INORGANIC-ORGANIC HYBRID COMPOUNDS INCLUDING ORGANIC PLATINUM-CONTAINING ANIONS, FOR USE IN MEDICINE

Abstract

The present invention relates to inorganic-organic hybrid compounds for use in medicine or for use as medication, consisting of an inorganic metal cation and an organic platinum-containing cytostatic anion, in particular also a cisplatin derivative.

Claims

1. Inorganic-organic hybrid compound for use in medicine, made up as ionic compounds from an inorganic metal cation selected from Ba.sup.2+, [ZrO].sup.2+, [HfO].sup.2+, Sc.sup.3+, y.sup.3+, .sub.Gd.sup.3+, [GdO].sup.+, [Gd(OH)].sup.2+, [LaO].sup.+, [La(OH)].sup.2+, Bi.sup.3+, A.sub.g.sup.+or a lanthanide, and an organic platinum-containing anion containing at least one phosphate, pyrophosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group as a functional group, wherein the compound has a molar solubility of 10′ mol/l in water and a particle diameter in the range from 1 to 100 nm.

2. Inorganic-organic hybrid compound for use in medicine according to claim 1, wherein the metal cation is selected from Ba.sup.2+, [ZrO].sup.2+, [HfO].sup.2+, [GdO].sup.+, [Gd(OH)].sup.2+, [LaO].sup.+, [La(OH)].sup.2+ or Ag.sup.+.

3. Inorganic-organic hybrid compound for use in medicine according to claim 1, wherein the organic platinum-containing anion contains at least one phosphate, pyrophosphate or phosphonate group as a functional group.

4. Inorganic-organic hybrid compound for use in medicine according to claim 1, wherein the organic platinum-containing anion is selected from [Pt.sub.2(POP).sub.4] (POP: pyrophosphate), [cisPt(AEP).sub.2].sup.4− (AEP: aminoethyl phosphate), or [cisPt(PAA).sub.2].sup.4− (PAA: phosphonoacetate).

5. Inorganic-organic hybrid compound for use in medicine according to claim 1, which further comprises a fluorescence dye anion and/or an active ingredient anion, which each carry a phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group as a functional group.

