WO2014121819A1 - Folate functionalized nanodiamond particles, method for its preparation and their use - Google Patents
Folate functionalized nanodiamond particles, method for its preparation and their use Download PDFInfo
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- WO2014121819A1 WO2014121819A1 PCT/EP2013/052261 EP2013052261W WO2014121819A1 WO 2014121819 A1 WO2014121819 A1 WO 2014121819A1 EP 2013052261 W EP2013052261 W EP 2013052261W WO 2014121819 A1 WO2014121819 A1 WO 2014121819A1
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- nanodiamond particles
- folate
- nanodiamond
- particles
- modified
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- 239000002245 particle Substances 0.000 title claims abstract description 77
- 239000002113 nanodiamond Substances 0.000 title claims abstract description 74
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims abstract description 61
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 51
- 239000011724 folic acid Substances 0.000 title claims abstract description 46
- 229940014144 folate Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title description 3
- 229960000304 folic acid Drugs 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000010432 diamond Substances 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 150000002224 folic acids Chemical class 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 9
- 229910003460 diamond Inorganic materials 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000003550 marker Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000005119 centrifugation Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052804 chromium Inorganic materials 0.000 claims description 4
- 239000011651 chromium Substances 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 150000002739 metals Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000006385 ozonation reaction Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- 210000004881 tumor cell Anatomy 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 229910052748 manganese Inorganic materials 0.000 claims description 3
- 239000011572 manganese Substances 0.000 claims description 3
- FIDRAVVQGKNYQK-UHFFFAOYSA-N 1,2,3,4-tetrahydrotriazine Chemical compound C1NNNC=C1 FIDRAVVQGKNYQK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical group 0.000 claims description 2
- 230000001588 bifunctional effect Effects 0.000 claims description 2
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical class [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 claims description 2
- 238000005474 detonation Methods 0.000 claims description 2
- 239000000975 dye Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- DPLOGSUBQDREOU-UHFFFAOYSA-N tert-butyl n-(5-aminopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCN DPLOGSUBQDREOU-UHFFFAOYSA-N 0.000 claims description 2
- OCUICOFGFQENAS-UHFFFAOYSA-N tert-butyl n-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOCCOCCN OCUICOFGFQENAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 1
- POHWAQLZBIMPRN-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCN POHWAQLZBIMPRN-UHFFFAOYSA-N 0.000 claims 1
- RVZPDKXEHIRFPM-UHFFFAOYSA-N tert-butyl n-(6-aminohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCCN RVZPDKXEHIRFPM-UHFFFAOYSA-N 0.000 claims 1
- 238000003384 imaging method Methods 0.000 abstract description 4
- 239000002105 nanoparticle Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013049 sediment Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 238000004061 bleaching Methods 0.000 description 2
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 2
- 229960005286 carbaryl Drugs 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000000695 excitation spectrum Methods 0.000 description 2
- 102000006815 folate receptor Human genes 0.000 description 2
- 108020005243 folate receptor Proteins 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 1
- 241001598984 Bromius obscurus Species 0.000 description 1
- 206010056740 Genital discharge Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 244000292604 Salvia columbariae Species 0.000 description 1
- 235000012377 Salvia columbariae var. columbariae Nutrition 0.000 description 1
- 235000001498 Salvia hispanica Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000009739 binding Methods 0.000 description 1
- 230000036782 biological activation Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 235000014167 chia Nutrition 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- HDIHOAXFFROQHR-UHFFFAOYSA-M n-(6-aminohexyl)carbamate Chemical compound NCCCCCCNC([O-])=O HDIHOAXFFROQHR-UHFFFAOYSA-M 0.000 description 1
- 150000004767 nitrides Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54346—Nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention refers to a method for preparing folate functionalized nanodiamond particles in which the nanodiamond particles are coupled with a folate linker.
- Such nano-particles are used in the field of biomedicine for selective delivery to active proliferated cells for their imaging and tracking in nano-scale range.
