WO2016088137A2 - A novel process for the synthesis of boron enriched magnetic nanoparticles - Google Patents
A novel process for the synthesis of boron enriched magnetic nanoparticles Download PDFInfo
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- WO2016088137A2 WO2016088137A2 PCT/IN2015/050180 IN2015050180W WO2016088137A2 WO 2016088137 A2 WO2016088137 A2 WO 2016088137A2 IN 2015050180 W IN2015050180 W IN 2015050180W WO 2016088137 A2 WO2016088137 A2 WO 2016088137A2
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- magnetic nanoparticles
- carborane
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- novel process
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- 239000002122 magnetic nanoparticle Substances 0.000 title claims abstract description 91
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims description 41
- 230000015572 biosynthetic process Effects 0.000 title claims description 20
- 238000003786 synthesis reaction Methods 0.000 title claims description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 o-carborane aldehyde Chemical class 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 claims abstract description 9
- KSCAZPYHLGGNPZ-UHFFFAOYSA-N 3-chloropropyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)CCCCl KSCAZPYHLGGNPZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims abstract description 7
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims abstract description 6
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 5
- 231100000324 minimal toxicity Toxicity 0.000 claims abstract description 4
- 238000012925 biological evaluation Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 10
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 10
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- GJLPUBMCTFOXHD-UPHRSURJSA-N (11z)-1$l^{2},2$l^{2},3$l^{2},4$l^{2},5$l^{2},6$l^{2},7$l^{2},8$l^{2},9$l^{2},10$l^{2}-decaboracyclododec-11-ene Chemical class [B]1[B][B][B][B][B]\C=C/[B][B][B][B]1 GJLPUBMCTFOXHD-UPHRSURJSA-N 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 229910001868 water Inorganic materials 0.000 claims description 7
- IAKBOYWEIQDJFI-UHFFFAOYSA-N [B]1[B][B][B][B][B][B][B][B]C2(C)C1[B]2 Chemical compound [B]1[B][B][B][B][B][B][B][B]C2(C)C1[B]2 IAKBOYWEIQDJFI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000012512 characterization method Methods 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000006249 magnetic particle Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000000975 co-precipitation Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000002114 nanocomposite Substances 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000000921 elemental analysis Methods 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 239000000696 magnetic material Substances 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 238000001035 drying Methods 0.000 claims 5
- 238000005406 washing Methods 0.000 claims 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 3
- 238000001914 filtration Methods 0.000 claims 3
- 239000002262 Schiff base Substances 0.000 claims 2
- 150000004753 Schiff bases Chemical class 0.000 claims 2
- 238000009835 boiling Methods 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 claims 2
- 238000010792 warming Methods 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 1
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 238000012306 spectroscopic technique Methods 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- 239000002105 nanoparticle Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000002082 metal nanoparticle Substances 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G49/00—Compounds of iron
- C01G49/02—Oxides; Hydroxides
- C01G49/08—Ferroso-ferric oxide [Fe3O4]
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/42—Magnetic properties
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
- C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
- C09C1/22—Compounds of iron
- C09C1/24—Oxides of iron
Definitions
- This invention relates to a novel process for the synthesis of boron enriched magnetic nanoparticles.
- the present invention generally relates to the field of synthetic inorganic and organic chemistry. Specifically, the present invention relates to a novel process for the synthesis of carborane-appended magnetic nanoparticles, which are termed as "boron enriched magnetic nanoparticles".
- nanotechnology One of the fastest moving and most exciting research areas is the interface between nanotechnology, biology and medicine. It has been stated by numerous researchers, that the application of nanotechnology in medicine, which is often referred to as “nanomedicine", offers many exciting possibilities for healthcare in the future, and may revolutionize the areas of targeted drug delivery, disease detection and tissue engineering.
- nanomedicine offers many exciting possibilities for healthcare in the future, and may revolutionize the areas of targeted drug delivery, disease detection and tissue engineering.
- the primary purpose of this patent is to process an invention of boron enriched magnetic nanoparticles that would deliver sufficient amount of boron to tumor cells (only) causing minimal toxicity to other healthy cells.
