ULTRASOUND-ASSISTED SYNTHESIS OF NANOPARTICLES CONSISTING OF AN IRON CORE COATED IN GOLD

Abstract

The invention relates to the field of nanoparticles usable for tumor treatment. More specifically, the invention concerns a process for synthesizing gold-coated iron oxide nanoparticles that are biocompatible through the use of reagents that comply with the principles of green chemistry. These novel nanoparticles are intended for theranostic use.

Description

Title of the invention: ULTRASOUND-ASSISTED SYNTHESIS OF NANOPARTICLES CONSISTING OF A GOLD-COATED FERRIC CORE

[0001] The invention relates to the field of nanoparticles usable for the treatment of tumors. More particularly, the invention relates to a method for synthesizing gold-coated iron oxide nanoparticles which are biocompatible thanks to the use of reagents which respect the principles of green chemistry. These new nanoparticles are intended for theranostic use.

[0002] Technical field

[0003] Drug delivery by magnetic nanoparticles opens the possibility of using local enhancement methods, so that the drug can accumulate and act in a predetermined area. The good magnetic properties and relatively high electron density of iron oxide nanoparticles make them promising sensitizing agents for cancer treatment by laser or X-ray photoplasmonic therapy and radiotherapy [1]. On the other hand, gold is an excellent biocompatible absorber of X-rays due to its chemical inertness and very high electron density [2, 3]. Theoretically, the combination of magnetic iron oxide and high-Z gold in Fe3O4@Au core-shell nanoparticles is promising for radiotherapy.The outer gold shell not only protects the inner magnetite core from dissolution in acidic or complexing media, but also reduces the interparticle magnetic dipole-dipole interaction, leading to the formation of more stable colloidal suspensions.

[0004] The standard method for synthesizing hybrid nanoparticles is to first create the iron oxide core, then complete with the gold layer. To prepare such nanoparticles, the state of the art proposes grafting small gold nanoparticles to the surface of the iron oxide. This grafting is based on the conventional Turkevich or Brust methods. These methods use powerful gold salt reducers and capping agents with a high affinity for gold to ensure their stability. These are thiols such as disulfides, polymers with thiol functions, or cyano groups. Once obtained, these small particles undergo ligand exchange using thiols, then are covalently grafted onto the iron oxide cores. The use of other coupling agents makes it possible to increase the size of the nanoparticle as well as improve the size distribution.

[0005] The critical steps in the preparation of core-shell nanoparticles are nucleation and growth of the nanoparticles. The weak reducing agents and weak capping agents of the Turkevich method lead to the production of large nanoparticles. Conversely, the NaBH4 used by the Brust method is a strong reducing agent, which increases the number of nucleations, but the use of a strong capping agent (alkanethiol) will reduce growth.

[0006] The "seeding" method, consisting of growing small nanoparticles on the surface, is an alternative to the formation of this gold layer on the surface of the iron oxide core. In order to limit nucleations, it has been demonstrated that the nanoparticle growth phase during seeding should be done gradually (high ratio of seeds / metal salt).

[0007] Recently, biocompatible Fe3O4@Au hybrid nanoparticles have been prepared using glutathione as a reducing and capping reagent [6]. However, the gold shell on the Fe3O4 surface of this material is not uniform and is composed of Au nanoparticles of about 2 nm attached to the magnetite core, which may lead to the dissolution of iron oxide in biological fluids containing complexing ligands through the junctions between the Au nanoparticles. In addition, the use of a large excess of glutathione during synthesis may lead to the reduction of Au(III) not only on the Fe3O4 surface but also in the bulk solution.

[0008] Sonochemistry has also been proposed for the preparation of Fe3O4@Au hybrid nanoparticles. While this technique is described as promising, the issue of dispersion is a critical element for obtaining nanoparticles with good physicochemical properties

[15] .

[0009] Despite the large number of prior art studies relating to the synthesis of core-shell Fe3O4@Au nanoparticles, the preparation of these particles with controlled size and morphology using biocompatible reagents in compliance with the principles of green chemistry remains a major challenge.

[0010] To date, there are no small iron oxide core / gold shell nanoparticles available that are biocompatible for use in health (diagnostics or therapy). Statement of the invention

[0011] The invention provides a method for depositing a layer of gold on the surface of magnetite nanoparticles in a controlled manner using biocompatible reagents only in accordance with the principles of green chemistry.

