FIDUCIAL MARKER FOR USE IN STEREOTACTIC RADIOSURGERY AND PROCESS OF PRODUCTION

Abstract

Composition in the form of a shaped device, for use as a fiducial marker in tissues in the animal body, in radiotherapy and/or radiosurgery, characterized in that it comprises: a core consisting of a colloidal dispersion of metal nanoparticles and/or oxides or metal salts having X-ray-contrast properties, where said nanoparticles are stabilized with surfactants, polymers or capping agents in a liquid vehicle, and a polymeric casing that encapsulates the core, said device having a minimum size of not less than 500 microns and a maximum size not greater than 3000 microns.

Claims

1-10. (canceled)

11. A composition in the form of a shaped device, for use as a fiducial marker in tissues in the animal body, in radiotherapy and/or radiosurgery, comprising: a core consisting of a colloidal dispersion of metal nanoparticles and/or metal oxides or salts having X-ray-contrast properties, where said nanoparticles are stabilized with surfactants, polymers or capping agents in a liquid vehicle, and a polymeric casing that encapsulates the core, said device having a minimum size of not less than 500 microns and a maximum size not greater than 3000 microns wherein said polymeric casing comprises an encapsulating polymeric material selected from silicone elastomers and/or polydimethylsiloxane.

12. The composition according to claim 11, wherein said nanoparticles include colloidal gold with size from 50 to 200 nm.

13. The composition according to claim 11, wherein said nanoparticles are coated with 4-2-hydroxyethyl-1-piperazinylethanesulphonic acid.

14. The composition according to claim 11, wherein said liquid vehicle is selected from the group consisting of water, glycerol, dimethyl sulphoxide, dimethylformamide and ethylene glycol or their aqueous solutions.

15. The composition according to claim 11, wherein said liquid vehicle is glycerol.

16. The composition according to claim 11, wherein said colloidal dispersion comprises said nanoparticles at a concentration from 50 to 800 mg/ml in the liquid vehicle.

17. A method of stereotactic radiosurgery carried out on human or animal body tissues comprising: providing a composition according to claim 11 and implanting said composition in said body tissue as a fiducial marker.

18. A process for the production of a composition according to claim 11, wherein said composition is shaped by moulding of a solution of the encapsulating polymeric material, introducing said dispersion of nanoparticles in volume from 0.01 to 100 l into said moulded solution and polymerizing said polymeric material in the mould.

19. Process for the production of a composition according to claim 11, comprising the steps of: moulding of a hollow polymeric body of the encapsulating polymeric material, introduction into the cavity of said body of a vehicle selected from water, glycerol, dimethyl sulphoxide, dimethylformamide or ethylene glycol or their aqueous solutions, polymerization of the encapsulating polymeric material, and insertion of said colloidal dispersion of nanoparticles in its liquid vehicle so as to replace the previous vehicle introduced in said cavity.

Description

[0071] In the attached drawings:

[0072] FIG. 1 is a photograph that illustrates fiducial markers that are the object of the invention consisting of a colloidal dispersion of AuNPs coated with silicone polymer obtained according to example 2 below;

[0073] FIG. 2 is a photograph that illustrates fiducial markers that are the object of the invention suspended in silicone-based liquid phase (Alfasil).

EXAMPLE 1: PREPARATION OF THE COLLOIDAL SOLUTION OF NANOPARTICLES

[0074] In a typical example of manufacture, the preparation procedure of the solution of nanoparticles, in this case of gold (AuNPs), is carried out as follows: AuNPs of approximately. 100 nm are synthesized by means of seed-mediated growth (using as seeds particles of gold of 15 nm, capped with citrate, synthesized by procedures of the Turkevich-Frens type). After the synthesis, the particles are stabilized by adding an appropriate amount of 4-2-hydroxyethyl-1-piperazinylethanesulphonic acid (HEPES) (from 1 to 5000 micromolar for example), and are then concentrated by means of repeated centrifugation and redispersal in glycerol until a concentration preferably >50 mg/ml is reached, in this case 300 mg/ml. Such solutions are stable for months even under ambient conditions, and are thus used for encapsulation in the polymer by the general procedure reported below.

