Novel metal oxide nanoparticles and compositions thereof for use as radioenhancers or for visualizing biological tissue

Abstract

The invention concerns inventive nanoparticles (NPs), their compositions and their use as therapeutic agents in particular in the field of oncology and / or as imaging agents. The NPs are composed of first nanoparticles of at least one high-Z metal oxide material, to which smaller second nanoparticles are covalently bonded at the first nanoparticles' surface. The second nanoparticles are composed of either a) at least one noble metal or at least one metal oxide, metal sulfide, metal selenide or metal sulfide / selenide that is a Fenton or Fenton-like reaction catalyst. The inventive NPs generate a surprisingly therapeutic effect when exposed to ionizing radiation such as X-Rays, γ-Rays, protons, neutrons, radioactive isotopes and / or electron beams. Thus, the NPs may be used as radioenhancers in the field of oncology. The nanoparticles may also be used as contrast agents.

Description

Novel Metal Oxide Nanoparticles and Compositions Thereof for Use as Radiosensitizers or Bio-tissue Imaging Agents Abstract This invention relates to innovative nanoparticles (NPs), compositions thereof, and their use as therapeutic agents (particularly in the field of oncology) and / or imaging agents. These nanoparticles consist of a first nanoparticle made of at least one high atomic number (high Z) metal oxide material, with smaller second nanoparticles covalently bonded to the surface of the first nanoparticles. The second nanoparticles consist of: a) at least one noble metal; or a) at least one metal oxide, metal sulfide, metal selenide, or metal sulfide / selenide, wherein the metal oxide, metal sulfide, metal selenide, or metal sulfide / selenide is a Fenton reaction or Fenton-like reaction catalyst. These novel nanoparticles produce surprising therapeutic effects upon exposure to ionizing radiation (e.g., X-rays, gamma rays, protons, neutrons, radioisotopes, and / or electron beams). Therefore, these nanoparticles can be used as radiosensitizers in the field of tumor treatment. Furthermore, these nanoparticles can also be used as contrast agents. Abstract

Claims

CLAIMS1. A nanoparticle (NP) or aggregate of nanoparticles (NPs), wherein the NP is composed of a first nanoparticle of at least one metal oxide (MxOy) or mixed metal oxide (MxM’zOy) having an atomic number Z of at least 40, the first nanoparticle having a density equal to or above (>) 7g / cm3and below (<)15 g / cm3, to which smaller second nanoparticles are covalently bonded at the surface of the first nanoparticle via a linker, wherein the second nanoparticles are composed of either: a. at least one noble metal chosen from gold (Au), platinum (Pt), Ruthenium (Ru), Rhodium (Rh), palladium (Rd), osmium (Os) and iridium (Ir), and / or b. at least one metal oxide, metal hydroxide, metal oxy-hydroxide, metal peroxide, metal sulfide, metal selenide, or metal sulfide / selenide that is a Fenton or Fenton-like reaction catalyst, wherein the metal is chosen from the group Fe, Co, Ni, Cu and Mn, and optionally, a negatively charged or neutrally charged biocompatible surface coating, wherein the first nanoparticle metal content / second nanoparticle metal content ratio is below 30 weight / weight (w / w).

2. The nanoparticle (NP) according to claim 1 wherein the high-Z metal oxide (MxOy) is HfCh or ZrO2.

3. The nanoparticle (NP) according to claim 1 or 2 wherein the second nanoparticles are composed of gold (Au).

4. The nanoparticle (NP) according to claim 1 or 2, wherein the second nanoparticles are composed of iron oxide (Fc iO-i).

5. The nanoparticle (NP) according to any one of claims 1-4, wherein the first nanoparticle metal content / second nanoparticle metal content ratio is between 20 and 30 weight / weight (w / w).

6. The nanoparticle (NP) according to any one of claims 1-5, wherein the linker on the first nanoparticle is an amino-silane and the linker on the second nanoparticle is a citrate.

7. The nanoparticle NP according to any one of claims 1-6, wherein the first nanoparticle has a size of between 40-100 nm.

8. The nanoparticle (NP) according to any one of claims 1-6, wherein each of the second nanoparticles has a size of between 2-15 nm.

9. A nanoparticle (NP) or an aggregate of nanoparticles (NPs) of any one of claims 1-8, for use in altering or destroying target tumor cells in a mammal when said cells are exposed to ionizing radiation chosen from X-rays, y-rays and protons.

10. The nanoparticle (NP) or aggregate for use according to claim 9, wherein cells are exposed to ionizing radiation in the context of a radiotherapy regimen selected from a conventionalfractionation regimen, an hyperfractionation regimen, an (accelerated) hypofractionation regimen, and a Stereo Ablative Body radiotherapy (SBAR) regimen.

11. The nanoparticle (NP) or aggregate for use according to claim 9 or 10, wherein the target cells are from a solid malignant tumor selected from a skin cancer, a central nervous system cancer, a head and neck cancer, a lung cancer, a breast cancer, a gastrointestinal cancer, a male genitourinary cancer, a gynecologic cancer, an adrenal and / or retroperitoneal cancer, a sarcoma and a pediatric cancer.

12. The nanoparticle (NP) or aggregates of nanoparticles (NPs) of any one of claims 1-8, for use in visualizing soft tissue and detecting tumor cells in a mammal.

13. A composition comprising a) nanoparticles (NPs) or aggregates thereof as described in any one of claims 1 to 8, or their mixtures, and b) a pharmaceutically acceptable carrier, vehicle or support.

14. A composition according to claim 13 for use in altering or destroying target tumor cells in a mammal, particularly in a human, when said cells are exposed to ionizing radiation.

15. A composition according to claim 13 for use in visualizing soft tissue and detecting tumor cells in a mammal, using CT scan.

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