- Nano-diamonds are imagining as new and promising cellular biomarkers with high potential. It is known from the prior art that nano-diamond particles have a suitable surface for biological activation and functionalization (J. Opitz, A. Pohl, J. Schreiber, M. Mkandawire, U. Krause-Buchhoiz, G. Roedel, W. Pompe, T. Gubarevich, V.
- the cell- membrane folate receptor is a potential molecular target for tumor selective drug delivery, including various folate-chelate conjugates for diagnostic imaging (US 7, 598, 335).
- nanodiamond particles with the features of claim 1 and nanodiamond particles with the features of claim 11 are provided.
- Claim 15 a use according to the present invention are described.
- a method for preparing folate functionalized nanodiamond particles comprising the following steps:
- the nanodiamond particles are provided by detonation of 2- methyl-l,3,5-trinitrobenzene (TNT) and l,3,5-trinitroper-hydro-l,3,5-triazine (RDX).
- TNT 2- methyl-l,3,5-trinitrobenzene
- RDX l,3,5-trinitroper-hydro-l,3,5-triazine
- the Afunctional linker preferably and amine, more preferably selected from the group consisting of N-tert-butoxycarbonyl-l,6-hexane-diamine, tert-butyi N-(6- aminohexyl)-carbamate, tert-butyl N-(5-aminopentyl)-carbamate, tert-butyl N-(3- aminopropyi)-carbamate, tert-butyl N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)- carbamate, and its mixtures.
- the coupling of the at least one folate with the Afunctional linker is performed by the following steps: - providing a suspension of the at least one folate in an organic solvent, preferably selected from the group consisting of dimethylsulfoxide, pyridine, dimethyl formamide and its mixtures,
- nanodiamond particles are ozonised by the following steps: providing a suspension of the nanodiamond particles in an alkaline water solution, preferably comprising sodium hydroxide, - feeding ozone into the solution, acidulation of the solution, preferably by adding hydrochloric acid, and isolating the modified nanodiamond particles by centrifugation.
- the nanodiamond particles are oxidised by liquid phase oxidation, preferably with organic acids, inorganic acids, potassium permanganate, manganese dioxide, chromium (VI) compounds, halogens and its compounds, dimethyl sulfoxide, and its mixtures, and/or by gas phase oxidation, pref- erably a mixture of 0 2 + N 2 (4 -20% 0 2 ), C0 2 +K 2 C0 3 , H 2 0 +K 2 C0 3 and/or 0 3 .
- the folate are preferably selected from the group consisting of folic acid, folic acid modified by l-ethyl-3-(3-dimethy!amino-propyl)-carboimide and N ' -hydroxy- succinimide.
- the nanodiamond particles can be provided as a polydispersion of single nanodiamond particles and its aggregates. It is further preferred that at least a part of the nanodiamond particles comprise optically active structures, preferably nitrogen vacancy centres in the core of diamond particles and various fluorescence species in the diamond shell, preferably admixtures of metals Cu, Ti, Cr, Si, Zn, AL, M n, Fe and their compounds as oxides, oxy- organic compounds and salts.
- nanodiamond particles with a functionalized surface comprising at least one folate are provided.
- Such particle is conjugated with the folates via a chemical bonding wherein the density of the folate groups is at least one group per particle.
- the nanodiamortd particles comprise optically active structures which are located on the surface and/or within the core of the particles, preferably nitrogen vacancy centres in the core of diamond particles or various fluorescence species in the diamond shell, preferably admixtures of metals Cu, Ti, Cr, Si, Zn, AL, Mn, Fe and their compounds as oxides, oxy- organic compounds and salts or modified by fluorescence organic dyes on surface shell.
- the nanodiamond particles are preferably polycrystalline and/or microcrystalline.
- Nanodiamond particles according to the present invention can be used as fluorescent marker for cells, in particular tumor cells, or as fluorescent tracking marker in tumor cells and active-proliferated cells.