6. Inorganic-organic hybrid compound for use in medicine according to claim 5, wherein the organic fluorescence dye anion is derived from fluorescence dyes selected from the group consisting of 1,1′-diethyl-2,2′-cyanine iodide, 1,2-diphenylacetylene, 1,4-diphenylbutadiene, 1,6-diphenylhexatriene, 2,5-diphenyloxazole, 2-methylbenzoxazole, 4′,6-diamidino-2-phenylindole (DAPI), 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyrane (DCM), 4-dimethylamino-4′-nitrostilbene, 5,10,15-triphenylcorrole, 5,10,15-tris(pentafluorophenyl)corrole, 5,10-diarylchlorin, 5,10-diarylcopperchlorin, 5,10-diarylcopperoxochlorin, 5,10-diarylmagnesiumoxochlorin, 5,10-diaryloxochlorin, 5,10-diarylzincchlorin, 5,10-diarylzincoxochlorin, 7-benzylamino-4-nitrobenz-2-oxa-1,3-diazole, 7-methoxycoumarin-4-acetic acid, 9,10-bis(phenylethynyl)anthracene, 9,10-diphenylanthracene, acridine orange, acridine yellow, adenine, anthracene, anthraquinone, auramine O, azobenzene, Bacteriochlorophyll A, benzoquinone, beta-carotene, bilirubin, biliverdin dimethyl ester, bis(5-mesyldipyrrinato)zinc, bis(5-phenyldipyrrinato)zinc, boron subphtalocyanine chloride, chlorin E6, chlorophyll A, chlorophyll B, cis-stilbene, coumarin and derivatives thereof, cresyl violet perchlorate, cryptocyanine, crystal violet, cytosine, dansylglycine, diprotonated-tetraphenylporphyrin, eosin and derivatives thereof, ethyl-(p-dimethylamino)benzoate, ferrocene, fluorescein and derivatives thereof, for example methylfluorescein, resorufin, amaranth, aluminum(III)-phthalocyanine chloride, tetrasulfonic acid, trypan blue, guanine, hematine, histidine, Hoechst 33258, indocarbocyanine and derivatives thereof, Lucifer yellow CH, magnesium octaethylporphyrin, magnesium phthalocyanine, magnesium tetramesitylporphyrin, magnesium tetraphenylporphyrin, malachite green, merocyanine, N,N′-difluoroboryl-1,9-dimethyl-5-(4-iodophenyl)-dipyrrin, N,N′-difluoroboryl-1,9-dimethyl-5-[(4-(2-trimethylsilylethynyl)phenyl]dipyrrin, N,N′-difluoroboryl-1,9-dimethyl-5-phenydipyrrin, tetraphenylporphyrin, naphthalene, Nile Blue, Nile Red, octaethylporphyrin, oxacarbocyanine and derivatives thereof, oxazine and derivatives thereof, p-quarterphenyl, p-terphenyl, perylene and derivatives thereof, phenol, phenylalanine, phenyldipyrrin, pheophorbide, phthalocyanine, pinacyanol iodide, piroxicam, porphine, proflavine, protoporphyrin-IX-dimethyl ester, pyrene, pyropheophorbide and derivatives thereof, pyrrole, quinine, rhodamine and derivatives thereof, riboflavin, Bengal red, squarylium dye III, TBP-beta-octa(COOBu)-Fb, TBP-beta-octa(COOBu)-Pd, TBP-beta-octa(COOBu)-Zn, TBP-meso-tetraphenyl-beta-octa(COOMe)-Fb, TBP-meso-tetraphenyl-beta-octa(COOMe)-Pd, TBP-meso-tetraphenyl-beta-octa(COOMe)-Zn, TCPH-meso-tetra(4-COOMe-phenyl)-Fb, TCPH-meso-tetra(4-COOMe-phenyl)-Pd, TCPH-meso-tetra(4-COOMe-phenyl)-Zn, tetra-t-butyl azaporphine, tetra-t-butylnaphthalocyanine, tetrakis(2,6-dichlorophenyl)porphyrin, tetrakis(o-aminophenyl)porphyrin, tetramesityl porphyrin, tetraphenylporphyrin, tetraphenylsapphyrin, thiacarbocyanine and derivatives thereof, thymine, trans-stilbene, tris(2,2′-bipyridyl)ruthenium(II), tryptophan, tyrosine, uracil, vitamin B12, zinc octaethylporphyrin, phthalocyanine and derivatives thereof, porphyrin and derivatives thereof, including tetra(o-amidophosphonophenyl)porphyrin, and umbelliferone, wherein the organic fluorescence dyes, which as such do not have a phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group, are modified with at least one of these functional groups.

