Inorganic nanoparticles compositions in combination with ionizing radiations for treating cancer

Abstract

The present application relates to activable inorganic nanoparticles which can be used in the health sector, in particular in human health, to disturb, alter or destroy target cancerous cells, tissues or organs. It more particularly relates to nanoparticles which can generate a surprisingly efficient therapeutic effect, when concentrated inside the tumor and exposed to ionizing radiations. The invention also relates to pharmaceutical compositions comprising a population of nanoparticles as defined previously, as well as to their uses.

Claims

1. A method for treating solid tumor cancer comprising administering to a human subject suffering from a solid tumor cancer by intra-tumoral injection a composition comprising a suspension of inorganic nanoparticles, determining the volume of the composition comprising the inorganic nanoparticles within the tumor volume by radiography or computed tomography, and exposing the tumor of the human subject to ionizing radiation, wherein the inorganic nanoparticles provide more than 7×10.sup.22 electrons to the tumor, the inorganic material constituting the nanoparticles having a theoretical (bulk) density of at least 7 and an effective atomic number (Z.sub.eff) of at least 25, and the volume of the composition (Vc) occupies between 2% and 55% of the tumor volume.

2. The method according to claim 1, wherein said ionizing radiation is selected from X-rays, ion beams, electron beams, gamma-rays, or a radioactive isotope.

3. The method according to claim 1, wherein said composition has a volume that is between 2% and 45% of the tumor volume.

4. The method according to claim 1, wherein the inorganic material constituting the nanoparticles is selected from an oxide, a metal, a sulfide and any mixture thereof.

5. The method according to claim 4, wherein the inorganic material constituting the nanoparticles is a metal oxide and is selected from Cerium (IV) oxide (CeO.sub.2), Neodymium (III) oxide (Nd.sub.2O.sub.3), Samarium (III) oxide (Sm.sub.2O.sub.3), Europium (III) oxide (EU.sub.2O.sub.3), Gadolinium (III) oxide (Gd.sub.2O.sub.3), Terbium (III) oxide (Tb.sub.2O.sub.3), Dysprosium (III) oxide (Dy.sub.2O.sub.3), Holmium oxide (Ho.sub.2O.sub.3), Erbium oxide (Er.sub.2O.sub.3), Thulium (III) oxide (Tm.sub.2O.sub.3), Ytterbium oxide (Yb.sub.2O.sub.3), Lutetium oxide (Lu.sub.2O.sub.3), Hafnium (IV) oxide (HfO.sub.2), Tantalum (V) oxide (Ta.sub.2O.sub.5), Rhenium (IV) oxide (ReO.sub.2), and Bismuth (III) oxide (Bi.sub.2O.sub.3) and any mixture thereof.

6. The method according to claim 4, the inorganic material constituting the nanoparticles is a metal selected from gold (Au), silver (Ag), platinum (Pt), palladium (Pd), tin (Sn), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (HI), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), lutetium (Lu) and any mixture thereof.

7. The method according to claim 4, wherein the inorganic material is selected from a hafnium oxide, zirconium oxide, rhenium oxide, europium oxide and any mixture thereof.

8. The method according to claim 1, wherein the inorganic nanoparticles comprise a mixture of an inorganic oxide and of a metal.

9. The method according to claim 1, wherein the largest dimension of a nanoparticle is between about 5 nm and about 250 nm.

10. The method according to claim 1, said method comprising determining the electron density of the volume of the composition comprising the inorganic nanoparticles (Vc) and administering to the human subject a volume of the inorganic nanoparticles that occupies between 2.5% and 50% of the tumor volume.

11. The method according to claim 10, wherein the inorganic nanoparticles comprise an inorganic material that has an effective atomic number (Z.sub.eff) of at least 40.