- Fe 3 0 4 one of the well-known magnetic nanoparticles play a major role in many areas of chemistry, physics and materials science.
- Chemical co-precipitation method is an easy to do method with the success rate from 96 to 99.9%. It can produce fine, stoichiometry particles of single and multi-component metal oxides. These magnetic nanoparticles are then appended to boron by the proposed new wet chemical methods, thereby making a necessary drug molecule with targeted delivery.
- US 2011/0044911 Al titled "Use of functionalized magnetic nanoparticles in cancer detection and treatment” discusses a method of detecting cancer cells, in an individual, methods of grading cancer, and methods of treating cancer.
- the methods involve the use of functionalized magnetic nanoparticles that comprise a moiety that provides for selective association with, and/or metabolic uptake into, a cancer cell.
- EP 1852107 Al titled "Magnetic nanoparticles compositions and uses thereof discusses the use of a biocompatible nanoparticle or nanoparticle aggregate, in combination with an external non-oscillating magnetic field for cancer therapy and tumor evolution monitoring. It further provides pharmaceutical compositions, deprived of any cell targeting agent comprising biocompatible magnetic nanoparticles to prevent or treat cancer.
- WO 2011/107290 Al titled “Magnetic nanoparticles for cancer diagnostic and treatment purposes” discusses magnetic metal nanoparticles for cancer diagnostic and treatment purposes, to an intermediate compound for obtaining said metal nanoparticles and to a method for preparing said intermediate compound and said nanoparticles. This invention also discusses a diagnostic or therapeutic use of such particles for cancer diagnostic and treatment purposes.
- US 6514481 Bl titled ''Magnetic Nanoparticles for selective therapy discusses a method for the preparation of nanoparticles and a method for the selective destruction of targeted cells, such as cancerous cells. This invention also discusses a novel nanosized particles termed as "nanoclinics" for therapeutic and/or diagnostic use.
- the objective of this invention is to provide a novel process for the synthesis of nanosized carborane appended magnetic particles termed as "boron enriched magnetic nanoparticles".
- Boron atoms can be enriched in an optimized nanocomposite to deliver sufficient amount of boron within tumor cells with minimal toxicity and to perform biological evaluation and thus improve the therapeutic efficiency.
- a further objective of this invention is to provide a method of making boron enriched magnetic nanoparticles (10-20 nm).
- the process of this invention involves the reaction of functionalized magnetic nanoparticles with substituted carboranes.
- Figure 1 shows the synthesis of the hydroxyl substituted magnetic (Fe 3 0 4 ) nanoparticles.
- Figure 2 shows a schematic flowchart for the overall process of synthesis of boron enriched magnetic nanoparticles.
- Figure 3 shows structure of boron enriched magnetic nanoparticles.
- the particles useful for the present invention need to be small enough in size to be able to diffuse into the tissue to enter the cells and large enough to respond to the applied external magnetic field at 37 °C for cancer treatment. Thus, particles less than 100 nm in diameter, preferably in the range of 10 to 20 nm are suitable for the present invention.
- the material forming the core may be therapeutic or diagnostic agents.
- the delivery agent forming the core is a magnetic material (Fe 3 0 4 ). Such materials include ferrous oxide and ferric oxide.
- the targeting agent carborane (boron source) has specific affinity towards the targeted cell.
- the spacer should be long enough to prevent or reduce steric hindrance between the interaction of the targeting agent and cell.
- Figure 1 shows the synthesis of the hydroxyl substituted magnetic (Fe 3 0 4 ) nanoparticles of the formula 1.
- FIG. 2 shows schematic flowchart for the overall process of synthesis of boron enriched magnetic nanoparticles.
- silyl tagged magnetic nanoparticles of the formula 3 wherein R is either NH 2 or CI particularly the silyl amine tagged magnetic nanoparticles of formula 3a and the silyl choride tagged magnetic nanoparticles of formula 3b will be prepared separately by the reaction of the hydroxyl substituted magnetic nanoparticles of the formula 1 with 3-substitutedpropyltriethoxysilane of the formula 2 wherein R is either NH 2 or CI.
