CN116495763A - Amorphous calcium carbonate-polyphenol hollow nanoparticle as well as preparation method and application thereof - Google Patents
Amorphous calcium carbonate-polyphenol hollow nanoparticle as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN116495763A CN116495763A CN202310414753.6A CN202310414753A CN116495763A CN 116495763 A CN116495763 A CN 116495763A CN 202310414753 A CN202310414753 A CN 202310414753A CN 116495763 A CN116495763 A CN 116495763A
- Authority
- CN
- China
- Prior art keywords
- calcium carbonate
- amorphous calcium
- polyphenol
- hollow
- nano particles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 190
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 120
- 239000011575 calcium Substances 0.000 title claims abstract description 120
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 120
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 174
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000003814 drug Substances 0.000 claims abstract description 45
- 229940079593 drug Drugs 0.000 claims abstract description 41
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 28
- 150000008442 polyphenolic compounds Chemical class 0.000 claims abstract description 24
- 235000013824 polyphenols Nutrition 0.000 claims abstract description 24
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000001099 ammonium carbonate Substances 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 16
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 13
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims abstract description 11
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims abstract description 11
- 235000012501 ammonium carbonate Nutrition 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 239000002244 precipitate Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 16
- 239000006185 dispersion Substances 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 229940126586 small molecule drug Drugs 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229920002521 macromolecule Polymers 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052788 barium Inorganic materials 0.000 claims description 4
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 4
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 4
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 150000002605 large molecules Chemical class 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 3
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- 239000010941 cobalt Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052733 gallium Inorganic materials 0.000 claims description 3
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 2
- 241001122767 Theaceae Species 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052793 cadmium Inorganic materials 0.000 claims description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 239000011651 chromium Substances 0.000 claims description 2
- 229930003935 flavonoid Natural products 0.000 claims description 2
- 150000002215 flavonoids Chemical class 0.000 claims description 2
- 235000017173 flavonoids Nutrition 0.000 claims description 2
- 229910052732 germanium Inorganic materials 0.000 claims description 2
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052750 molybdenum Inorganic materials 0.000 claims description 2
- 239000011733 molybdenum Substances 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052706 scandium Inorganic materials 0.000 claims description 2
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 229920001864 tannin Polymers 0.000 claims description 2
- 239000001648 tannin Substances 0.000 claims description 2
- 235000018553 tannin Nutrition 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 abstract description 13
- 238000011068 loading method Methods 0.000 abstract description 10
- 238000005538 encapsulation Methods 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 2
- 239000008204 material by function Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 229960005069 calcium Drugs 0.000 description 100
- 239000001263 FEMA 3042 Substances 0.000 description 89
- 229920002258 tannic acid Polymers 0.000 description 89
- 229940033123 tannic acid Drugs 0.000 description 89
- 235000010216 calcium carbonate Nutrition 0.000 description 80
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 22
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 22
- 235000015523 tannic acid Nutrition 0.000 description 22
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 22
- 230000005540 biological transmission Effects 0.000 description 21
- 239000008055 phosphate buffer solution Substances 0.000 description 21
- 239000002953 phosphate buffered saline Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 18
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 16
- 108010015776 Glucose oxidase Proteins 0.000 description 12
- 239000004366 Glucose oxidase Substances 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 12
- 229910021641 deionized water Inorganic materials 0.000 description 12
- 229940116332 glucose oxidase Drugs 0.000 description 12
- 235000019420 glucose oxidase Nutrition 0.000 description 12
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 12
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 12
- 229960002930 sirolimus Drugs 0.000 description 12
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 11
- 229910001431 copper ion Inorganic materials 0.000 description 11
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 10
- 238000009826 distribution Methods 0.000 description 10
- 102000006382 Ribonucleases Human genes 0.000 description 9
- 108010083644 Ribonucleases Proteins 0.000 description 9
- 235000012754 curcumin Nutrition 0.000 description 9
- 239000004148 curcumin Substances 0.000 description 9
- 229940109262 curcumin Drugs 0.000 description 9
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 9
- 229960004679 doxorubicin Drugs 0.000 description 8
- 229940030275 epigallocatechin gallate Drugs 0.000 description 7
- 229940074391 gallic acid Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 208000035143 Bacterial infection Diseases 0.000 description 4
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 4
- 208000022362 bacterial infectious disease Diseases 0.000 description 4
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 4
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 4
- 229910001437 manganese ion Inorganic materials 0.000 description 4
- 239000002077 nanosphere Substances 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 238000004627 transmission electron microscopy Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 235000004515 gallic acid Nutrition 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- -1 silicate ion Chemical class 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229910021532 Calcite Inorganic materials 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229920001007 Nylon 4 Polymers 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940057499 anhydrous zinc acetate Drugs 0.000 description 1