12. The method according to claim 1, wherein the method comprises a step of calculating the quantity of electrons provided by the inorganic nanoparticles to the tumor using the following formula:
Quantity of electrons=V.sub.NP(cm.sup.3)×ρ.sub.e.sup.−.sub.material, with ρ.sub.e.sup.−.sub.material=d.sub.material×e.sup.−.sub.material and V.sub.NP (cm.sup.3)=X.sub.mean× Vc (cm.sup.3)/d.sub.material (g/cm.sup.3)/1000 (cm.sup.3), wherein d.sub.material is the theoretical (bulk) density of material constituting the inorganic nanoparticles, e.sup.−.sub.material is the number of electrons per gram of the material constituting the inorganic nanoparticles, Vc represents volume composition and corresponds to the volume of the suspension of inorganic nanoparticles which is administered to the human subject, and X.sub.mean corresponds to the concentration of the suspension of inorganic nanoparticles which is injected into the tumor.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication, with color drawing(s), will be provided by the Office upon request and payment of the necessary fee.

(2) FIG. 1 shows that, once administered, the volume (Vc) of the composition of the invention occupies between 2 and 50% of the tumor volume (Vt). Each inorganic nanoparticle of the composition has a volume (Vin) having an electron density at least 5 times the electron density of the corresponding volume 1 (Vw1) of water. These inorganic nanoparticles provide at least, preferably more than 3×10.sup.22 electrons, for example more than about 3.2×10.sup.22 electrons, preferably more than 7×10.sup.22 electrons, to the tumor mass. The volume composition (Vc) (further) has an electron density of at least 3% of the electron density of the corresponding volume 2 (Vw2) of water.

(3) FIG. 2 shows the distribution and dispersion over time of a biocompatible suspension of HfO.sub.2 nanoparticles after intra tumoral injection into Swiss nude mice bearing HCT116 tumor. Computed Tomography has been performed on tumor, 2 and 15 days following injection.

(4) FIG. 3 shows the X-ray attenuation as a function of gold concentration for gold nanoparticles with sizes equal to 15 nm (GOLD-15), 30 nm (GOLD-30), 60 nm (GOLD-60), 80 nm (GOLD-80) and 105 nm (GOLD-105). HU value as a function of [Au] (g/L) of GOLD-15: diamond dots. HU value as a function of [Au] (g/L) of GOLD-30: square dots. HU value as a function of [Au] (g/L) of GOLD-60: triangle dots. HU value as a function of [Au] (g/L) of GOLD-80: cross dots. HU value as a function of [Au] (g/L) of GOLD-105: + dots.

(5) FIG. 4 shows the % of cell killing (postoperative pathological examination) after the treatment at the time of surgery. More than 70% of cell killing was observed for patients having received the high electron density nanoparticle suspension, intra-tumorally injected within the tumor mass such that the quantity of electrons provided by the nanoparticles to the tumor mass is more than 7×10.sup.22.

(6) FIGS. 5A-5B show the distribution and dispersion over time (during all sessions of radiotherapy: 2*25 Gy) of a biocompatible suspension of HfO.sub.2 nanoparticles after intra tumoral injection into a human subject bearing a soft tissue sarcoma of the extremity. Computed Tomography has been performed on tumor, 1 day (before the first session of radiotherapy; FIG. 5A) and 65 days (after all sessions of radiotherapy, before surgery) following injection (FIG. 5B). The tumor size reduction (tumor volume evolution) is of 53%.

EXAMPLE

(7) A composition comprising hafnium oxide nanoparticles with a concentration equal to 53 g/L is intra-tumorally injected in patients with advanced soft tissue sarcomas of the limbs. The injection volume corresponds to 2.5% of the tumor volume at baseline. Patients received 50 Gy of radiation therapy during 5 weeks and then underwent tumor resection.