- the amine and choride tagged magnetic nanoparticles of formula 3a and 3b are prepared using either 3- aminopropyltriethoxysilane of the formula 2a or 3-chloropropyltriethoxysilane 2b, respectively in toluene.
- carborane-appended magnetic nanoparticles 6 or 7 will be prepared by reacting substituted o-carborane of formula 4 wherein Ri is either hydrogen or methyl group in the presence of n-butyllithium with compound of formula 3.
- Detail steps for synthesis of boron enriched magnetic nanoparticles are as follows.
- silyl amine tagged magnetic nanoparticles 3a Hydroxyl substituted magnetic nanoparticles will be suspended in dried toluene and 3- aminopropyltriethoxysilane (2-3 g, 9-10 mmol) 2a will be added. The reaction mixture will be heated under reflux for 2-3 hours and filtered, washed with dichloromethane and dried under vacuum to yield silyl amine tagged magnetic nanoparticles.
- silyl chloride tagged magnetic nanoparticles 3b Hydroxyl substituted magnetic nanoparticles will be suspended in dried toluene and 3- chloropropyltriethoxysilane (2-3 g, 9-10 mmol) 2b will be added.
- the reaction will be quenched with dilute HC1 at -78 °C and warmed to room temperature. Excess ether will be removed on a rotary evaporator at room temperature. Water will be added to the reaction product. The desired product will be extracted from the resulting oil with hexanes, and the combined extracts will be dried and concentrated. Purification of the crude product on silica gel using hexane will be afforded the desired o-carborane aldehyde 5.
- Figure 3 shows structure of boron enriched magnetic nanoparticles 6 and 7.
- the compounds used in the present invention for the preparation of boron enriched magnetic nanoparticles are: Formula 1 - hydroxyl substituted magnetic nanoparticles
- Formula 4b - 1 -methyl-o-carborane i.e. Ri is methyl.
- the present invention is directed to a synthesis of boron enriched magnetic nanoparticles having these structures. Using the concept of "imine formation” and “elimination reactions”, carborane cages will be successfully attached to magnetic nanoparticles for the first time. The resulting nanocomposites will be found to accumulate in tumor cells in high concentration in the presence of external magnetic field. These results will provide new hope for the treatment of different types of cancers.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The preparation method of the boron enriched magnetic nanoparticles includes steps of: (a) reacting hydroxyl substituted magnetic nanoparticles with 3-chloropropyltriethoxysilane and 3-aminopropyltriethoxysilane to form silyl amine and silyl chloride tagged magnetic nanoparticles; (b) reacting silyl amine tagged magnetic nanoparticles with o-carborane aldehyde to form carborane-appended magnetic nanoparticles; and (c) reacting silyl chloride tagged magnetic nanoparticles with 1-methyl-o-carborene in presence of n-butyllithium to form carborane-appended magnetic nanoparticles. The boron enriched magnetic nanoparticles are nontoxic and shows the magnetic property at room temperature. Hopefully, these boron enriched magnetic nanoparticles would deliver sufficient amount of boron within tumor cells with minimal toxicity and to perform biological evaluation.
Description
A NOVEL PROCESS FOR THE SYNTHESIS OF BORON ENRICHED MAGNETIC NANOP ARTICLES
BACKGROUND OF THE INVENTION This invention relates to a novel process for the synthesis of boron enriched magnetic nanoparticles.
FIELD OF THE INVENTION
The present invention generally relates to the field of synthetic inorganic and organic chemistry. Specifically, the present invention relates to a novel process for the synthesis of carborane-appended magnetic nanoparticles, which are termed as "boron enriched magnetic nanoparticles".
DISCUSSION OF PRIOR ART
Now-a-days the development of nanomaterials has moved beyond the discovery of totally new materials and compositions. Instead, the center of attention has moved to the investigation of more complex, composite systems, in which the recombination of known materials into structures of higher complexity opens new possibilities of functionality. While scientific diligence of designing such new composite or hybrid materials is speeding up, industrial producers have begun merchandising the earliest discovered nanomaterials, and, in fact, are developing novel applications for them to fit the desired needs. Besides other commercial applications, magnetic nanoparticles are intensively being investigated for utilization in many different scientific and industrial fields, ranging from medicine to catalysis.