- These particles can be used as a nanoscale biomarker for cancer or chronic inflammatory diseases or as tracking imaging agent, e.g. to visualize the process of cancer tumors.
- the present invention uses raw of the unique features of nanodiamond particles, including the nanoscale sizing, large chemically active surface area to mass ratio, surface modification, long-term photo stability, and fluorescence blinking and bleaching.
- the present invention uses the fluorescence of the nanodiamond particles conjugated with the folate.
- the visualization of the nanodiamond particles can be done by fluorescence provided from nanodiamond particles or their aggregates.
- the selective imaging of cancer or inflammatory cells is realized by the folate func- tionalized nanodiamond particles. It is an advantage of the present invention that the long-term imaging and tracking incomp!ex cellular cancer or inflammatory envi- ronments can be improved due to the exceptionally photostability without photo- bleaching and photoblinking of the inventive nanodiamond particles.
- the own fluorescence properties of the nanodiamond particles enables the visualization of cancer cells and the folate enables the selective delivery of the particles to the cancer cells.
- Fig. 1 shows fluorescence excitation spectra of ultradispurse diamonds (UDD)for different wavelengths.
- Fig. 2a and 2b show structural setup of the nanodiamond particles coupled with the folates. The synthesis of these structures is carried out in three stages:
- Fig, 3 shows spectra of fluorescence excitation for folic acid, nanodiamond particles and nanodiamond particles coupled with folic acid.
- Ultradisperse diamonds obtained by explosive synthesis are known to be elementary particles with the size of 4-6 nm and surrounded by the coating of various non-diamond forms of carbon.
- carboxyl group situated on the UDD particle.
- UDD cleaned by the method ⁇ method of back titration contains one carboxyl group for 5000-6000 carbon units, that is, in our opinion, is not effective at conjugate synthesis.
- the increasing content of carboxyl groups can be made by additional oxidation of lower degrees of carbon as hydroxyl, carbonyl and isolated double bindings; and also thanks to hidden forms of carboxy!
- Ozonization of UDD suspension with the concentration of 5 g per 1 liter of water was made on the set-up for obtaining ozone with the flow speed of 10-15 ml per second and content of ozone in gas mixture of 3-5 %.
- the ozone was obtained of air mixture, cleaned by series connection of Tischenko bottles: starting with the concentrated sulfuric acid and then with dry granulated caustic soda.
- 0.1 g of caustic soda was added and while mixing through the bubble tube there was passing the current of ozone for 2 hours ⁇ excess is more than in 300 times). Additional oxidation was made by adding 30 ml of 30% hydrogen peroxide and holing the mixture during 1 hour.
- ND-FA complex is fine-dispersed dry powder of grayish-yellow color with the characteristic spectral properties.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Medicinal Chemistry (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Carbon And Carbon Compounds (AREA)
Abstract
The present invention refers to a method for preparing folate functionaltzed nanodiamond particles in which the nanodiamond particles are coupled with a folate linker. Such nanoparticles are used in the field of biomedicine for selective delivery to active proliferated cells for their imaging and tracking in nano-scale range.
Description
Folate functionalized nanodiamond particles,
method for its preparation and their use
The present invention refers to a method for preparing folate functionalized nanodiamond particles in which the nanodiamond particles are coupled with a folate linker. Such nano-particles are used in the field of biomedicine for selective delivery to active proliferated cells for their imaging and tracking in nano-scale range.
Nano-diamonds are imagining as new and promising cellular biomarkers with high potential. It is known from the prior art that nano-diamond particles have a suitable surface for biological activation and functionalization (J. Opitz, A. Pohl, J. Schreiber, M. Mkandawire, U. Krause-Buchhoiz, G. Roedel, W. Pompe, T. Gubarevich, V.