[0012] More specifically, the invention relates to a method for preparing an iron oxide nanoparticle covered with a layer of gold and respecting the principles of green chemistry, comprising the steps of: 1. Synthesis of an iron oxide nanoparticle using ultrasound 2. Incubation of said nanoparticle in a solution of L-cysteine ​​then rinsing in an aqueous solution, these two solutions having a pH between 6 and 7 3. Deposition of a layer of gold on said nanoparticle covered with L-cysteine ​​by fractional additions of an aqueous gold solution while maintaining the pH between 6 and 7.

[0013] The invention also relates to a biocompatible nanoparticle of the iron oxide core / gold shell type having a hydrodynamic diameter measured by an indirect technique, DLS, of less than 1000 nm. Nanoparticles of a size less than 200 nm (hydrodynamic diameter obtained by light scattering) will be retained for therapeutic applications. Nanoparticles having a size greater than 200 nm may be good candidates for diagnosis by medical imaging.

[0014] Finally, the invention relates to the use of the nanoparticles according to the invention for treating cancer.

[0015] Advantages of the invention

[0016] Most of the methods for preparing core-shell type metal nanoparticles, in particular Fe3O4@Au type nanoparticles described in the literature use reagents that are not biocompatible. The innovative nature of the present invention is based on the combination of the use of ultrasound and a natural amino acid - cysteine ​​- which makes it possible to control the size of the particles formed and to carry out the deposition of the gold layer specifically on the oxide surface.

[0017] The new nanoparticles produced using the process according to the invention have several advantages: controlled and homogeneous size and morphology, the absence of contaminants hazardous to health, good reactivity properties following irradiation. Obtaining nanoparticles having the characteristic of being monodisperse results directly from the 3-step process, in particular from the use of cysteine ​​as a capping agent which makes it possible to confer dispersion stability to the ferric nanocomposite (Fe / Au in particular).

[0018] These hybrid nanoparticles, which combine two metals (iron and gold), combine the physical properties of these two metals in a single therapeutic agent. They have the properties required to treat deep tumors by hyperthermia via plasmonic, magnetic or ultrasonic phototherapy, inaccessible by the first technology based on gold nanoparticles. Finally, magnetic guidance could be studied once these nanoparticles are injected hybrids. They constitute promising candidates for theranostic applications.

[0019] They open the way to new therapeutic approaches for diseases for which no specific treatment exists to date, such as pancreatic adenocarcinomas. One of the objectives of the present invention is therefore to provide a targeted treatment for pancreatic adenocarcinomas. The use of the nanoparticles according to the invention would make it possible to destroy the tumor microenvironment by hyperthermia in the case of infrared laser treatment, or by the generation of ROS in the case of radiotherapy treatment, and in a targeted manner in a single injection, in order to increase the patient's chances of recovery. Description of the embodiments

[0020]

[0021] A first subject of the invention relates to a method for preparing an iron oxide nanoparticle covered with a layer of gold and respecting the principles of green chemistry, comprising the steps of: 1. Synthesis of an iron oxide nanoparticle using ultrasound 2. Incubation of said nanoparticle in a solution of L-cysteine ​​then rinsing in an aqueous solution having, these two solutions having a pH between 6 and 7 3. Deposition of a layer of gold on said nanoparticle covered with L-cysteine ​​by fractional additions of an aqueous gold solution, while maintaining the pH between 6 and 7.

[0022] This process is innovative because it complies with the principles of green chemistry, which are based in particular on less dangerous synthesis methods, the use of less polluting solvents and auxiliaries, the design of chemical products that are safer for the environment and the consumer, and fundamentally more reliable chemistry.

[0023] Similarly, the quality of the solutions is important to obtain NPs with good properties. The solutions used must have high purity, especially aqueous solutions (deionized water, NaOH and high purity hydrochloric acid), including the gold solution (HAuC14). In particular, hydrazine and ammonia were excluded to respect the principles of green chemistry.

[0024] This “green” process is controlled and reproducible, it meets all the criteria of an industrializable process and is particularly advantageous compared to existing processes.

[0025] The prepared nanoparticle (NP) comprises a core consisting of a metal oxide. The metal oxide is preferably chosen from Fe3O4, γ-Fe2O3, α-Fe2O3.

[0026] In a particular embodiment of the method of the invention, step 1 of preparing an iron oxide NP consists of a coprecipitation of Fe(II) and Fe(III) in an alkaline solution free of hydrazine and ammonia under low-frequency ultrasound so as to obtain an Fe3O4 NP. The low-frequency ultrasound used during step 1 has a frequency of between 16 and 100 kHz, preferably 16 to 40 kHz. The frequency used may be 20 kHz.