One of the fastest moving and most exciting research areas is the interface between nanotechnology, biology and medicine. It has been stated by numerous researchers, that the application of nanotechnology in medicine, which is often referred to as
"nanomedicine", offers many exciting possibilities for healthcare in the future, and may revolutionize the areas of targeted drug delivery, disease detection and tissue engineering. Thus, the primary purpose of this patent is to process an invention of boron enriched magnetic nanoparticles that would deliver sufficient amount of boron to tumor cells (only) causing minimal toxicity to other healthy cells. Fe304 (magnetite) one of the well-known magnetic nanoparticles play a major role in many areas of chemistry, physics and materials science. Chemical co-precipitation method is an easy to do method with the success rate from 96 to 99.9%. It can produce fine, stoichiometry particles of single and multi-component metal oxides. These magnetic nanoparticles are then appended to boron by the proposed new wet chemical methods, thereby making a necessary drug molecule with targeted delivery.
US 2011/0044911 Al titled "Use of functionalized magnetic nanoparticles in cancer detection and treatment" discusses a method of detecting cancer cells, in an individual, methods of grading cancer, and methods of treating cancer. The methods involve the use of functionalized magnetic nanoparticles that comprise a moiety that provides for selective association with, and/or metabolic uptake into, a cancer cell.
EP 1852107 Al titled "Magnetic nanoparticles compositions and uses thereof discusses the use of a biocompatible nanoparticle or nanoparticle aggregate, in combination with an external non-oscillating magnetic field for cancer therapy and tumor evolution monitoring. It further provides pharmaceutical compositions, deprived of any cell targeting agent comprising biocompatible magnetic nanoparticles to prevent or treat cancer.
WO 2011/107290 Al titled "Magnetic nanoparticles for cancer diagnostic and treatment purposes" discusses magnetic metal nanoparticles for cancer diagnostic and treatment purposes, to an intermediate compound for obtaining said metal nanoparticles and to a method for preparing said intermediate compound and said
nanoparticles. This invention also discusses a diagnostic or therapeutic use of such particles for cancer diagnostic and treatment purposes.
US 6514481 Bl titled ''Magnetic Nanoparticles for selective therapy" discusses a method for the preparation of nanoparticles and a method for the selective destruction of targeted cells, such as cancerous cells. This invention also discusses a novel nanosized particles termed as "nanoclinics" for therapeutic and/or diagnostic use.
SUMMARY OF THE INVENTION
The objective of this invention is to provide a novel process for the synthesis of nanosized carborane appended magnetic particles termed as "boron enriched magnetic nanoparticles". Boron atoms can be enriched in an optimized nanocomposite to deliver sufficient amount of boron within tumor cells with minimal toxicity and to perform biological evaluation and thus improve the therapeutic efficiency.
A further objective of this invention is to provide a method of making boron enriched magnetic nanoparticles (10-20 nm). The process of this invention involves the reaction of functionalized magnetic nanoparticles with substituted carboranes.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the synthesis of the hydroxyl substituted magnetic (Fe304) nanoparticles.
Figure 2 shows a schematic flowchart for the overall process of synthesis of boron enriched magnetic nanoparticles.
Figure 3 shows structure of boron enriched magnetic nanoparticles.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The particles useful for the present invention need to be small enough in size to be able to diffuse into the tissue to enter the cells and large enough to respond to the applied external magnetic field at 37 °C for cancer treatment. Thus, particles less than 100 nm in diameter, preferably in the range of 10 to 20 nm are suitable for the present invention. The material forming the core may be therapeutic or diagnostic agents. In a preferred embodiment, the delivery agent forming the core is a magnetic material (Fe304). Such materials include ferrous oxide and ferric oxide. The targeting agent carborane (boron source) has specific affinity towards the targeted cell. The spacer should be long enough to prevent or reduce steric hindrance between the interaction of the targeting agent and cell.