(8) The following table recapitulates The tumor volume at baseline (cm.sup.3); The composition volume which is the volume of nanoparticle (composed of hafnium oxide material) suspension which has been intra-tumorally injected and corresponds to 2.5% of the tumor volume at baseline (cm.sup.3); the nanoparticle concentration, equal to 53 g/L; the electron density of each nanoparticle (with volume Vin) with respect to the electron density of same nanoparticle (with volume Vw1) composed of water molecules:

(9) $\frac{{\rho }_{e-\mathrm{HfO}2}}{{\rho }_{e-\mathrm{water}}}=\frac{d_{\mathrm{HfO}2}\times e_{\mathrm{HfO}2}^{-}}{d_{\mathrm{water}}\times e_{\mathrm{water}}^{-}}=\frac{9.6\times 2.52\times {10}^{23}}{1.\times 3.34\times {10}^{23}}=7.3;$ the electron density of the volume composition (Vc) with respect to the electron density of the same volume (Vw2) composed of water molecules:

(10) 0$\frac{\left(\mathrm{Vc}-V_{\mathrm{HfO}2}\right){\rho }_{e-\mathrm{eau}}+V_{\mathrm{HfO}2}\times {\rho }_{e-\mathrm{HfO}2}}{V_c\times {\rho }_{e-\mathrm{eau}}}=1.034;$ the quantity of electrons given by the nanoparticles to the tumor mass:
Quantity of electrons=V.sub.HfO2(cm3)×ρ.sub.e-HfO2(e−/cm3); and % of nanoparticles within the tumor, expressed as weight of nanoparticles by weight of tumor (e.g. 0.13% refers to 0.13 g of nanoparticles per 100 g of tumor).

(11) TABLE-US-00001 Vt: Tumor volume (cm3) 55.0 55.0 95.9 158.0 212.0 476.0 1814.4 Vc: Composition volume 1.4 1.4 2.4 4.0 5.3 11.9 45.0 (2.5% of the tumor volume) (cm3) Xmean: Mean concentration (g/L) 53.0 53.0 53.0 53.0 53.0 53.0 53.0 Electron density of each ρ e.sup.− .sub.Vin/ 7.3 7.3 7.3 7.3 7.3 7.3 7.3 nanoparticle with respect to the ρ e.sup.− .sub.vw1 electron density of same nanoparticle composed of water molecules: e-density (Vin)/e-density (Vw1) Electron density of the volume ρ e.sup.− .sub.Vc/ 1.03442 1.03442 1.03442 1.03442 1.03442 1.03442 1.03442 composition (Vc) with respect to ρ e.sup.− .sub.vw2  3.4%  3.4%  3.4%  3.4%  3.4%  3.4%  3.4% electron density of the same volume composed of water molecules: e-density (Vc)/e-density (Vw2) quantity of e-given by the 1.87E+22 1.87E+22 3.20E+22 5.27E+22 7.07E+22 1.59E+23 6.00E+23 nanoparticles to the tumor mass % of nanoparticles within the 0.13% 0.13% 0.13% 0.13% 0.13% 0.13% 0.13% tumor expressed in weight of nanoparticles by weight of tumor % of cancer cell killing 44 47 10 55 93 72 93

(12) FIG. 4 shows the % of cell killing (postoperative pathological examination) after the treatment at the time of surgery. More than 70% of cell killing was observed for patient having received the high electron density nanoparticle suspension, intra-tumorally injected within the tumor mass such that the quantity of electrons provided by the nanoparticles to the tumor mass is of at least 7×10.sup.22.

(13) Interestingly, the percentage (%) of nanoparticles within the tumor expressed as weight of nanoparticles by weight of tumor is equal to 0.13% (0.13% refers to 0.13 g of nanoparticles per 100 g of tumor). This value corresponds to 0.11% of hafnium element within the tumor (i.e. 0.11 g of Hafnium element per 100 g of tumor). This % of nanoparticles by weight does not enhance markedly the tumor response to radiotherapy unless the quantity of electrons provided by the nanoparticles to the tumor mass is more than 3×10.sup.22, preferably more than 7×10.sup.22.

(14) Results presented here demonstrate that only a composition comprising high electron density inorganic nanoparticles (i.e. each nanoparticle has an electron density at least 5 times the electron density of the same nanoparticle composed of water molecules) occupying between 2 and 50% of the tumor volume are able to induce more than 44% or 47%, preferably more than 70% of cancer cell killing when the inorganic nanoparticles provide more than 3×10.sup.22, preferably more than 7×10.sup.22 electrons to the tumor mass.