[0027] Step 2 of the process of the invention consists of adsorption of L-cysteine ​​on the surface of the magnetite particles. This step is carried out in a solution having a pH between 6 and 7 under mechanical stirring. The incubation time necessary for the adsorption of L-cysteine ​​is generally between 12 and 24 hours, preferably around 24 hours ([Fig.l]). The NPs are then rinsed in an aqueous solution also having a pH between 6 and 7, before adding the gold solution.

[0028] The washing step of the L-cysteine-coated NPs must be carried out carefully before adding gold. Indeed, during the deposition of the gold shells, the Au(III) is reduced by L-cysteine; the presence of L-cysteine ​​(even residual) in the base solution would lead to the formation of Au NPs in association with L-cysteine ​​instead of a gold deposition on the surface of the iron oxide nanoparticles covered with L-cysteine.

[0029] Regarding the concentration / quantity of L-cysteine, it is necessary to count between 0.08 g and 0.2 g of L-cysteine ​​dissolved in 10 mL of ultrapure water for 250 mg of magnetite. In a preferred embodiment, this value will be 0.1 g / 10 mL of solution. A higher concentration can be used but will lead to a decrease in the percentage of total L-cysteine ​​adsorbed and will require additional suspension washing steps in order to remove the residual L-cysteine ​​from the reaction medium which is a key step for the deposition of gold and will consequently determine the quality of the iron oxide core-gold shell NP obtained.

[0030] Step 3 of the method consists of covering the NPs with gold; this step must be carried out by controlling the pH so that it is always between 6 and 7. For this purpose, the gold solution is brought into contact with the NPs covered with L-cysteine ​​by successive fractional additions. Thus, the gold layer is homogeneous on the surface of the NPs.

[0031] In another particular embodiment of the method of the invention, step 3 of depositing the gold layer on the NP consists of: - incubate the nanoparticle coated with L-cysteine ​​in an aqueous solution having a pH between 6 and 7 under ultrasound then - deposit a layer of gold on said nanoparticle by fractional additions of a gold solution (HAuC14) with stirring while maintaining a pH between 6 and 7 - rinse the gold-coated nanoparticle.

[0032] Preferably, the gold / iron oxide nanoparticle mass ratio is less than 6%, preferably between 4% and 6%, and most preferably 5%.

[0033] In a preferred embodiment, the NP obtained is of the Fe3O4 @Au core-shell type.

[0034] The concentration of the gold solution used is of little importance; what matters is the concentration of gold in the reaction medium. Those skilled in the art will know how to adjust this parameter.

[0035] A second subject of the invention relates to a biocompatible nanoparticle of the iron oxide core-gold shell type having a hydrodynamic size measured by DLS of less than 1000 nm.

[0036] In a preferred embodiment, the NPs according to the invention have a hydrodynamic size of less than 800 nm, most preferably less than 500 nm. Preferably, the NPs used both in diagnosis and in therapy have a hydrodynamic size of between 200-500 nm.

[0037] In a preferred embodiment, the NP is of the Fe3O4@Au core-shell type.

[0038]

[0039] A third object of the invention relates to the use of a nanoparticle as described previously in the treatment of cancer.

[0040] This therapeutic approach is suitable for the treatment of a large number of cancers in which the use of nanoparticles activatable by plasmonic phototherapy (use of near infrared) or by radiotherapy is desirable.

[0041] The present invention will be better understood from reading the following examples, provided for illustration purposes and in no way to be considered as limiting the scope of the present invention.

[0042] Brief description of the drawings

[0043]

[0044] [Fig. 1] [Fig. 1]: Kinetics of the adsorption of L-Cyst on Fe3O4 nanoparticles.

[0045]

[0046] EXAMPLES

[0047]

[0048] EXAMPLE 1: Principle of the process according to the invention - Application to the preparation of Fe 3 O 4 @Au nanoparticles

[0049]

[0050] The synthesis strategy to access monodisperse Fe3O4@Au core-shell nanoparticles involves a three-step green process. First, Fe3O4 nanoparticles were prepared by Fe(II)-Fe(III) co-precipitation under the effect of ultrasound. Then, cysteine ​​was adsorbed on the surface of Fe3O4 nanoparticles. Finally, a gold shell was loaded onto the cysteine-capped Fe3O4 nanoparticles by reduction of Au(III) ions. Some experiments were carried out with ascorbic acid for comparison. According to recent studies, ascorbic acid not only acts as a reducing agent for Au(III) but also, the oxidized form of ascorbic acid (dehydro-ascorbic acid) acts as a capping agent to impart dispersion stability to the iron oxide / gold nanocomposite

[13] .