Lapina, Nanodiamonds - a new quantum dot material and its possible applications in biology, VDI-Berichte Nr 2027, 105-110, 2008 and M. Mkandawire, A. Pohl, T. Gubarevich, V. Lapina, D. Appelhans, G. Roedel, J. Schreiber, J. Opitz; Selective targeting of green fluorescent nanodiamond conjugates to mitochondria in HeLa Cells, Biophotonics 2, No. 10, 596-606 (2009), J. Opitz, M. Mkandawire, M. Sorge, N. Rose, M. Rudolph, P. Krueger, 1. Hannstein, V. Lapina, D. Appelhans, W. Pompe, J.
Schreiber, G. Roedel; Green fluorescent nanodiamond conjugates and their possible applications for biosensing, Proceedings of SPIE 7754-7768, 2010).
The Application of nano-diamond particles as light scattering labels and luminescent optical marker has been reported in Yuen Yung Hui, Chia -Liang Cheng and Huan- Cheng Chang,„Nanodiamonds for optical bioimaging", J.Phys. D: Appl.Phys. V.43, N.37., p.4021.2010.
Moreover, it is known that the vitamin folic acid has been extensively investigated for targeting various cancer cells, including ovary, kidney, uterus, testis, brain, colon, lung, and myelocytic blood that overexpress folic acid receptors. The cell- membrane folate receptor is a potential molecular target for tumor selective drug delivery, including various folate-chelate conjugates for diagnostic imaging (US 7, 598, 335).
Though different applications for the use of nanodiamond particles as optical marker are known there is still a need for optical markers with improved long-term photostability.
It was therefore the object of the present invention to provide nanodiamond particles with a high photostability which are easy to prepare.
For solving this problem, the method for preparing folate functionalized
nanodiamond particles with the features of claim 1 and nanodiamond particles with the features of claim 11 are provided. In Claim 15, a use according to the present invention are described.
According to the present invention a method for preparing folate functionalized nanodiamond particles is provided comprising the following steps:
- providing nanodiamond particles,
- modifying the nanodiamond particles with carboxyi groups by oxidation or ozonization to increase the number of reactive groups at its surface,
- coupling at least one folate with a bifunctional linker which is linkable to the carbon groups of the nanodiamond surface and to the folate, wherein one functionality of the biofunctional linker is blocked by a protective group, and
- reacting the modified folate with the modified nanodiamond particles.
It is preferred that the nanodiamond particles are provided by detonation of 2- methyl-l,3,5-trinitrobenzene (TNT) and l,3,5-trinitroper-hydro-l,3,5-triazine (RDX).
The Afunctional linker preferably and amine, more preferably selected from the group consisting of N-tert-butoxycarbonyl-l,6-hexane-diamine, tert-butyi N-(6- aminohexyl)-carbamate, tert-butyl N-(5-aminopentyl)-carbamate, tert-butyl N-(3- aminopropyi)-carbamate, tert-butyl N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)- carbamate, and its mixtures.
In a preferred embodiment the coupling of the at least one folate with the Afunctional linker is performed by the following steps: - providing a suspension of the at least one folate in an organic solvent, preferably selected from the group consisting of dimethylsulfoxide, pyridine, dimethyl formamide and its mixtures,
- adding the linker having a protective group to the solvent,
- eliminating the protective group, and
- purifying the modified folate. It is preferred that nanodiamond particles are ozonised by the following steps: providing a suspension of the nanodiamond particles in an alkaline water solution, preferably comprising sodium hydroxide, - feeding ozone into the solution, acidulation of the solution, preferably by adding hydrochloric acid, and isolating the modified nanodiamond particles by centrifugation.
In a further preferred embodiment the nanodiamond particles are oxidised by liquid phase oxidation, preferably with organic acids, inorganic acids, potassium permanganate, manganese dioxide, chromium (VI) compounds, halogens and its compounds, dimethyl sulfoxide, and its mixtures, and/or by gas phase oxidation, pref- erably a mixture of 02 + N2 (4 -20% 02), C02 +K2C03, H20 +K2C03 and/or 03.