The present invention describes more specifically with reference to the following embodiments. It is to be noted that the following descriptions of preferred embodiments of this invention are presented herein for the purpose of illustration and description only; it is not intended to be exhaustive or to be limited to the precise form disclosed. The following example is illustrative of the best mode now contemplated for carrying out the invention.
Materials: Several important chemicals of the present invention will be illustrated as follows. Anhydrous FeCl2-4H20, FeCl3.6H20, 3-chloropropyltriethoxysilane, 3- aminopropyltriethoxysilane, o-carborane, 1-methyl-o-carborane, n-butyllithium, absolute ethanol, dichloromethane, toluene, methyl formate, ethyl acetate, magnesium sulfate, hexane, and HC1 will be purchased commercially.
Figure 1 shows the synthesis of the hydroxyl substituted magnetic (Fe304) nanoparticles of the formula 1. The magnetic nanoparticles will be prepared via improved chemical co-precipitation method [1]. Typically, mixture of 0.3967 g of FeCl2.4H20 (2 mmol) and 0.5406 g FeCl3.6H20 (2 mmol) is dissolved in 200 mL of deionized water, such that Fe2 +/Fe3 + = 1. The mixed solution was stirred for 30
minutes at 80 C. Then 5 mL of NH4OH solution was added with vigorous stirring to produce a black solid and the reaction was continued for another 30 minutes. The magnetic (Fe304) nanoparticles were isolated by applying an external magnet, and washed with 50-100 mL deionized water for three times and then dried at 80 °C for 10 hours.
Figure 2 shows schematic flowchart for the overall process of synthesis of boron enriched magnetic nanoparticles. Briefly, silyl tagged magnetic nanoparticles of the formula 3 wherein R is either NH2 or CI, particularly the silyl amine tagged magnetic nanoparticles of formula 3a and the silyl choride tagged magnetic nanoparticles of formula 3b will be prepared separately by the reaction of the hydroxyl substituted magnetic nanoparticles of the formula 1 with 3-substitutedpropyltriethoxysilane of the formula 2 wherein R is either NH2 or CI. The amine and choride tagged magnetic nanoparticles of formula 3a and 3b are prepared using either 3- aminopropyltriethoxysilane of the formula 2a or 3-chloropropyltriethoxysilane 2b, respectively in toluene. Then, carborane-appended magnetic nanoparticles 6 or 7 will be prepared by reacting substituted o-carborane of formula 4 wherein Ri is either hydrogen or methyl group in the presence of n-butyllithium with compound of formula 3. Detail steps for synthesis of boron enriched magnetic nanoparticles are as follows. i) Synthesis of silyl amine tagged magnetic nanoparticles 3a: Hydroxyl substituted magnetic nanoparticles will be suspended in dried toluene and 3- aminopropyltriethoxysilane (2-3 g, 9-10 mmol) 2a will be added. The reaction mixture will be heated under reflux for 2-3 hours and filtered, washed with dichloromethane and dried under vacuum to yield silyl amine tagged magnetic nanoparticles.