[0051] EXAMPLE 2: Preparation of Fe 3 O 4 @Au nanoparticles

[0052] Step 1: Preparation of Fe3O4 nanoparticles by sonochemistry

[0053] The synthesis of Fe3O4 nanoparticles is carried out using an ultrasonic reactor. In the experiments, 40 mL of solution was irradiated by a 1 cm2 ultrasonic probe made of Ti-6A1-4V alloy. The piezoelectric transducer was powered by a 20 kHz generator (Vibra-Cell VCX 750 W). The probe was reproducibly immersed 3 cm from the bottom of the reactor. The temperature in the reactor during the process was maintained at a stable temperature of 25±1°C. Pure argon (O 2 <1 ppm, Air Liquide) was bubbled at a rate of 100 mL-min 'for about 30 min before and during the ultrasonic treatment. The specific absorbed acoustic power, Pac = 19+1 W, transmitted to the solution was measured by the conventional thermal probe method. All aqueous solutions were prepared with deionized water (Milli-Q 18 QM.cm at 25 °C). Hydrochloric acid and NaOH were of the highest purity.

[0054] The co-precipitation of Fe(II) and Fe(III) is described by the following equation:

[0055] FeCl2 + 2FeCl, + ÜNaOH Fe3O4+4H2O + SNaCl

[0056] For the synthesis, a freshly prepared mixture of 1.5 mmol of FeCl3-6H2O (97%, Aldrich) and 0.75 mmol of FeCl2-4H2O (99%, Aldrich) in 5 mL of 0.05 M HCl was rapidly injected via a thin plastic tube into 35 mL of 0.33 M NaOH solution under high-power ultrasound at 25°C in an argon stream. The injection was carried out into the active zone of the sonic reactor via a thin plastic tube. Solids with a characteristic black color of magnetite were precipitated immediately after injection. The mixture was sonicated for 10 min. Then, the sediments were separated using a permanent magnet, and washed twice with water. The pH of the solution after washing was adjusted to 6.4. In general, the procedure for the preparation of Fe3O4 nanoparticles was similar to that reported previously [7]. The only difference is that in this synthesis, hydrazine and ammonia were excluded to comply with the principles of green chemistry.The TEM image (data not shown) reveals . monodisperse magnetite nanoparticles with an average size of 9 ± 2 nm. However, the hydrodynamic size measured with the DLS technique was found to be equal to 1895+138 nm indicating strong aggregation of the bare magnetite nanoparticles. The prepared Fe3O4 nanoparticles should be kept as a suspension (slurry) in water without being dried.

[0057] Step 2: Capping of Fe3O4 nanoparticles with cysteine.

[0058]

[0059] A 0.05 M solution of L-cysteine ​​(L-Cyst) was prepared by dissolving L-cysteine ​​hydrochloride hydrate (HSCH2 CH(NH2)CO2H - xHCl - xH20) in pure water. This solution should be stored in a refrigerator to avoid degradation. 50 mg of Fe3O4 nanoparticles were dispersed in 40 mL of water for 10 min using an ultrasonic reactor. Then, 5 mL of L-Cyst was added to the suspension under continuous ultrasonic treatment for 5 minutes. Then, the suspension was stirred by mechanical stirring for 65 hours using a second reactor. Samples of the suspension were removed from the reactor, washed with water and analyzed for carbon content using a TOC analyzer. [Fig.l] shows the adsorption kinetics of L-Cyst on the magnetite surface, indicating that about 70% of L-Cyst is adsorbed by Fe3O4 nanoparticles.After establishing sorption equilibrium, the particles were washed several times with distilled water. Particle separation after each wash was performed with a permanent magnet. It should be noted that careful washing of Fe3O4-L-Cyst nanoparticles is important for successful deposition of Au shells since Au(III) is reduced by L-Cyst and its presence in the stock solution would result in the formation of Au nanoparticles in the solution and not on the surface of Fe3O4-L-Cyst nanoparticles.

[0060] Step 3: Deposition of the gold shell on the Fe 3O 4-L-Cysteine ​​nanoparticles

[0061] 50 mg of Fe3O4-L-Cyst nanoparticles suspended in water as described in Step 2 were mixed with 40 mL of water (pH = 5.05) and sonicated for 10 min. Then, this suspension was placed in the reactor with the mechanical stirrer and every 15 min 0.5 mL of HAuC14 solution (0.5 g-L1) was added under stirring up to a total volume of 5 mL in order to reach 5 mass.% gold with respect to magnetite. After 2h 15min of stirring, the suspension was removed from the reactor and washed twice with pure water until the pH = 6-7. HRTEM images (not shown) revealed nanoparticles with an average size of 8+1 nm which is quite similar to the size of bare Fe3O4 nanoparticles. STEM / EDX study showed a homogeneous distribution of gold, assuming a core-shell morphology of the obtained material. Table 1 revealed a sharp decrease in the hydrodynamic size of core-shell type Fe3O4-L-Cyst@Au particles compared to that of bare Fe3O4 nanoparticles, indicating that gold coating significantly decreases the aggregation of Fe3O4 nanoparticles.