It is further preferred that in step {d): the modified nanodiamond particles are activated with 1,1- carbonyldiimidazol, the activated nanodiamond particles are reacted with the modified folates in an organic solvent, and the folate functionalized nanodiamond particles are purified by centrifuga- tion.
The folate are preferably selected from the group consisting of folic acid, folic acid modified by l-ethyl-3-(3-dimethy!amino-propyl)-carboimide and N'-hydroxy- succinimide.
The nanodiamond particles can be provided as a polydispersion of single nanodiamond particles and its aggregates. It is further preferred that at least a part of the nanodiamond particles comprise optically active structures, preferably nitrogen vacancy centres in the core of diamond particles and various fluorescence species in the diamond shell, preferably admixtures of metals Cu, Ti, Cr, Si, Zn, AL, M n, Fe and their compounds as oxides, oxy- organic compounds and salts.
According to the present invention also nanodiamond particles with a functionalized surface comprising at least one folate are provided. Such particle is conjugated with the folates via a chemical bonding wherein the density of the folate groups is at least one group per particle.
It is further preferred that the nanodiamortd particles comprise optically active structures which are located on the surface and/or within the core of the particles, preferably nitrogen vacancy centres in the core of diamond particles or various fluorescence species in the diamond shell, preferably admixtures of metals Cu, Ti, Cr, Si, Zn, AL, Mn, Fe and their compounds as oxides, oxy- organic compounds and salts or modified by fluorescence organic dyes on surface shell.
The nanodiamond particles are preferably polycrystalline and/or microcrystalline.
Nanodiamond particles according to the present invention can be used as fluorescent marker for cells, in particular tumor cells, or as fluorescent tracking marker in tumor cells and active-proliferated cells.
These particles can be used as a nanoscale biomarker for cancer or chronic inflammatory diseases or as tracking imaging agent, e.g. to visualize the process of cancer tumors.
The present invention uses raw of the unique features of nanodiamond particles, including the nanoscale sizing, large chemically active surface area to mass ratio, surface modification, long-term photo stability, and fluorescence blinking and bleaching.
The present invention uses the fluorescence of the nanodiamond particles conjugated with the folate. The visualization of the nanodiamond particles can be done by fluorescence provided from nanodiamond particles or their aggregates.
The selective imaging of cancer or inflammatory cells is realized by the folate func- tionalized nanodiamond particles. It is an advantage of the present invention that the long-term imaging and tracking incomp!ex cellular cancer or inflammatory envi- ronments can be improved due to the exceptionally photostability without photo- bleaching and photoblinking of the inventive nanodiamond particles. The own fluorescence properties of the nanodiamond particles enables the visualization of cancer cells and the folate enables the selective delivery of the particles to the cancer cells.
The present invention is explained in more detail with the reference to the following examples and figures. However, it has to be noted that these are only specific embodiments which do not limit the invention as claimed. Fig. 1 shows fluorescence excitation spectra of ultradispurse diamonds (UDD)for different wavelengths.
It can be seen from the spectra that UDD water suspension reveals a number of fluorescent centers with different characteristics. Various position of λ max. fluores- cence from 360 up to 540 nm. The fluorescence excitation spectrum practically coincides for 'blue' and 'red' diamonds.
Fig. 2a and 2b show structural setup of the nanodiamond particles coupled with the folates. The synthesis of these structures is carried out in three stages:
1) . Connection of FA carboxyl group with a one amino group of the linker.
2) . Activation of carboxy! group of UDD by N-hydroxysuccinimide.
3) . Reaction of activated UDA with another group of the linker. Fig, 3 shows spectra of fluorescence excitation for folic acid, nanodiamond particles and nanodiamond particles coupled with folic acid.
It can be seen from spectra that obtained conjugate ND-FA has new own fluorescent centers with λ max. fluorescence excitation under 330 nm.