ii) Synthesis of silyl chloride tagged magnetic nanoparticles 3b: Hydroxyl substituted magnetic nanoparticles will be suspended in dried toluene and 3- chloropropyltriethoxysilane (2-3 g, 9-10 mmol) 2b will be added. The reaction mixture will be heated under reflux for 2-3 hours and filtered, washed with dichloromethane and dried under vacuum to yield silyl chloride tagged magnetic nanoparticles. iii) Synthesis of o-carborane aldehyde 5: To a stirring solution of o-carborane (1-2 g, 6-12 mmol) 4a in diethyl ether at -78 °C will be added to n-butyllithium (4-8 mL, 7-14 mmol, 1.6 M in hexanes) over 20 minutes, and stirring will be continued for another 3 hours at the same temperature. Methyl formate (1-3 mL, excess) will be added to the reaction mixture, and stirring will be continued for an additional 2 hours. The reaction will be quenched with dilute HC1 at -78 °C and warmed to room temperature. Excess ether will be removed on a rotary evaporator at room temperature. Water will be added to the reaction product. The desired product will be extracted from the resulting oil with hexanes, and the combined extracts will be dried and concentrated. Purification of the crude product on silica gel using hexane will be afforded the desired o-carborane aldehyde 5. iva) Synthesis of carborane-appended magnetic nanoparticles 6: A solution of silyl amine tagged magnetic nanoparticles in absolute ethanol will be added to a solution of o-carborane aldehyde 5 (0.34-0.68 g, 2-4 mmol) in absolute ethanol and boiled under reflux for 6-8 hours under nitrogen atmosphere. The precipitate of carborane-appended magnetic nanoparticles obtained will be filtered, washed with ethanol, and dried in high vacuum 6. ivb) Synthesis of carborane-appended magnetic nanoparticles 7: 1-Methyl-o- carborane (0.30-0.70 g, 3.0-6.0 mmol) 4b will be dissolved in dry THF at -78 °C, and n-butyllithium (4-8 mL, 7-14 mmol) in hexanes will be added. The mixture will be warmed to room temperature and stirred for an hour and then silyl chloride tagged
magnetic nanoparticles will be added. The solution will be refluxed for 16-18 hours, allowed to cool and then the solvent will be removed. The residue will be dissolved in ethyl acetate and washed with water. The organic layer will be dried over anhydrous magnesium sulfate and the solvent will be removed using a rotary evaporator to yield carborane- appended magnetic nanoparticles 7 as a solid.
Figure 3 shows structure of boron enriched magnetic nanoparticles 6 and 7.
The compounds used in the present invention for the preparation of boron enriched magnetic nanoparticles are: Formula 1 - hydroxyl substituted magnetic nanoparticles
Formula 2 - 3-substitutedpropyltriethoxysilane
Formula 2a - 3-aminopropyltriethoxysilane
Formula 2b - 3-chloropropyltriethoxysilane
Formula 3 - silyl tagged magnetic nanoparticles of the formula Formula 3a - silyl amine tagged magnetic nanoparticles
Formula 3b - silyl chloride tagged magnetic nanoparticles
Formula 4 - o-carborane wherein Ri is H or CH3.
Formula 4a - o-carborane wherein Ri is H
Formula 4b - 1 -methyl-o-carborane i.e. Ri is methyl. Formula 5 - o-carborane aldehyde
The present invention is directed to a synthesis of boron enriched magnetic nanoparticles having these structures. Using the concept of "imine formation" and "elimination reactions", carborane cages will be successfully attached to magnetic nanoparticles for the first time. The resulting nanocomposites will be found to
accumulate in tumor cells in high concentration in the presence of external magnetic field. These results will provide new hope for the treatment of different types of cancers.
Characterization: All the synthesized compounds will go through a series of characterization to determine the desired product. The procedures that will be used for characterization are; spectroscopic (!H NMR, 13C NMR, UB NMR, IR, and Mass), microscopic (SEM, and TEM) techniques, and elemental analysis.
1. Liang et. al., Chemistry Letters , 33, 1468-1469.
10
15
20
Claims
A novel process for the synthesis of nanosized carborane appended magnetic particles termed as "boron enriched magnetic nanoparticles" of the formula 6 or 7 comprising the steps of:
a. Synthesizing substituted silyl tagged magnetic nanoparticles of the formula 3, wherein R is either NH2 or CI, by reacting hydroxyl substituted magnetic nanoparticles 1 with a 3-substitutedpropyltriethoxysilane of the formula 2 wherein R is either NH2 or CI, in toluene; and
b. substituted o-carborane of formula 4 wherein Ri is either hydrogen or methyl group are reacted in the presence of n-butyllithium with compound of formula 3 obtained in step (a) to form the compound of formula 6 or 7.