7. Inorganic-organic hybrid compound for use in medicine according to claim 5, wherein the active ingredient anion is derived from acetaminophen phosphate, betamethasone phosphate, dexamethasone phosphate, uridine monophosphate, 5′-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), methylprednisolone phosphate, triamcinolone phosphate, estrone phosphate, testosterone phosphate, estramustine phosphate, codeine phosphate, clindamycin phosphate, thiamine pyrophosphate, thiamine phosphate; aracytidinmonophosphat, cyclic-3′,5′adenosine monophosphate, vidaribine phosphate, 9-[9-(phosphonomethoxy)ethoxy]adenine, fospropofol, fosphenytoin, pho sphoryl oxym ethyl oxym ethyl phenytoin, phosphoryloxymethylphenylbutazone, pho sphoryl oxym ethyl oxym ethyl phenylbutaz one, phosphoryloxymethylphenindione, phosphoryloxymethyloxymethylphenindione, N-phosphonooxymethylcinnarizine, N-phosphonooxymethylloxapine, N-phosphonooxymethylamiodarone, alendronate, canrenoate, doxycycline hydrate, doxorubicin hydrochloride, aztreonam, tigemonam, D-glucosamine-6-sulphate, colistin methanesulphate, cefsulodin, fosamprenavir, tenofovir, adefovir, combretastatin A-4 phosphate, folic acid, fosphenytoin, 2-mercaptoethanesulfonate/mesna, fosfomycin, glyphosate, glufosinate, zolendronate, aminotrim ethyl ene phosphonic acid, diethyl enetri amine p enta(m ethyl ene phosphonic acid), ethylenediamine tetra(methylene phosphonic acid), fosbretabulin, a-tocopherol phosphate, VAPOL hydrogenphosphate, pyridoxa1-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′,8′-disulfonate), (11bR)-2,6-di-9-phenanthrenyl-4-hydroxy-dinaphtho[2,1-d:1′,2′-f][1,3,2] dioxaphosphepine-4-oxide, 8-bromo-cyclic adenosine diphosphate ribose, phytic acid, glucose-6-phosphate or other phosphoric acid esters of sugars or naturally occurring and synthetic nucleotides including adenosine monophosphate (AMP), adenosine diphosphate (ADP), adenosine triphosphate (ATP), guanosine monophosphate (GMP), guanosine diphosphate (GDP), guanosine triphosphate (GTP), cytidine monophosphate (CMP), cytidine diphosphate (CDP), cytidine triphosphate (CTP), uridine monophosphate (UMP), uridine diphosphate (UDP), uridine triphosphate (UTP), deoxyadenosine monophosphate (dAMP), deoxyadenosine diphosphate (dADP), deoxyadenosine triphosphate (dATP), deoxyguanosine monophosphate (dGMP), deoxyguanosine diphosphate (dGDP), deoxyguanosine triphosphate (dGTP), deoxycytidine monophosphate (dCMP), deoxycytidine diphosphate (dCDP), deoxycytidine triphosphate (dCTP), deoxythymidine monophosphate (dTMP), deoxythymidine diphosphate (dTDP) deoxythymidin triphosphate (dTTP).

8. Inorganic-organic hybrid compound for use in medicine according to claim 5, wherein the additionally incorporated organic active ingredient anion is derived from acetaminophen phosphate, betamethasone phosphate, dexamethasone phosphate, 5′-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), methyl prednisolone phosphate, triamcinolone phosphate, estrone phosphate, estramustine phosphate, codeine phosphate, clindamycin phosphate, fospropofol, alendronate, canrenoate, doxycycline hydrate, doxorubicin, aztreonam, tigemonam, cefsulodin, fosamprenavir, tenofovir, adefovir, folic acid, fosfomycin, α-tocopherol phosphate or glucose-6-phosphate.

9. Inorganic-organic hybrid compound for use in medicine according to claim 1, which is in an X-ray amorphous form.

10. Inorganic-organic hybrid compound for use in medicine according to claim 1, wherein it is free from corresponding matrices or encapsulations surrounding it, in particular for example an SiO.sub.2 matrix, and free from any phospholipid matrices or encapsulations.

11. Inorganic-organic hybrid compound for use in medicine according to claim 1, which is further functionalized with one or more tumor-specific ligands.

12. A method for producing an inorganic-organic hybrid compound according to claim 1, comprising the steps of: (a) providing a solution of a platinum-containing anion compound, which has one or more functional groups selected from phosphate, pyrophosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate groups, (b) providing a solution of a soluble metal salt containing metal cations selected from Ba.sup.2+, [ZrO].sup.2+, [HfO].sup.2+, Sc“, Y”, Gd.sup.3+, [GdO].sup.+, [Gd(OH)].sup.2+, [LaO].sup.+, [La(OH)].sup.2+, Fe.sup.3+, Ag.sup.+ or a lanthanide, (c) combining the two solutions by stirring in order to precipitate the hybrid compound, and (d) isolating and/or purifying the precipitated hybrid compound.

Description

[0056] The figures show:

[0057] FIG. 1 the production of the inorganic-organic hybrid [ZrO].sub.2.sup.2+[Pt.sub.2(POP).sub.4].sup.4−,

[0058] FIG. 2 the production of the inorganic-organic hybrid [ZrO].sup.2+.sub.2[cisPt(AEP).sub.2].sup.4,

[0059] FIG. 3 the production of the inorganic-organic hybrid [Ag].sup.+.sub.2[cisPt(SA).sub.2].sup.2−, and

[0060] FIG. 4 the production of the inorganic-organic hybrid [ZrO].sup.2+.sub.2[cisPt(PAA).sub.2].sup.4−.