Example 1
Preparation of nanodiamonds to the synthesis of conjugate Ultradisperse diamonds (UDD) obtained by explosive synthesis are known to be elementary particles with the size of 4-6 nm and surrounded by the coating of various non-diamond forms of carbon. For bench mark of functionaltzation of UDD of folic acid we propose to use carboxyl group situated on the UDD particle. UDD cleaned by the method {method of back titration) contains one carboxyl group for 5000-6000 carbon units, that is, in our opinion, is not effective at conjugate synthesis. The increasing content of carboxyl groups can be made by additional oxidation of lower degrees of carbon as hydroxyl, carbonyl and isolated double bindings; and
also thanks to hidden forms of carboxy! as complex ethers, amides, nitrides. Due to the last argument we have used the method of ozonolization of Sp2 hybridized atom of carbon of the UDD surface in water-alkaline medium. The use of sodium hydroxide as a medium allows one to oxidize the appearing ozonid till carboxyl group and hydrolyze complex-ether groups till carboxyl group. Further stage is aciduiation of
UDD suspension by the solution of hydrochloric acid to pH=2-6 with the following centrifugation and up to ten / water cleaning. The process described above allowed one to increase the content of carboxyl groups in 2-3 times. Example 2
Ozonization of UDD suspension.
Ozonization of UDD suspension with the concentration of 5 g per 1 liter of water was made on the set-up for obtaining ozone with the flow speed of 10-15 ml per second and content of ozone in gas mixture of 3-5 %. The ozone was obtained of air mixture, cleaned by series connection of Tischenko bottles: starting with the concentrated sulfuric acid and then with dry granulated caustic soda. To the suspension of UDD, 0.1 g of caustic soda was added and while mixing through the bubble tube there was passing the current of ozone for 2 hours {excess is more than in 300 times). Additional oxidation was made by adding 30 ml of 30% hydrogen peroxide and holing the mixture during 1 hour. Then 10% hydrochloric acid was added up to receiving acid reaction and it was also hold during 1 hour. The upper transparent layer was decanted carefully and lower one was sent to centrifuging with the following water washing for 8-10 times. The remains of water were eliminated by double washing by dioxane. After drying for 24 hours at room temperature, the content of carboxyl groups was determined by the method described above. The molecular weight (without sorptive water) was within the limits of 1300-1560 (depending of various tests). Example 3
Synthesis of the nanodiamond particles-folic acid complex has been made in 3 stages according to the following scheme: 1. Addition of spacer of N-Boc-1,6- diamtnohexan (where, N-Boc = tret- butoxycarbontl) to folic acid (FA). 2. Elimination of protection (N-Boc) from aminogroups. 3. Activation of carbonyl group in nanodiamond and joint of FA.
1. Synthesis of y-[tertbuty!-N-(aminohexyl)carbomate] of folic acid (I)
To the suspension of folic acid (0.805 g, 1.83 miliimo!e) in a mixture of waterless dimethy!sulfoxide(DMSO) (30 ml) and pyridine (15 ml), N-Boc-l,6-diaminohexane
(0.44 g; 2.02 millimole) and dicyclohexylcarbodiimide (DCC) (0.949 g, 4.6 millimole) was added and mixed on the magnetic mixer in the atmosphere of nitrogen for 18 hours at room temperature. Subsequently the reaction mixture was filtered, and anhydrous diethyl ether (0.5 liter) cooled up to 0°C was added to the filtrate while mixing. Deposited yellow crystals were filtered and washed with diethyl ether and then dried under vacuum. The product output is 0.5 g (95%). In the result of the reaction there has been obtained y-[tertbuty!-l\l-(aminohexyl)carbomate) of folic acid (FA-AMH - BOC, I). NMR spectrum of FA-AMH-BOC: NMR spectrum. IDvlP Ή, (,lWCO-d6): 011,49 (br s,
1 H), 7,82 (br t,lH, NH),7,65 (d,j =8.8Hz) 6,93 (Br t, 1 Η,ΝΗ), 6,74 (Br n 1 H, NH), 6,63 (d,j=8.8 HZ,2H), 4,49(d,j=5.6 Hz, 2H), 4.36-4.23 (m, 1 H), 3.01 (td, j=6.0,6.0 Hz, 2 H), 2.88 (d,j=6.4 Hz, 2H), 2.29-2.15 (m,2H), 1.98-1 .82 (m, 2H), 1 .41-1.16 (m, 8H), 1.36 (s, 9H).