The novel process of Claim 1, wherein the hydroxyl substituted magnetic nanoparticles 1 are prepared via improved chemical co-precipitation method, comprising the steps of:
a. Dissolving required quantities of FeCl2.4H20 and FeCl3.6H20 in deionized water such that Fe2 +/Fe3 + = 1 ;
b. Transferring the mixed solution into a three-necked flask where required quantity of NH3.H20 is injected into the mixture and stirred rapidly;
c. Adjusting the pH value of the solution to a range of about 9 to 10 by adding additional NH3.H20 and allowing the growth of Fe304 nanocrystalline to proceed for about 30 minutes in the suspension; and d. Collecting of the Fe304 precipitates using a magnet and the washing three times with deionized water.
The novel process of Claim 2, wherein the concentration of FeCl2.4H20 and FeCl3.6H20 is about 2 mmol and the quantity required is about 0.3967 g and 0.5406 g respectively, and the concentration of NH3.H20 is about 1.5 mol/L.
The novel process of Claim 1, wherein the siiyl amine tagged magnetic nanoparticles 3a are synthesized further comprising the steps of:
a. Suspending the hydroxyl substituted magnetic nanoparticles 1 in dried toluene;
b. Adding a required quantity of 3-aminopropyltriethoxysilane 2a;
c. Heating the reaction mixture under reflux for about 2 to 3 hours;
d. Filtering the heated reaction mixture and washing it with dichloromethane; and
e. Drying the washed mixture under vacuum.
The novel process of Claim 4, wherein the 3-aminopropyltriethoxysilane 2a is of a concentration of about 9 mmol to 10 mmol and the quantity required is about 2 grams to 3 grams.
The novel process of Claim 1, wherein the silyi chloride tagged magnetic nanoparticles 3b are synthesized further comprising the steps of:
a. Suspending the hydroxyl substituted magnetic nanoparticles 1 in dried toluene;
b. Adding a required quantity of 3-chloropropyltriethoxysilane 2b;
c. Heating the reaction mixture under reflux for about 2 to 3 hours;
d. Filtering the heated reaction mixture and washing it with dichloromethane; and
e. Drying the washed mixture under vacuum.
7. The novel process of Claim 6, wherein the 3-chloropropyltriethoxysilane 2b is of a concentration of about 9 mmol to 10 mmol and a quantity of about 2 grams to 3 grams is required.
8. A novel process for the synthesis of nanosized carborane appended magnetic particles termed as "boron enriched magnetic nanoparticles" of the formula
6 comprising the steps of:
a. Synthesizing silyl amine tagged magnetic nanoparticles of the formula 3a, by reacting hydroxyl substituted magnetic nanoparticles 1 which is suspended in toluene, with 3-aminopropyltriethoxysiIane of the formula 2a;
b. Synthesizing o-carborane aldehyde 5, by reacting o-carborane 4a wherein Ri is H, with an n-butyllithium and a methyl formate; and c. Synthesizing carborane-appended magnetic nanoparticles 6, by Schiff base reaction of the amine tagged magnetic nanoparticles 3a with the o-carborane aldehyde 5.
9. A novel process of Claim 8, wherein the o-carborane aldehyde 5 is synthesized further comprising the steps of:
a. Mixing required quantity of o-carborane 4 in diethyl ether at -78°C and stirring continuously for about 20 minutes;
b. Adding a required quantity of n-butyllithium to the solution and stirring for about 3 hours at the same temperature of -78°C;
c. Adding a required quantity of methyl formate to the reaction mixture and stirring continuously for another 2 hours;
d. Quenching the reaction mixture with dilute HC1 at -78 °C and warming it to room temperature;
e. Removing excess ether from the mixture on an evaporator at room temperature;
f. Adding water to the reaction product;
g. Extracting the desired product from the resulting oil from hexanes;
h. Drying and concentrating the combined extracts; and
i. Purifying the crude product on silica gel using hexane.
10. A novel process of Claim 8, wherein the concentration of o-carborane 4 is about 6 mmol to 12 mmol and an amount of about 1 gram to 2 grams is required and the n-butyllithium of concentration about 7 mmol to 14 mmol, 1.6M in hexanes and the quantity required is about 4 mL to 8 mL, also about 1 mL to 3 mL of methyl formate is needed.
