DEVICES AND METHODS FOR THE TREATMENT OF CANCER

Abstract

The invention relates to the treatment of cancer. In particular the invention relates to an internal therapeutic product comprising: (i) an anti-cancer component selected from one or both of: a radionucleotide, a cytotoxic drug; and (ii) a silicon component selected from one or more of: resorbable silicon, biocompatible silicon, bioactive silicon, porous silicon, polycrystalline silicon, amorphous silicon, and bulk crystalline silicon, the internal therapeutic product being for the treatment of cancer.

Claims

1. An internal therapeutic product comprising: (i) an anti-cancer component comprising at least one radionucleotide and/or at least one cytotoxic drug; and (ii) a silicon component selected from one or more of: resorbable silicon, biocompatible silicon, bioactive silicon, porous silicon, polycrystalline silicon, amorphous silicon, and bulk crystalline silicon.

2. An internal therapeutic product according to claim 1, wherein therapeutic product comprises at least one implant.

3. An internal therapeutic product according to claim 2, wherein the or at least one is of the implants comprises at least part of the silicon component and at least part of the anti-cancer component.

4. An internal therapeutic product according to claim 1, wherein the silicon component comprises resorbable silicon.

5. An internal therapeutic product according to claim 1, wherein the silicon component comprises resorbable silicon and the anti-cancer component comprises a radionucleotide, the radionucleotide being distributed through at least part of the resorbable silicon.

6. An internal therapeutic product according to claim 3, wherein the or at least one of the implants comprises resorbable silicon and a radionucleotide, the resorbable silicon having a structure and composition such that substantially all the radionucleotide remains in and/or on at least part of the or at least one of the implants for a period, measured from the time of implantation, greater than the half life of the radionucleotide.

7. An internal therapeutic product according to claim 3, wherein the or at least one of the implants may comprise resorbable silicon and a cytotoxic drug, the resorbable silicon having a structure and composition such that the implant remains sufficiently intact to substantially localise the drug release at the site of the implant.

8. An internal therapeutic product according to claim 1, wherein anti-cancer agent comprises a radionucleotide, and the radionucleotide is selected from one or more of: .sup.90Y, .sup.32P, .sup.124Sb, .sup.114In, .sup.59Fe, .sup.76As, .sup.140La, .sup.47Ca, .sup.103Pd, .sup.89Sr, .sup.131I, .sup.125I, .sup.60Co, .sup.192Ir, and .sup.198Au.

9. A method of treating a cancer, the method comprising the step of introducing an internal therapeutic product into a patient, the internal therapeutic product comprising: (i) a silicon component selected from one or more of: resorbable silicon, biocompatible silicon, bioactive silicon, porous silicon, polycrystalline silicon, amorphous silicon, bulk crystalline silicon; and (ii) an anti-cancer component comprises at least one radionucleotide and/or at least one cytotoxic drug.

10. A method according to claim 9, wherein the internal therapeutic product comprises at least one implant, the step of introducing the internal therapeutic product comprising the step of implanting the or at least one of the implants into the body of a patient.

11. A method according to claim 10, wherein the or at least one of the implants comprises at least part of the silicon component and at least part of the anti-cancer component.

12. A method according to claim 11, wherein the or at least one of the implants comprises resorbable silicon and a cytotoxic drug, the method of treating a cancer to comprising the further step of releasing at least part of the cytotoxic drug in such a manner that the release of the cytotoxic drug remains substantially localised to the point of implantation.

13. A method according to claim 11, wherein the or at least one of the implants comprises resorbable silicon and a radionucleotide, the method of treating a cancer comprising the step of treating part of the patient's body with radiation from the radionucleotide in such a manner that the radiation treatment is localised to the point of implantation, and comprising the further step of allowing the silicon to substantially completely resorb once the half life of the radionucleotide has been exceeded.

14. A method according to claim 9, wherein the internal therapeutic product comprises a radionucleotide and a cytotoxic drug and the method of is treating cancer comprises the further step of combining the radionucleotide and the cytotoxic agent less than 10 hours prior the introduction of the therapeutic product to the patient.

15. An internal therapeutic product according to claim 1, wherein the anti-cancer component comprise a radionucleotide having a structure and composition obtainable by the transmutation of porous silicon.

16. An internal therapeutic product according to claim 1, wherein the anti-cancer component comprise a radionucleotide having a structure and composition obtainable by the transmutation of germanium atoms that form part of a porous silicon germanium alloy.