- 239000004410 anthocyanin Substances 0.000 description 1
- 235000010208 anthocyanin Nutrition 0.000 description 1
- 229930002877 anthocyanin Natural products 0.000 description 1
- 150000004636 anthocyanins Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- ISPYRSDWRDQNSW-UHFFFAOYSA-L manganese(II) sulfate monohydrate Chemical compound O.[Mn+2].[O-]S([O-])(=O)=O ISPYRSDWRDQNSW-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940085991 phosphate ion Drugs 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001947 vapour-phase growth Methods 0.000 description 1
- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
- C01F11/00—Compounds of calcium, strontium, or barium
- C01F11/18—Carbonates
- C01F11/181—Preparation of calcium carbonate by carbonation of aqueous solutions and characterised by control of the carbonation conditions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/84—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by UV- or VIS- data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
-
- 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
- C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Ceramic Engineering (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Geology (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of inorganic functional materials, and discloses amorphous calcium carbonate-polyphenol hollow nano particles, a preparation method and application thereof, wherein the preparation method comprises the following steps: the calcium ion solution reacts with ammonium carbonate or ammonium bicarbonate to obtain amorphous calcium carbonate nano particles; then mixing with polyphenol water solution or polyphenol water solution and medicine solution to obtain amorphous calcium carbonate-polyphenol hollow nano particles with or without medicine encapsulation; the catalyst can be used for loading metal ions subsequently, has high encapsulation efficiency and loading rate, and solves the problem of single loading function in the existing carrier. And the amorphous calcium carbonate-polyphenol hollow nano particles for encapsulating the drug or loading the metal ions can respond to the acid to release the loaded drug or ions, have good controllable loading-releasing capacity, and can be applied to the fields of daily chemicals, medicines and the like.
Description
Technical Field
The invention relates to the technical field of inorganic functional materials, in particular to amorphous calcium carbonate-polyphenol hollow nano particles, and a preparation method and application thereof.
Background
Amorphous Calcium Carbonate (ACC) has the advantages of small particles, large specific surface area, good biocompatibility and the like, so that the amorphous calcium carbonate has excellent performance in improving the bioavailability of the medicine and overcoming the biological barrier in vivo. However, amorphous calcium carbonate is very unstable in water and can be converted to crystalline calcium carbonate such as vaterite, aragonite or calcite within minutes, severely affecting its stability and drug release capacity.
In order to expand the application of amorphous calcium carbonate in drug carriers, a simple and stable means for improving the stability of amorphous calcium carbonate in water is required to be developed at present. The means currently in common use are additives (stabilizers), for example: inorganic ions such as magnesium ion, silicate ion, and phosphate ion, and organic macromolecules such as polyaspartic acid, carboxyl group-rich proteins, and phosphorylated proteins. As CN 113350510A, a method for preparing amorphous nano calcium carbonate which can exist stably is disclosed, in which polypyrrolidone is used for stabilizing a colloidal solution of amorphous calcium carbonate. The amorphous calcium carbonate prepared by the method has larger size and irregular morphology, and the preparation process involves high-pressure reaction and is more complex.
In addition, CN 115196661A discloses a hollow calcium carbonate nanosphere doped with metal oxide or peroxide, a preparation method and application thereof, which discloses a process for preparing amorphous calcium carbonate nanospheres by vapor phase growth method, and uses the obtained hollow calcium carbonate nanospheres to adsorb metal ions, however, a stable dispersion means of the obtained calcium carbonate nanospheres in water is not explored. Therefore, there is still a need to develop a means for rapidly preparing amorphous calcium carbonate which is stable in water and has uniform size and stable morphology.
In addition, most of the amorphous calcium carbonates reported to date are relatively single in function and can only encapsulate small molecule drugs or metal ions. If the amorphous calcium carbonate nanoparticle which can encapsulate small molecular drugs and large molecular drugs and can load metal ions can be developed, the amorphous calcium carbonate nanoparticle has important significance in the combined treatment of diseases and also has wide application prospect.
Disclosure of Invention
Aiming at the problems of poor stability, poor size uniformity and single function of amorphous calcium carbonate in water in the prior art, the invention provides a preparation method of amorphous calcium carbonate-polyphenol hollow nano particles, and the prepared particles can be stably dispersed in water, can encapsulate various small molecular drugs, macromolecular drugs and/or loaded metal ions, release the loaded drugs or ions in acid response, and have excellent and controllable load-release capacity.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a method for preparing amorphous calcium carbonate-polyphenol hollow nano-particles, comprising the following steps:
step 1, reacting a calcium ion solution with ammonium carbonate or ammonium bicarbonate, centrifuging, and taking out precipitates to obtain amorphous calcium carbonate nano particles;
step 2, adding a polyphenol aqueous solution into the alcohol dispersion liquid of the amorphous calcium carbonate nano particles prepared in the step 1, mixing, centrifuging and taking out precipitate to obtain amorphous calcium carbonate-polyphenol hollow nano particles;
or, step 2 is replaced with the following step S:
and S, sequentially or simultaneously adding a drug solution and a polyphenol water solution into the alcohol dispersion liquid of the amorphous calcium carbonate nano particles prepared in the step 1, mixing, centrifuging and taking out precipitate to obtain the drug-encapsulated amorphous calcium carbonate-polyphenol hollow nano particles.