[0061] In summary, the present invention has the following advantages over the prior art: [0062] inorganic-organic hybrid nanoparticles with platinum-containing anions as a novel material concept with a novel chemical composition [0063] chemical composition with inorganic metal cations like Ba.sup.2+, [ZrO].sup.2+, [HfO].sup.2+, Sc.sup.3+, Y.sup.3+, Gd.sup.3+, [GdO].sup.+, [Gd(OH)].sup.2+, [LaO].sup.+, [La(OH)].sup.2+, Fe.sup.3+, Bi.sup.3+, Ag.sup.+ or a lanthanide and a platinum-containing anion carrying phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate groups [0064] high content of platinum-containing anions of 30 to 90% by weight [0065] high effectiveness and high uptake in cells with low side effects (compared to conventional cisplatin derivatives) [0066] simple and inexpensive synthesis in water [0067] possibility of combining different active ingredient anions in one nanoparticle [0068] possibility of combining active ingredient anions and fluorescence dye anions [0069] multifunctional imaging including optical and/or photoacoustic and/or magnetic imaging [0070] synergistic tumor treatment through chemical/cytostatic and physical effects. Physical effects can be magnetothermal effects and/or photo-induced effects [0071] inorganic-organic hybrid nanoparticles are usually not crystalline (i.e., X-ray amorphous). The complex synthesis of crystalline materials or the formation of core-shell structures is not necessary [0072] selective uptake in tumors through EPR effect (Enhanced Permeability and Retention) through transport in macrophages and/or the attachment of suitable antibodies.

[0073] The present invention will be explained in further detail by the following non-limiting examples.

EXAMPLES

Embodiment 1

[ZrO].SUB.2..SUP.2+.[Pt.SUB.2.(POP).SUB.4.].SUP.4−

[0074] The inorganic-organic hybrid [ZrO].sub.2.sup.2+[Pt.sub.2(POP).sub.4] (POP: pyrophosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (6.5 mg) in demineralized water (5.0 ml). Solution 2 contains potassium pyrophosphatoplatinate(II) (K.sub.4[Pt.sub.2(POP).sub.4)], 20.3 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the yellow solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH =7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sub.2.sup.2+[Pt.sub.2(POP).sub.4].sup.4− (cf. FIG. 1), which contains [ZrO].sup.2+ as an inorganic cation and the cytostatic and green emitting anion [Pt.sub.2(POP).sub.4].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 40 nm.

[0075] Potassium pyrophosphatoplatinate (K.sub.4[Pt.sub.2(POP).sub.4)] (cf. FIG. 1) is produced according to a synthesis procedure known from the literature (cf. M. A. Filomena Dos Remedios Pinto, P. J. Sadler, S. Neidle, M. R. Sanderson, A. Subbiah, R. Kuroda, J. Chem. Soc.—Chem. Commun. 1980, 1, 13).

Embodiment 2

[ZrO].SUP.2+..SUB.2.[cisPt(AEP).SUB.2.].SUP.4−

[0076] The inorganic-organic hybrid [ZrO].sup.2+.sub.2[cisPt(AEP).sub.2].sup.4− (AEP: aminoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (52 mg) in demineralized water (5.0 ml). Solution 2 contains potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50.0 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the dark brown solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts.

[0077] Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH =7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sup.2+.sub.2[cisPt(AEP).sub.2].sup.4− (cf. FIG. 2), which contains [ZrO].sup.2+ as an inorganic cation and the cytostatic anion [cisPt(AEP).sub.2].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 30 nm.

[0078] For the preparation of potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50 mg of K.sub.2PtCl.sub.4 and 34 mg of aminoethyl phosphate (AEP) are dissolved in 10 mL water and the pH value is set to 7-10 using NaOH. The solution is heated to 50° C. for 60 min. Here, a color change from light orange to dark brown takes place. The brown product (K.sub.4[cisPt(AEP).sub.2].sup.4− (cf. FIG. 2) is then air-dried.