[0062] [Tables 1] Particles Hydrodynamic particle size measured by DLS (nm) HRTEM particle size (nm) Fe3O4 1895 + 138 9 + 2 Fe 3 O 4 -L-Cyst@A u 291+40 8+1

[0063] Table 1. Hydrodynamic particle size and TEM of coated and uncoated Fe3 O4 nanoparticles.

[0064] It was found that at a gold content above 5 wt% / % of nanoparticles, gold NPs are formed in the bulk solution in addition to the formation of a gold shell on the surface of Fe3O4. Therefore, 5 wt% gold relative to % of Fe 3O 4-L-Cyst NPs is an optimal ratio for the core-shell structure.

[0065] EXAMPLE 3: Deposition of gold nanoparticles on Fe 3 O 4 in the absence of L-Cysteine ​​

[0066] Fe3O4 nanoparticles were prepared according to the procedure described in Example 2, Step 1. Then, Au(III) was added to the aqueous suspension of Fe3O4 nanoparticles as in Example 2, Step 2 but without preliminary sorption of L-Cysteine. HRSTEM and EDX images show the formation of large Au nanoparticles in the solution and not on the surface of the Fe3O4 nanoparticles. This result unequivocally demonstrates the necessity of an L-Cysteine ​​coating for efficient deposition of the gold shell on the Fe3O4 nanoparticles to obtain a core-shell structure. It has been reported that Fe3O4 allows the reduction of Au(III) even in the absence of other reducing reagents

[14] . However, our experiments showed that the adhesion of gold to the surface of Fe3O4 is not sufficient for the formation of the core-shell structure.

[0067] An additional experiment was performed with bare Fe3O4 nanoparticles and Au(III) solution in the presence of ultrasound instead of mechanical stirring. However, this attempt to obtain a core-shell structure without L-Cyst also failed.

[0068] EXAMPLE 4#: Deposition of gold nanoparticles on Fe 3 O 4 in the presence of ascorbic acid

[0069] This experiment was carried out using the same procedure as in Example 2 but ascorbic acid was used instead of L-Cysteine. HRSTEM / EDX analysis showed the reduction of Au(III). However, the Au nanoparticles are formed in the bulk solution rather than on the surface of Fe3O4. Bibliographic references

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[0079]

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[0083]

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[0084]

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Claims

Claims

1. A method for preparing an iron oxide nanoparticle coated with a layer of gold and respecting the principles of green chemistry, comprising the steps of:

1. Preparation of an iron oxide nanoparticle using ultrasound 2. Incubation of said nanoparticle in a solution of L-cysteine ​​then rinsing in an aqueous solution, these two solutions having a pH between 6 and 7 3.Deposition of a layer of gold on said nanoparticle coated with L-cysteine ​​by fractional additions of an aqueous gold solution while maintaining a pH between 6 and 7, and in which step 3 of deposition of said layer of gold consists of: - incubating the nanoparticle coated with L-cysteine ​​in an aqueous solution having a pH between 6 and 7 under ultrasound, then, - depositing a layer of gold on said nanoparticle by fractional additions of a gold solution (HAuC14) under stirring while maintaining a pH between 6 and 7, - rinsing the nanoparticle coated with gold.

2. The method of claim 1 wherein said nanoparticle consists of a metal oxide core selected from Fe3O4, γ-Fe2O 3, and α-Fe2O3.

3. Method according to claim 1 in which step 1 of preparing an iron oxide nanoparticle consists of a coprecipitation of Fe(II) and Fe(III) in an alkaline solution free of hydrazine and ammonia under ultrasound at a frequency between 16 and 100 kHz so as to obtain an Fe3O4 nanoparticle.

4. Method according to one of claims 1 to 3 in which the gold / iron oxide nanoparticle mass ratio is less than 6%.

5. Method according to one of claims 1 to 4 in which the aqueous solution used in step 2 is distilled water.

6. Biocompatible nanoparticle of the metallic core-gold shell type characterized in that it is obtained by the method according to one of

7.

8. any of the preceding claims and in that it has a hydrodynamic size measured by DLS of less than 1000 nm. Nanoparticle according to claim 6 characterized in that it is a nanoparticle of the Fe3O4@Au core-shell type. Nanoparticle as defined in one of claims 6 or 7 for its use in the treatment of cancer.

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