the interaction of electrons and secondary ions with DNA, can be considered as minor contributions [23–25]. As explained above, the presence of metal modifies locally the dose deposition. It is thus related to the ionization cross section of the metal and depends on its atomic mass ( Z ).

4. Discussion The interaction of ionizing particles (charged particles, photons) with biological matter is extensively described in the review of Mozumder and Hatano [19]. Briefly, ionization of water molecules and the production of secondary electrons along the primary track are considered as the major processes that take place in the early stage (t < 10−12 s) (see figure 5). 5


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In order to explain the difference observed between platinum atoms and platinum nanoparticles, additional mechanisms, specific to nano-designed architectures, must be invoked. In the nanoparticles, atoms are closely bound. Therefore, electrons emitted by a platinum atom—Auger electrons and valence electrons—can excite surrounding metal atoms. As a consequence, the advantage of metal nanoparticles stems from the auto-amplification of electronic cascades generated inside nanoparticles that leads to a neat enhancement of the electron emission and the production of water radicals. This strong perturbation, which is induced in a nanometer scale volume around the nanoparticles, explains the relative increase of lethal damage (DSBs) compared to SSBs. Indeed DSBs, which require two bond breaks separated by a few nanometers (the two DNA strands being separated by 2 nm), are strongly catalyzed by nanoparticles. On the contrary, SSBs, which require only single events for bond breaking, decrease in the presence of nanoparticles because of the reduced number of platinum sites on DNA. After electron emission, platinum nanoparticles are left with highly positive charges in the medium. Therefore multiple charge transfer from surrounding molecules onto positively charged nanoparticles may efficiently contribute to the ionization of the surrounding water molecules and thus to the production of radicals in the close vicinity. Calculations are in process in order to quantify the contributions of the different pathways.

References [1] Ferrari M 2008 Nanoncology Organisation-of-EuropeanCancer-Institutes Scientific Week (Genoa: Pensiero Scientifico Editor) [2] Le Sech C, Takakura K, Saint-Marc C, Frohlich H, Charlier M, Usami N and Kobayashi K 2000 Strand break induction by photoabsorption in DNA-bound molecules Radiat. Res. 153 454–8 [3] Le Sech C, Takakura K, Saint-Marc C, Frohlich H, Charlier M, Usami N and Kobayashi K 2001 Enhanced strand break induction of DNA by resonant metal-innershell photoabsorption Can. J. Physiol. Pharmacol. 79 196–200 [4] Kobayashi K, Frohlich H, Usami N, Takakura K and Le Sech C 2002 Enhancement of x-ray-induced breaks in DNA bound to molecules containing platinum: a possible application to hadrontherapy Radiat. Res. 157 32–7 [5] Kobayashi K, Usami N, Sasaki I, Frohlich H and Le Sech C 2003 Study of Auger effect in DNA when bound to molecules containing platinum. A possible application to hadrontherapy Nucl. Instrum. Methods Phys. Res. B 199 348–55 [6] Biston M C, Joubert A, Adam J F, Elleaume H, Bohic S, Charvet A M, Esteve F, Foray N and Balosso J 2004 Cure of fisher rats bearing radioresistant F98 glioma treated with cis-platinum and irradiated with monochromatic synchrotron x-rays Cancer Res. 64 2317–23 [7] Usami N, Kobayashi K, Furusawa Y, Frohlich H, Lacombe S and Le Sech C 2007 Irradiation of DNA loaded with platinum containing molecules by fast atomic ions C6+ and Fe26+ Int. J. Radiat. Biol. 83 569–76 [8] Usami N, Furusawa Y, Kobayashi K, Frohlich H, Lacombe S and Le Sech C 2005 Fast He2+ ion irradiation of DNA loaded with platinum-containing molecules Int. J. Radiat. Biol. 81 515–22 [9] Brown C L, Bushell G, Whitehouse M W, Agrawal D S, Tupe S G, Paknikar K M and Tiekink E R 2007 Nanogold-pharmaceutics—(i) the use of colloidal gold to treat experimentally-induced arthritis in rat models; (ii) characterization of the gold in Swarna bhasma, a micro particulate used in traditional Indian medicine Gold Bull. 40 245–50 [10] Jain P K, El-Sayed I H and El-Sayed M A 2007 Au nanoparticles target cancer Nano Today 2 18–29 [11] Hainfeld J F, Slatkin D N and Smilowitz H M 2004 The use of gold nanoparticles to enhance radiotherapy in mice Phys. Med. Biol. 49 N309–15 [12] Kong T, Zeng J, Wang X P, Yang X Y, Yang J, McQuarrie S, McEwan A, Roa W, Chen J and Xing J Z 2008 Enhancement of radiation cytotoxicity in breast-cancer cells by localized attachment of gold nanoparticles Small 4 1537–43 [13] Foley E A, Carter J D, Shan F and Guo T 2005 Enhanced relaxation of nanoparticle-bound supercoiled DNA in x-ray radiation Chem. Commun. 3192–4 [14] Butterworth K T, Wyer J A, Brennan-Fournet M, Latimer C J, Shah M B, Currell F J and Hirst D G 2008 Variation of strand break yield for plasmid DNA irradiated with high- Z metal nanoparticles Radiat. Res. 170 381–7 [15] Cho S H 2005 Estimation of tumour dose enhancement due to gold nanoparticles during typical radiation treatments: a preliminary Monte Carlo study Phys. Med. Biol. 50 N163–73 [16] Robar J L, Riccio S A and Martin M A 2002 Tumour dose enhancement using modified megavoltage photon beams and contrast media Phys. Med. Biol. 47 2433–49 [17] McMahon S J, Mendenhall M H, Jain S and Currell F 2008 Radiotherapy in the presence of contrast agents: a general

5. Conclusion We present here the first study that highlights the prominent sensitizing properties of platinum nanoparticles in comparison to metal atoms. Effects on DNA have been investigated in order to compare and optimize the biological efficiencies of sensitizers in biological conditions. Irradiation by fast carbon ions is considered in this work in order to envisage applications in one of the most promising techniques for cancer treatments, hadron therapy. Our major result is that platinum nanoparticles enhance strongly the biological efficiency of radiations. The nanodesign architecture of the particles plays a crucial role. The sensitizing properties of nanoparticles are ascribed to specific auto-amplified electronic cascades together with charge transfer processes. The fast propagation of these effects in a nanometer scale volume explains the amplification of lethal damage in DNA. Finally, this work shows that the combination of platinum nanoparticles with fast ions opens new perspectives in cancer therapy. Further optimizations are in progress in order to combine the sensitizing and targeting properties of nanoparticles together with the ballistic effects of ions.

Acknowledgment The authors acknowledge Patricia Beaunier, Laboratoire de Réactivité de Surfaces, Université Paris VI, for TEM, high resolution TEM (HRTEM) observations. 6


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[22] Chang M Y, Shiau A L, Chen Y H, Chang C J, Chen H H W and Wu C L 2008 Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice Cancer Sci. 99 1479–84 [23] Boudaiffa B, Cloutier P, Hunting D, Huels M A and Sanche L 2000 Resonant formation of DNA strand breaks by low-energy (3 to 20 eV) electrons Science 287 1658–60 [24] Sellami L, Lacombe S, Hunting D, Wagner R J and Huels M A 2007 Novel apparatus to measure hyperthermal heavy ion damage to DNA: strand breaks, base loss, and fragmentation Rev. Sci. Instrum. 78 085111 [25] Lacombe S and Le Sech C 2009 Advances in radiation biology: radiosensitization in DNA and living cells Surf. Sci. 603 1953–60

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