Description

[0125] The invention will now be described by way of example only.

Administration of Therapeutic Products, According to the Invention, to a Patient

[0126] Therapeutic products according to the present invention may have a variety of forms suitable for administration by subcutaneous, intramuscular, intraperitoneal, or epidermal techniques.

[0127] Therapeutic products according to the invention comprise a silicon component that may be spherical, lozenge shaped, rod shaped, in the form of a strip, or cylindrical. The silicon component may form part of or at least part of: a powder, a suspension, a colloid, an aggregate, and/or a flocculate. The therapeutic product may comprise an implant or a number of implants, the or each implant comprising silicon and an anti-cancer component.

[0128] Such an implant or implants may be implanted into an organ in which a tumour is located in such a manner as to optimise the therapeutic effect of the anti-cancer component.

[0129] In one aspect of the invention, the method of treatment may involve brachytherapy, and the organ to undergo the brachytherapy may be surgically debulked and the residual space filled with the therapeutic product. In another aspect the organ to be treated may be cored with an array of needles and the cores back filled with the therapeutic product of the invention, such a procedure being suitable for brachytherapy of the prostate.

[0130] If the therapeutic product is to be used for the treatment of liver cancer, a composition may be administered to the liver by injection of silicon microparticles into the hepatic or celiac artery; the microparticles being delivered in the form of a suspension in an isotonic solution such as a phosphate buffered saline solution or serum/protein based solution. The size of the microparticles is such that the blood carries them into, but not out of, the liver. The microparticles follow the flow of blood to the tumour, which has a greater than normal blood supply.

[0131] In a yet further aspect, the therapeutic product may comprise a multiplicity of porous silicon particles, said multiplicity of porous silicon particles being divided into two types of porous silicon particles: one type having a cytotoxic drug and no radionucleotide, and a second type having a radionucleotide and no cytotoxic drug. Both types of particle may be administered to a patient at the same time, though they may be stored separately prior to administration. In this way the proportion of the cytotoxic drug and radionucleotide may be selected to correspond to the condition of the patient. Separate storage of the two types of microparticle prior to administration to a patient may be required if the cytotoxic agent is degraded by exposure to radiation from the radionucleotide.

[0132] To improve targeting further, a vasoconstricting drug such as angiotensin II may be infused prior to silicon microparticle administration. This drug constricts the fully developed non-tumour associated vasculature, and thereby directs the microparticles away from normal liver parenchyma.

Generation and/or Incorporation of the Radionucleotide

[0133] A therapeutic product according to the invention may comprise silicon component and a radionucleotide. The radionucleotide may be combined with the silicon component, and/or it may be fabricated by the transmutation of silicon. There are several methods by which a radionucleotide may be combined with a silicon component, or generated by the transmutation of silicon, to form the or at least part of a therapeutic product according to the invention. Four of these methods are given in sections (A) to (D) below.

[0134] (A) Fabrication of a .sup.32P doped porous silicon powder

[0135] (Ai)

[0136] A standard set of CZ Si wafers, degenerately doped with phosphorous (210.sup.20 cm.sup.3) is formed into a powder by ball milling, sieving, and wet etching. The milling and sieving is carried out in such a manner that silicon microparticles having a largest dimension in the range 25 to 50 m are obtained. The powder is then rendered porous by stain etching in an HF based solution as described in Appl Phys Lett 64(13), 1693-1695 (1994) to yield porous silicon microparticles.

[0137] Alternatively a CZ Si wafer, degenerately doped with phosphorous (210.sup.20 cm.sup.3) wafer may be anodised in an HF solution, for example a 50% aqueous or ethanolic solution, to form a layer of porous silicon. The anodisation may be carried out in an electrochemical cell by standard methods such as that described in U.S. Pat. No. 5,348,618. For example a wafer may be exposed to an anodisation current density of between 5 and 500 mAcm.sup.2 for between 1 and 50 minutes. In this way a layer of porous silicon having a porosities in the range 1% to 90% may be fabricated.

[0138] The porous silicon layer may then be detached from the underlying bulk substrate by applying a sufficiently high current density in a relatively dilute electrolyte, for example a current density of greater than 50 mAcm.sup.2 for a period of 10 seconds. The detached porous silicon layer may then be crushed to yield porous silicon particles.