11. A novel process of Claim 8, wherein the Schiff base reaction of amine tagged magnetic nanoparticles 3a with o-carborane aldehyde 5 further comprising the steps of:
a. Preparing a solution of silyl amine tagged magnetic nanoparticles 3a in absolute ethanol;
b. Preparing a solution of o-carborane aldehyde 5 in absolute ethanol;
c. Adding the solutions of silyl amine tagged magnetic nanoparticles 3a and o-carborane aldehyde 5;
d. Boiling the mixed solution under reflux for 6 to 8 hours under nitrogen atmosphere;
e. Obtaining the precipitate of boron enriched magnetic nanoparticles; and f. Filtering and washing the precipitate with ethanol and drying it in hig vacuum, to yield solid boron enriched magnetic nanoparticles 6.
12. A novel process of Claim 11, wherein the concentration of o-carborane aldehyde 5 is about 2 mmol to 4 mmol and the quantity required is about 0.34 grams to 0.68 grams.
13. A novel process for the synthesis of nanosized carborane appended magnetic particles termed as "boron enriched magnetic nanoparticles" of the formula
7 comprising the steps of: a. Synthesizing silyi chloride tagged magnetic nanoparticles of the formula 3b, by reacting hydroxy! substituted magnetic nanoparticles 1 which is suspended in toluene, with 3-chloropropyltriethoxysilane of the formula 2b; and
b. Synthesizing carborane-appended magnetic nanoparticles 7, by reacting 1 - methyl-o-carborane dissolved in dry Tetrahydrofuran at -78 °C and n- butyllithium in hexane followed by the addition of silyl chloride tagged magnetic nanoparticles.
14. A novel process of Claim 13, wherein the elimination reaction of chloride tagged magnetic nanoparticles 3b with 1 -methyl-o-carborane 4b further comprising the steps of: a. Dissolving a required quantity of 1 -methyl-o-carborane 4b in dry THF at - 78 °C;
b. Adding a required quantity of n-butyllithium in hexanes;
c. Warming the mixture to room temperature and stirring for 1 hour;
d. Adding the silyl chloride tagged magnetic nanoparticles 3b;
e. Boiling the solution under reflux for about 16 to 18 hours, allowing it to cool;
f. Removing the solvent from the solution and collecting the residue;
g. Dissolving the residue in ethyl acetate and then washing it with water; h. Drying the obtained organic layer over anhydrous magnesium sulphate; and
i. Removing the solvent using an evaporator, to yield solid boron enriched magnetic nanoparticles of the formula 7.
15. A novel process of Claim 14, wherein the concentration of 1-methyl-o- carborane 4b is 3.0 mmol to 6.0 mmol and the quantity required is about 0.30 grams to 0.70 grams, and the n-butyllithium concentration is about 7 mmol to 14 mmol, and the quantity required is about 4 mL to 8 mL.
16. A novel process of Claim 14, wherein characterizing the synthesized compounds is done by passing all the synthesized compounds through different processes of characterization, such as spectroscopic techniques, microscopic techniques, and elemental analysis.
17. Boron enriched magnetic nanoparticles, in which one or more boron atoms are enriched in an optimized nanocomposite to deliver a sufficient amount of boron within tumor cells with minimal toxicity and to perform biological evaluation and thus improve the therapeutic efficiency.
18. The boron enriched magnetic nanoparticles of Claim 17, wherein the size of the particles is small enough to be able to diffuse into the tissue to enter the cells and large enough to respond to the applied external magnetic field at
37 °C for cancer treatment.
19. The boron enriched magnetic nanoparticles of Claim 17, wherein the size of the particles is in the range of lOnm to 20nm and the material forming a core is a magnetic material such as ferrous oxide and ferric oxide.
20. The boron enriched magnetic nanoparticles as in claim 17, which are carborane appended magnetic nanoparticles of the formula 6.
21. The boron enriched magnetic nanoparticles as in claim 17, which are carborane appended magnetic nanoparticles of the formula 7.
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