Embodiment 3

[Ag].SUP.+..SUB.2.[cisPt(SA).SUB.2.].SUP.2−

[0079] The inorganic-organic hybrid [Ag].sup.+.sub.2[cisPt(SA).sub.2].sup.2− (SA: succinate) is prepared by mixing two solutions. Solution 1 contains AgNO.sub.3 (12 mg) in demineralized water (0.3 ml). Solution 2 contains cis,cis,trans-diamminedichloridodisuccinatoplatinum(IV) (20.0 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the yellow solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH =7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [Ag].sup.+.sub.2[cisPt(SA).sub.2].sup.2− (cf. FIG. 3), which contains [Ag]+as an inorganic cation and the cytostatic, orange-emitting anion [cisPt(SA).sub.2].sup.2−, is obtained as amorphous nanoparticles with a diameter of about 30 nm.

[0080] Synthesis of cis-diamminedichloridoplatinum(II) (cisplatin). Modified according to a synthesis known from the literature, 166 mg of K.sub.2PtCl.sub.4, 60 mg of KCI and 124 mg of NH4OAc are dissolved in 4 mL of water. The red-orange solution is heated in the microwave to 90° C. within one minute and kept at this temperature for a further 14 minutes. Subsequently, the reaction vessel (50 mL flask) is cooled in an ice bath and 16 mL of ethanol are added to completely precipitate the yellow-orange product. The precipitate is separated off by centrifugation (10 min, 15,000 min.sup.−1). It is then extracted with 4 mL of DMF in order to separate off any platinum that may have formed (centrifugation, 10 min, 15000 min.sup.−1). The product is precipitated from the yellow solution again with four times the amount of ethanol and purified by washing with ethanol twice. After drying, it is recrystallized in 0.1 M HCl at 90° C. The yellow-orange product cis-diamminedichloridoplatinum(II) (cf. FIG. 3) crystallizes out upon cooling, is centrifuged off, washed twice with ethanol and then dried.

[0081] Synthesis of cis,cis,trans-diamminedichloridodihydroxidoplatinum(IV) (cisplatinOH). Modified according to a synthesis known from the literature, 100 mg of cisplatin are suspended in 5 mL of water and an excess of 30% H.sub.2O.sub.2 (0.6 mL) is added. The mixture is stirred with stirring for 6 h at 70° C. and then overnight at room temperature. A color change from yellow-orange to light yellow takes place. The water is removed under vacuum, the light yellow product cis, cis,trans-diamminedichloridodihydroxidoplatinum(IV) (cf. FIG. 3) is purified by washing twice with ethanol and then dried.

[0082] Synthesis of cis, cis, trans-diamminedichloridodisuccinatoplatinum(I V) (cisplatinSA). Modified according to a synthesis known from the literature, 100 mg (0.3 mmol) of cisplatinOH and 180 mg (1.8 mmol) of succinic anhydride are dissolved in 3 mL of DMSO and heated to 70° C. for 24 h with stirring. The solvent is then removed under vacuum and with heating to 50° C. Solvent residues are removed by repeatedly adding a few mL of water and then dry-drawing under vacuum. The yellow product cis,cis,trans-diamminedichloridodisuccinatoplatinum(IV) is washed with acetone and dried before further use (cf. FIG. 3).

Embodiment 4

[ZrO].SUP.2+..SUB.2.[cisPt(PAA).SUB.2.].SUP.4−

[0083] The inorganic-organic hybrid [ZrO].sup.2+.sub.2[cisPt(PAA).sub.2].sup.4− (PAA: phosphonoacetate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (21 mg) in demineralized water (0.3 ml). Solution 2 contains cis,cis,trans-diamm inedichloridodiphosphonoacetatoplatinum(IV) (20.0 mg) in dem ineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the yellow solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sup.2+.sub.2[cisPt(PAA).sub.2].sup.4− (cf. FIG. 4), which contains [ZrO]2+ as an inorganic cation and the cytostatic, orange-emitting anion [cisPt(PAA).sub.2].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 30 nm.