[0139] Alternatively the anodised wafer may be treated ultrasonically to detach the layer of porous silicon and to break up the layer into particles of porous silicon. Exposure to ultrasound in this way may be performed in a solvent, the solvent being chosen to minimise agglomeration of the resulting particles. Ultrasonic treatment in this way results in the formation of porous silicon particles. Some control over particle sizes, of the porous silicon particles resulting from the ultrasonic treatment, may be achieved by centrifuging the resulting suspension to separate the different particle sizes. The porous silicon particles may also be sized by allowing the suspension to gradually settle as described in Phys. Solid State 36(8) 1294-1297 (1994).

[0140] Whether porosification is by stain etching or by anodisation, the porosity of the porous silicon may be selected so that the overall density of the microparticles for administration to the patient is between 1.5 and 2.5 g cm.sup.3. The density of the porous silicon may be tailored to take account of the density of the radionucleotide and or cytotoxic agent with which it is to be combined.

[0141] Silicon powders of micron particle size are available commercially and nanometre size particles can be fabricated by processes such as ball milling, sputtering, and laser ablation of bulk silicon.

[0142] (Aii)

[0143] A sample of porous silicon particles, fabricated according to step (Ai), are subjected to thermal neutron bombardment in a nuclear reactor to bring about neutron transmutation doping of the silicon. The irradiation conditions are chosen to maximise .sup.32P production within the porous silicon. In this way 10-20 mCi levels may be obtained which are suitable for treatment of liver cancer tumours of 1 to 3 cm.

[0144] Phosphorous doping of silicon via neutron transmission doping of silicon is a well established means of producing phosphorous doped silicon at approximately 10.sup.15 cm.sup.3:

.sup.30Si+n.sup.0=.sup.31P

[0145] Further neutron capture is also possible:

.sup.31P+n.sup.0=.sup.32P

[0146] The amount of .sup.32P (a radionucleotide) present depends primarily on the amount of .sup.31P produced and on the amount of P originally present, as well as the neutron flux.

[0147] If necessary, prior to the neutron radiation described in this section, concentrations of phosphorous in porosified particles could be raised by doping the porous silicon microparticles or particles with phosphine gas at 500 to 700 C or orthophosphoric acid followed by an anneal at 600 to 1000 C. Alternatively doping of the porous silicon microparticles or particles may be achieved by exposure to phosphorous oxychloride vapour at 800 to 900 C., as described in IEEE Electron Device Lett. 21(9), p 388-390 (2000). In this way concentrations of phosphorous between 10.sup.21 and 510.sup.22 cm.sup.3 may be achieved.

[0148] (B) Isotope Exchange

[0149] Tritium gas is incubated with hydride passivated porous silicon. The hydride passivated porous silicon is irradiated with an electron beam in such a manner that the silicon-hydrogen bonds are progressively broken to allow replacement of the hydrogen with tritium. The electron beam may be a 1-10 MeV beam. The process results in the formation of tritiated porous silicon. A similar process of isotope exchange may also be used for the introduction of other radioactive gaseous species such as .sup.131I that may become bonded to the internal surface of the pores. Isotope exchange may be promoted by the application of heat and/or light and/or particle bombardment.

[0150] (C) Ion Implantation

[0151] A sample of porous silicon may be oxidised by a low temperature oxidation process before ion implantation of the radionucleotide by standard techniques to fabricate a monolayer of oxide on the internal surface of the pores. The low temperature oxidation of the porous silicon being performed in such a manner that sintering of the porous silicon microstructure, by the ion implantation, is prevented. The low temperature oxidation may be performed by heating a sample of porous silicon at 300 C for 1 hour in substantially pure oxygen gas. The ion implantation may be performed in such a manner that ions of the radionucleotide are implanted between 1 and 5 microns below the surface of the porous silicon. Acceleration voltages for ion implantation may be in the range 5 KeV to 500 KeV and ion doses may be in the range 10.sup.13 to 10.sup.17 ion cm.sup.2. The temperature of the porous silicon may be maintained at a substantially fixed temperature during ion implantation. The temperature of the porous silicon may be in the range 200 C to +1000 C. Examples of ions that may be ion implanted in this way are .sup.90Y, .sup.140La, .sup.125I, .sup.131I, .sup.32P, and .sup.103Pd.

[0152] (D) Liquid Infiltration

[0153] A sample of porous silicon is immersed in an aqueous solution of a salt of the radioisotope to be introduced. The salt is thermally decomposed by a first heat treatment, and the radioisotope is driven into the skeleton of the porous silicon by a second heat treatment.