EXAMPLE 2: PREPARATION OF THE MARKER

[0075] In a typical preparation example, the silicone elastomer Sylgard 184 is used mixed in a 10:1 proportion with the corresponding curing agent. Into the solution thus prepared, a volume of nanoparticulate dispersion prepared as described is added. This is therefore heated so that the decomposing organic peroxides can result in the ethylenic bridge between the polymeric chains. The polymerization temperature does not exceed 60 C. in order not to alter the nanoparticulate solution contained within the fiducial marker that is the object of the study. In an alternative, which is moreover preferred, the silicone elastomer MED-4750 NuSil Technology may be used, the polymerization being carried out according to standard procedures (at ambient temperature for example).

[0076] Fiducial markers of spheroidal shape (of 2 mm diameter for example) were produced using the polymers cited above using the moulding procedure in the mould previously described. The colloidal gold solution obtained according to example 1 in glycerol vehicle was introduced into the silicone polymer solution in the mould in an amount of 2 The polymerization, as indicated above, was conducted at a temperature of 60 C. for a period of 2 hours.

[0077] These innovative fiducial markers are able to generate high intensity X-rays (Hounsfield number equal to 7000 compared to values for standard fiducial markers equal to 3000-5000). The use of nanoparticles makes it possible to obtain a high contrast with lower doses relative to corresponding non-nanostructured material, this advantage being apparent in the extremely reduced size of these objects (less than 3 mm) which makes them particularly applicable to be inserted in the patient endoscopically, allowing areas of the body to be reached, therefore, currently unexplored by radiosurgery. The fiducial markers that are the object of the invention possess many distinctive characteristics relative to injectable compositions of nanoparticles of contrast agents in gel-forming materials intended for systemic administration. Furthermore, the coating polymer used presents an excellent combination of properties of flexibility, elasticity and robustness and may be readily modelled and/or micro/nano-structured and/or chemically modified such that the fiducial marker may be inserted even more easily in the target tissue endoscopically and so that involuntary migration of the fiducial marker is minimized if not completely absent. Furthermore, the physical and chemical isolation offered by the polymer allows a durable colloidal stability of the nanoparticulate solution and thus a prolonged contrast efficiency. Another advantage offered by the external polymer consists of the biocompatability which makes it ideal as a long-lasting implantable medical device. Drugs and/or natural and/or synthetic compounds may also be added to the polymer for controlled release of such substances in the organ in which the marker is implanted. Furthermore, the particular technology allows extremely stable devices to be produced with a significantly lower overall cost than that of a single gold fiducial marker currently present on the market.

[0078] The marker thus assembled may be subjected to variations in size and/or micro/nanostructuring of the surface and/or surface chemistry, if desired, to facilitate the positioning using endoscopic techniques and/or to modulate the spontaneous migration of the implanted fiducial markers. This result may easily be obtained by means of appropriate moulding processes or 3D printing and/or post-production processes such as: cutting procedures (by blade or laser) and/or mechanical abrasion and/or chemical abrasion.

[0079] The object thus produced may be subjected to processes of chemical functionalization of its external surface to evaluate the modulation of a possible spontaneous migration of the implanted fiducial markers.

[0080] Drugs and/or natural compounds may be added to the polymer which encases the colloidal solution for controlled release of such substances in the organ in which the marker is implanted, so that the possibility can be evaluated of conferring also a drug-carrier function to the fiducial marker.

[0081] The possibility of also inserting in such capsules magnetic nanoparticles with high contrast under magnetic resonance opens up possible applications for fiducial markers based on MRI diagnostic imaging. By virtue of the extremely high concentrations of the AuNPs, the capsules so produced provide high contrast in X-ray imaging, finding application as fiducial markers to be employed in applications of Stereotactic Radiosurgery (SRS) and in particular as markers for radiosurgical treatment using CyberKnife instrumentation.

BIBLIOGRAPHY

[0082] 1. Badawi, M. I., et al., Effect of Gold Nanoparticles Contrast Agent Concentration on X-Ray Diagnoses: Experimental and Computational Study. American Journal of Nano Research and Application, 2014. 2(4): p. 63-69. [0083] 2. Jolck, R. I., et al., Injectable colloidal gold in a sucrose acetate isobutyrate gelating matrix with potential use in radiation therapy. Adv Healthc Mater, 2014. 3(10): p. 1680-7. [0084] 3. Astolfo, A., et al., A simple way to track single gold-loaded alginate microcapsules using x-ray CT in small animal longitudinal studies. Nanomedicine, 2014. 10(8): p. 1821-8. [0085] 4. US2014/0343413. [0086] 5. Meagher, M. J., et al., Dextran-encapsulated barium sulfate nanoparticles prepared for aqueous dispersion as an X-ray contrast agent. Journal of Nanoparticle Research, 2013. 15(12).