[0084] Synthesis of cis, cis, trans-diamminedichloridodiphosphonoacetatoplatinum(IV) (cisplatinumPAA). 100 mg of cisplatinOH and 168.0 mg of phosphonoacetic acid (PAA) are dissolved in 3 mL of DMSO and heated to 70° C. for 24 h while stirring. The solvent is then removed under vacuum and warming to 50° C. Solvent residues are removed by repeatedly adding a few mL of water and then dry-drawing under vacuum. The yellow product cis,cis,trans-diammindichloridodiphosphonoacetatoplatinum(IV) (cf. FIG. 4) is washed with acetone and dried before further use.

Embodiment 5

[HfO].SUB.2..SUP.2+.[Pt.SUB.2.(POP).SUB.4.].SUP.4−

[0085] The inorganic-organic hybrid [HfO].sub.2.sup.2+[Pt.sub.2(POP).sub.4].sup.4− (POP: pyrophosphate) is prepared by mixing two solutions. Solution 1 contains HfOCl.sub.2×nH.sub.2O (5.3 mg) in demineralized water (5.0 ml). Solution 2 contains potassium pyrophosphatoplatinate(II) (K.sub.4[Pt.sub.2(POP).sub.4)], 20,3 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the yellow solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [HfO].sub.2.sup.21Pt.sub.2(POP)41.sup.4−, which contains [HfO].sup.2+ as an inorganic cation and the cytostatic, green-emitting anion [Pt.sub.2(POP).sub.4].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 40 nm.

[0086] Potassium pyrophosphatoplatinate (K.sub.4[Pt.sub.2(POP).sub.4)] is produced according to a synthesis procedure known from the literature.

Embodiment 6

[Gd(OH)].SUP.2+.[cisPt(SA).SUB.2.].SUP.2−

[0087] The inorganic-organic hybrid [Gd(OH)].sup.2+[cisPt(SA).sub.2].sup.2− (SA: succinate) is prepared by mixing two solutions. Solution 1 contains GdCl.sub.3×6H.sub.2O (13 mg) in demineralized water (0.3 ml). Solution 2 contains cis,cis,trans-diamminedichloridodisuccinatoplatinum(IV) (20.0 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the colorless solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH =7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [Gd(OH)].sup.2[cisPt(SA).sub.2].sup.2−, which contains [Gd(OH)].sup.2+ as an inorganic cation and the cytostatic, orange-emitting anion [cisPt(SA).sub.2].sup.2−, is obtained as amorphous nanoparticles with a diameter of about 50 nm.

[0088] Synthesis of cis-diamminedichloridoplatinum(II) (cisplatin). Modified according to a synthesis known from the literature, 166 mg of K.sub.2PtCl.sub.4, 60 mg of KCl and 124 mg of NH4OAc are dissolved in 4 mL of water. The red-orange solution is heated in the microwave to 90° C. within one minute and kept at this temperature for a further 14 minutes. Subsequently, the reaction vessel (50 mL flask) is cooled in an ice bath and 16 mL of ethanol are added to completely precipitate the yellow-orange product. The precipitate is separated off by centrifugation (10 min, 15,000 min.sup.−1). It is then extracted with 4 mL of DMF in order to separate off any platinum that may have formed (centrifugation, 10 min, 15000 min.sup.−1). The product is precipitated from the yellow solution again with four times the amount of ethanol and purified by washing with ethanol twice. After drying, it is recrystallized in 0.1 M HCl at 90° C. The yellow-orange product cis-diamminedichloridoplatinum(II) crystallizes out upon cooling, is centrifuged off, washed twice with ethanol and then dried.

[0089] Synthesis of cis,cis,trans-diamminedichloridodihydroxidoplatinum(IV) (cisplatinOH). Modified according to a synthesis known from the literature, 100 mg of cisplatin are suspended in 5 mL of water and an excess of 30% H.sub.2O.sub.2 (0.6 mL) is added. The mixture is stirred with stirring for 6 h at 70° C. and then overnight at room temperature. A color change from yellow-orange to light yellow takes place. The water is removed under vacuum, the light yellow product cis, cis,trans-diamminedichloridodihydroxidoplatinum(IV) is purified by washing twice with ethanol and then dried.