2. Synthesis of y-(6-aminohexyl) of folic acid (II)
To the junction I (0.995g, 0.38 milltmole) trifluoroacetic acid (TFA) (8 ml) was added and mixed on the magnetic mixer at the room temperature for 2 hours. TFA was eliminated from reaction mixture at high vacuum on the rotary evaporator. The obtained sediment was dissolved in anhydrous dimethylformamide (DMFA). Anhydrous pyridine was added drop to the obtained solution by drop up to setting of yellow sediment. After filtration, the sediment was washed with ether and dried under vacuum. The product output is 0.84 g (99 %). In the result of the reaction y- (6-aminohexy!) of folic acid (FA-AMH) has been obtained.
NMR spectrum of FA-AMH-BOC: NMR spectrum Ή, (.D;MCO d6): 88.65 (s, 1 H), 7.96 (m, 1 H, NH), 7.84 (m, 1 H, NH), 7.73 (m, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.32 (br s, 1 H),6.64 (d, J = 7.6 Hz, 2H), 4.50 (s, 2H), 4.38-4.24 (m, 1 H), 3.04 (br td, 2H), 2.77 (m, 2H), 2.38 - 1.77 (m, 4H), 1.73 - 1.16 (m, 8H).
3. Synthesis of complex of nanodiamond-[y-(6-aminohexYl) folic acid]
For elimination of residual moisture, powder of nanodiamonds (50 mg) was crushed thoroughly in agate mortar and placed into a round-bottom flask with the capacity of 50 mt. Subsequently, 30 ml of anhydrous toluene was added and left for 1 hour. The toluene was removed by distillation and the product was dried under vacuum. In the atmosphere of nitrogen, 30 ml of anhydrous dimethylsulfoxide and 25 mg of 1,1-carbonyldiimidazol were added into the dried nanodiamonds and mixed for 10 minutes on the magnetic stirrer. The junction I! (60 mg) in the mixture of anhydrous DMSO (4.0 ml) and pyridine (2.4 ml) was added to the reaction flask and mixed for 24 hours. After mixing for 24 hours, 80 ml of anhydrous diethyl ether cooled up to 0°C was added to the reaction mixture. Light-yellow sediment was centrifugated and washed consequently by diethyl ether, dichloromethane and water. DMSO was added to the dried sediment and for 10 minutes processed by ultrasound and centrifugated at 4 000 g. The sediment was marked as ND-FA complex and studied by spectrophotometry methods. The obtained ND-FA complex is fine-dispersed dry powder of grayish-yellow color with the characteristic spectral properties.
Claims
1. Method for preparing folate functionalized nanodiamond particles with the following steps: a) providing nanodiamond particles, b) modifying the nanodiamond particles with carboxyl groups by oxidation or ozonization to increase the number of reactive groups at its surface, c) coupling at least one folate with a Afunctional linker which is linkable to the carbon groups of the nanodiamond surface and to the folate, wherein one functionality of the binfunc- tional linker is blocked by a protective group, and d) reacting the modified folate with the modified nanodiamond particles.
2. Method of claim 1,
characterised in that the nanodiamond particles are provided by detonation of 2-methyl-l,3,5-trinitrobenzene (TNT) and 1,3,5-trinitroper- hydro-l,3,5-triazine (RDX).