[0154] Alternatively if the salt of the radioisotope has a relatively low melting point the salt may be melted on the surface of the porous silicon, the molten salt being drawn into the porous silicon by capillary action. The salt may then be thermally decomposed and driven into the porous silicon skeleton by a two stage heating process as described in WO 99/53898.

[0155] (E) Fabrication of a Radionucleotide by Transmutation of a Silicon Germanium Alloy

[0156] (Ei)

[0157] A boron-doped polycrystalline silicon germanium bulk alloy may be grown by oriented crystallisation within a crucible using standard techniques such as the Polix method. The alloy may be fabricated in such a manner that the alloy comprises 1-15 at % Ge and has a resistivity of 1 to 0.01 ohm cm. The resulting ingot of the alloy may be mechanically sawn into sheets having thickness 200 to 500 microns, which may then be subjected to a wet polish etch to remove saw damage. Anodisation may then be performed at current densities in the range 5 to 500 mAcm.sup.2 in HF based electrolytes for periods between 5 minutes and 5 hours.

[0158] The resulting layer of porous Silicon germanium may then be converted to a powder of porous silicon germanium particles by similar methods to those described in section Ai.

[0159] The porous Silicon germanium powder may then be subjected to particle bombardment, for example neutron bombardment, to transmute .sup.70Ge to the radionucleotide .sup.71Ge.

[0160] (Eii)

[0161] Alternatively a standard Si or SOI wafer may be coated with a crystalline Si.sub.xGe.sub.(1-x) layer, or with alternate ultrathin layers of crystalline silicon and germanium. The Si and Ge being fabricated from silane and germane by standard CVD techniques. The CVD deposition temperature may be in the range 300K to 1000K. For situations in which a silicon substrate is used porosification of the silicon germanium alloy may be by anodisation or by stain etching. For situations in which a SOI substrate is used, stain etching may be used to both porosify and detach the silicon alloy from the substrate.

[0162] Formation of the porous silicon alloy powder and transmutation is then preformed in a similar manner as that described in (Ei).

Fabrication of Porous Silicon Implants having a Well Defined Shape and Well Defined Dimensions

[0163] A first Si wafer, having a sacrificial organic film applied to one surface, is etched using standard MEMS processing to form a first array of photolithographically defined objects. If the entire Si wafer thickness is etched through, then the first array is held in place by the sacrificial organic film. The first array is then bonded to a second electrically conductive wafer in preparation for subsequent anodisation. The second wafer may be silicon having the same conductivity type and different resistivity, or a metal coated silicon wafer having the same conductivity type and same resistivity as the first silicon wafer. The first array is then treated with solvent to remove the organic film. Anodisation in HF based electrolyte is then performed until the first array is completely porosified. Incorporation of the radioisotope may then be performed by treatment of the first array in powder form, or by treatment of the first array while bonded to the second wafer.

[0164] A similar process for the preparation of a second array of porous silicon photolithographically defined objects may also be performed by etching a SOI wafer by standard MEMS processing.

Combination of Silicon Microparticles with Cytotoxic Agent

[0165] The porous silicon microparticles, fabricated either by step (Ai) alone or by step (Ai) in combination with step (Aii), are then impregnated with a cytotoxic drug used for treating liver cancer, such as 5-fluorouracil.

[0166] There are a number of methods by which a cytotoxic drug may be associated with the microparticle. The cytotoxic drug may be dissolved or suspended in a suitable solvent, the microparticles may then be incubated in the resulting solution for a period of time. The cytotoxic drug may then be deposited on the surface of the microparticles. If the microparticles comprise porous silicon, then a solution of the cytotoxic drug may be introduced into the pores of the porous silicon by capillary action. Similarly if the microparticles have a cavity then the solution may also be introduced into the cavity by capillary action. If the cytotoxic drug is a solid but has a sufficiently high vapour pressure at 20 C then it may be sublimed onto the surface of the microparticles. If a solution or suspension of the cytotoxic drug can be formed then the substance may be applied to the microparticles by successive immersion in the solution/suspension followed by freeze drying.

[0167] A further method by which a cytotoxic drug may be associated with porous silicon is through the use of derivatised porous silicon. The cytotoxic drug may be covalently attached directly to the derivatised silicon by a SiC or SiOC bond. The release of the cytotoxic agent is achieved through biodegradation of the porous silicon.