Embodiment 7

[Ba].SUP.2+..SUB.2.[cisPt(AEP).SUB.2.].SUP.4−

[0090] The inorganic-organic hybrid [Ba].sup.2+.sub.2[cisPt(AEP).sub.2].sup.4− (AEP: aminoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains BaCl.sub.2×2H.sub.2O (34 mg) in demineralized water (5.0 ml). Solution 2 contains potassium cis-dichloridodiam inoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50,0 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the dark brown solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [Ba].sup.2+.sub.2[cisPt(AEP).sub.2].sup.4−, which contains Ba.sup.2+ as an inorganic cation and the cytostatic anion [cisPt(AEP).sub.2].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 30 nm.

[0091] For the preparation of potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50 mg of K.sub.2PtCl.sub.4 and 34 mg of aminoethyl phosphate (AEP) are dissolved in 10 mL water and the pH value is set to 7-10 using NaOH. The solution is heated to 50° C. for 60 min. Here, a color change from light orange to dark brown takes place. The brown product (K.sub.4[cisPt(AEP).sub.2].sup.4− is then air-dried.

Embodiment 8

[ZrO].SUP.2+..SUB.2.[(cisPt(AEP).SUB.2.).SUB.0.995.(DUT).SUB.0.005.].SUP.4−

[0092] The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sub.0.995(DUT).sub.0.0051].sup.4− (AEP: aminoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (52 mg) in demineralized water (5.0 ml). Solution 2 contains potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50.0 mg) as well as the near infrared emitting dye-modified nucleoside triphosphate DY-647-dUTP (H.sub.4(DUT), 1.0 mg, Dyomics) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the brown solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring.

[0093] Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sub.0.995(DUT).sub.0.005].sup.4−, which contains [ZrO].sup.2+ as an inorganic cation, the cytostatic anion [cisPt(AEP).sub.2].sup.4− and the infrared-emitting fluorescence dye anion [DUT].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 30 nm.

[0094] For the preparation of potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50 mg of K.sub.2PtCl.sub.4 and 34 mg of aminoethyl phosphate (AEP) are dissolved in 10 mL water and the pH value is set to 7-10 using NaOH. The solution is heated to 50° C. for 60 min. Here, a color change from light orange to dark brown takes place. The brown product (K.sub.4[cisPt(AEP).sub.2].sup.4− is then air-dried.

Embodiment 9

[ZrO].SUP.2+..SUB.2.[(cisPt(AEP).SUB.2.).SUB.0.5.(AIPCS.SUB.4.).SUB.0.5.].SUP.4−

[0095] The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sub.0.5(AlPCS.sub.4).sub.0.5].sup.4− (AEP: aminoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (52 mg) in demineralized water (5.0 ml). Solution 2 contains potassium cis-dichloridodiam inoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50.0 mg) and alum inum(III)chloride phthalocyanine tetrasulfonate (H.sub.4(AIPCS.sub.4), 72 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the dark brown solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts.

[0096] Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sub.0.5(AIPCS.sub.4).sub.0.5].sup.4−, which contains [ZrO].sup.2+ as an inorganic cation, the cytostatic anion [cisPt(AEP).sub.2].sup.4− and the photo-active and red-emitting active ingredient anion [AIPCS.sub.4].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 40 nm.

[0097] For the preparation of potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50 mg of K.sub.2PtCl.sub.4 and 34 mg of aminoethyl phosphate (AEP) are dissolved in 10 mL water and the pH value is set to 7-10 using NaOH. The solution is heated to 50° C. for 60 min. Here, a color change from light orange to dark brown takes place. The brown product (K.sub.4[cisPt(AEP).sub.2].sup.4− is then air-dried.

Embodiment 10

[ZrO].SUB.2..SUP.2.+[(Pt.SUB.2.(POP).SUB.4.).SUB.0.5.(cisPt(AEP).SUB.2.).SUB.0.5.].SUP.4−

[0098] The inorganic-organic hybrid [ZrO].sub.2.sup.2+[(Pt.sub.2(POP).sub.4).sub.0.5(cisPt(AEP).sub.2).sub.0.5].sup.4− (POP: pyrophosphate, AEP: aminoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (52 mg) in demineralized water (5.0 ml). Solution 2 contains potassium pyrophosphatoplatinate(II) (K.sub.4[Pt.sub.2(POP).sub.4)], 80.0 mg) and potassium cis-dichloridodiam inoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 25.0 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the yellow solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts.