3. Method of any of the preceding claims,
characterised in that the bifunctional linker is an amine, preferably selected of the group consisting of N-tert- butoxycarbonyl-l,6-hexane-diamine, tert-butyl N-(6-aminohexyl)- carbamate, tert-butyl N-(5-aminopentyl)-carbamate, tert-butyl N-(3- aminopropyl)-carbamate, tert-butyl N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)carbamate, and its mixtures.
4. Method of any of the preceding claims,
characterised in that the coupling of the at least one folate with the bi- functional linker is performed by
- providing a suspension of the at least one folate in an organic solvent, preferably selected from the group consisting of di- methylsulfoxide, pyridine, dimethyl formamide and its mixtures,
- adding the linker having a protective group to the solvent,
- eliminating the protective group, and
- purifying the modified folate.
5. Method of any of the preceding claims,
characterised in that the nanodiamond particles are ozonised by
- providing a suspension of the nanodiamond particles in an alkaline water solution, preferably comprising sodium hydroxide,
- feeding ozone into the solution,
- acidulation of the solution, preferably by adding hydrochloric acid, and
- isolating the modified nanodiamond particles by centrifugation.
6. Method of any of the preceding claims,
characterised in that the nanodiamond particles are oxidised by liquid phase oxidation, preferably with organic acids, inorganic acids, potassium permanganate, manganese dioxide, chromium (VI) compounds, halogens and its compounds, dimethyl sulfoxide, and its mixtures, and/or by gas phase oxidation, preferably a mixture of 02 + N2 {4 -20% 02), C02 +K2C03, H20 + 2CO3 and/or 03-
7. Method of any of the preceding claims,
characterised in that in step d)
~ the modified nanodiamond particles are activated with 1,1- carbonyldtimidazol,
- the activated nanodiamond particles are reacted with the modified folates in an organic solvent, and
- the folate functionalized nanodiamond particles are purified by centrifugation.
Method of any of the preceding claims,
characterised in that the folates are selected from the group consisting of folic acid, folic acid modified by l-ethyl-3-(3-dimethylamino-propyl)- carboimide and N'-hydroxysuccinitnide.
Method of any of the preceding claims,
characterised in that the nanodiamond particles are provided as a polydispersion of single nanodiamond particles and its aggregates.
Method of any of the preceding claims,
characterised in that at least a part of the nanodiamond particles comprise optically active structures, preferably nitrogen vacancy centres in the core of diamond particles and various fluorescence species in the diamond shell, preferably admixtures of metals Cu, Ti, Cr, Si, Zn, AL, Mn, Fe and their compounds as oxides, oxy- organic compounds and salts.
Nanodiamond particle with a functionalized surface comprising at least one folate wherein the particle is conjugated with the folates via a chemical bonding,
characterized in that the density of the folate groups is at least one group per particle.
12. Nanodiamond particle of claim 11,
characterised in that the nanodiamond particles comprise optically active structures which are located on the surface and/or within the core of the particles, preferably nitrogen vacancy centres in the core of diamond particles or various fluorescence species in the diamond shell, preferably admixtures of metals Cu; Ti, Cr, Si, Zn, AL, Mn, Fe and their compounds as oxides, oxy- organic compounds and salts or modified by fluorescence organic dyes on surface shell.
13. Nanodiamond particle of claim 11 or 12,
characterised in that the nanodiamond particles are polycrystalline and/or microcrystalline.
14. Nanodiamond particles of claim and prepared by the method of any of the claims l to 10.
15. Use of nanodiamond particles of any of the claims 11 to 14 as fluorescent marker for cells, in particular tumor cells, or as fluorescent tracking marker in tumor cells and active-proliferated cells.
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| EP3987313A4 (en) * | 2019-06-18 | 2023-10-18 | Debina Diagnostics, Inc. | Compositions and articles comprising (nano)diamond particles |
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