[0099] Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sub.2.sup.2+[(Pt.sub.2(POP).sub.4).sub.0.5(cisPt(AEP).sub.2).sub.0.5].sup.4−, which contains [ZrO].sup.2+as an inorganic cation, the cytostatic and green-emitting anion [Pt.sub.2(POP).sub.4].sup.4− and the cytostatic anion [cisPt(AEP).sub.2].sup.4−, is obtained as amorphous nanoparticles with a diameter of about 40 nm.

[0100] Potassium pyrophosphatoplatinate (K.sub.4[Pt.sub.2(POP).sub.4)] is produced according to a synthesis procedure known from the literature.

[0101] For the preparation of potassium cis-dichloridodiaminoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50 mg of K.sub.2PtCl.sub.4 and 34 mg of aminoethyl phosphate (AEP) are dissolved in 10 mL water and the pH value is set to 7-10 using NaOH. The solution is heated to 50° C. for 60 min. Here, a color change from light orange to dark brown takes place. The brown product (K.sub.4[cisPt(AEP).sub.2].sup.4− is then air-dried.

Embodiment 11

[ZrO].SUP.2+..SUB.2.[(cisPt(AEP).SUB.2.).SUP.4−..SUB.0.5.(BMP).SUP.2−..SUB.1.0.].SUP.4−

[0102] The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sup.4−.sub.0.5(BMP).sup.2−.sub.1.0].sup.4− (AEP: am inoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (52 mg) in demineralized water (5.0 ml). Solution 2 contains potassium cis-dichloridodiam inoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50.0 mg) and sodium betamethasone phosphate (Na.sub.2(BMP), 129 mg) in demineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the dark brown solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sup.4−.sub.0.5(BMP).sup.2−.sub.1.0].sup.4−, which contains [ZrO].sup.2+ as an inorganic cation, the cytostatic anion [cisPt(AEP).sub.2].sup.4− and the glucocorticoid anion [BMP].sup.2−, is obtained as amorphous nanoparticles with a diameter of about 50 nm.

Embodiment 12

[ZrO].SUP.2+..SUB.2.[(cisPt(AEP).SUB.2.).SUB.0.5.(FdUMP).SUB.1.0.].SUP.4−

[0103] The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sub.0.5(FdUMP).sub.1.0].sup.4− (AEP: aminoethyl phosphate) is prepared by mixing two solutions. Solution 1 contains ZrOCl.sub.2×8H.sub.2O (52 mg) in demineralized water (5.0 ml). Solution 2 contains potassium cis-dichloridodiam inoethylphosphatoplatinate(II) (K.sub.4[cisPt(AEP).sub.2].sup.4−, 50.0 mg) and sodium-5′-fluoro-2′-deoxyuridine-5′-monophosphate (Na.sub.2(FdUMP), 82 mg) in dem ineralized water (50 ml). Solution 2 was heated to 50° C. and stirred powerfully (about 1000 min.sup.−1). Solution 1 was then injected quickly with a syringe with intensive stirring. After stirring for two minutes, the dark brown solid is separated off by centrifugation (15 min at 22,500 min.sup.−1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove any remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively, the centrifugate is resuspended in demineralized water (3.1 ml). A solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O) is subsequently dripped into this suspension with stirring. Alternatively, the nanoparticles can be redispersed in demineralized water only. In all cases, the demineralized water used is made free of dust and germs using a sterile syringe filter (PA, 0.20 μm) in advance prior to use. The inorganic-organic hybrid [ZrO].sup.2+.sub.2[(cisPt(AEP).sub.2).sub.0.5(FdUMP).sub.1.0].sup.4−, which contains [ZrO].sup.2+ as an inorganic cation and the cytostatic anions [cisPt(AEP).sub.2].sup.4− and [FdUMP].sup.2−, is obtained as amorphous nanoparticles with a diameter of about 40 nm.