Firstly, preparing amorphous calcium carbonate nano particles, and then etching the amorphous calcium carbonate nano particles by using polyphenol to obtain amorphous calcium carbonate-polyphenol hollow nano particles; or simultaneously adding the drug and the polyphenol into the dispersion liquid of the amorphous calcium carbonate nano particles to directly obtain the drug-encapsulated amorphous calcium carbonate-polyphenol hollow nano particles. The obtained amorphous calcium carbonate-polyphenol hollow nano particles encapsulated by the drug are very stable in water, have high encapsulation efficiency, can respond to release of the carried drug under acidic conditions, and have good controllable load-release capacity.
Step 1 more specifically comprises: and (3) reacting the calcium ion solution with ammonium carbonate or ammonium bicarbonate solid in a closed container, centrifuging to obtain precipitate, and washing to obtain amorphous calcium carbonate nano particles.
More specifically, the calcium ion solution is placed in a reaction container, the air-permeable paper is covered at the opening of the reaction container, ammonium carbonate or ammonium bicarbonate is placed on the air-permeable paper, the reaction container and the ammonium carbonate or ammonium bicarbonate are sealed and coated together, heating reaction is carried out, the precipitate is centrifugally taken, and amorphous calcium carbonate nano particles are obtained after washing.
In some embodiments, the calcium ion solution comprises any one or more of water, methanol, ethanol, or propanol of a soluble calcium salt; the molar concentration of calcium ions in the calcium ion solution is 10mmol/L-1mol/L; the morphology and dispersibility of the particles obtained at this concentration are better.
And in some embodiments, the soluble calcium salt comprises any one or more of calcium chloride, calcium sulfate, calcium nitrate, and hydrates thereof.
The mass ratio of calcium ions to ammonium carbonate or ammonium bicarbonate is generally 1:2-10, the reaction speed is proper under the process, and the obtained nano particles are uniform in size.
In some embodiments, the reaction temperature of step 1 is 50-80 ℃ and the reaction time is 0.5-24 hours; such as 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or any value therebetween; the reaction time is 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, 18h, 20h, 22h, or any value therebetween; or the reaction is deemed to end with no further precipitation.
In some embodiments, the polyphenols comprise one or more of tannins or tea polyphenols, flavonoids, gossypols, anthocyanins; tannic acid is preferred;
in some embodiments, the molar concentration of polyphenols in the aqueous polyphenol solution is from 5 μmol/L to 5mmol/L;
in some embodiments, in step 2 or step S, the mass ratio of amorphous calcium carbonate nanoparticles to polyphenols produced in step 1 is 1:0.1-10. The addition amount of polyphenol can influence the size and stability of the finally obtained nano particles, and the amorphous calcium carbonate-polyphenol hollow nano particles obtained in the range have higher yield, uniform size and better stability.
In some embodiments, the mass ratio of amorphous calcium carbonate nanoparticles to polyphenols produced in step 1 is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or any value therebetween.
In some embodiments, the mass ratio of amorphous calcium carbonate nanoparticles to polyphenols produced in step 1 is 1:1-4. Too low an amount of polyphenol added may result in incomplete reaction, and too high an amount of polyphenol added may result in a decrease in stability of the resultant product in water.
In some embodiments, in step 2 or step S, the mixing time is 5S or more; the reaction process is very rapid, in some embodiments, the mixing time is 10s-2 hours; such as 15s, 20s, 30s, 60s, 2min, 5min, 10min, 30min, 1h, 1.5h, etc., or any value therebetween. Preferably, the reaction time is 30 seconds.
In some embodiments, the drug comprises a small molecule drug and/or a large molecule drug; because the interaction exists between the polyphenol molecules and most of the drug molecules, the amorphous calcium carbonate nano particles can encapsulate small-molecule drugs, can encapsulate large-molecule drugs, can encapsulate small-molecule drugs and large-molecule drugs at the same time, have very wide loading capacity, and can be used for the combined treatment of multiple drugs.
The small molecule drugs comprise small molecule drugs which are conventional in the medical field, including but not limited to any one or more of hydrophobic small molecule drugs such as doxorubicin, curcumin, cisplatin, rapamycin and the like; the macromolecular drugs also comprise macromolecular drugs common in the medical field, such as any one or more of various polypeptides, nucleic acids, proteins, enzymes and other biological macromolecules.
In some embodiments, in the step S, the mass ratio of the drug to the amorphous calcium carbonate nanoparticle prepared in the step 1 is 0-100:1, and the drug is not 0. The nano particles obtained under the conditions have uniform size and higher encapsulation efficiency.
In some embodiments, in step S, the mass ratio of the drug to the amorphous calcium carbonate nanoparticle produced in step 1 is 0.1:1, 0.5:1, 1:1, 2:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, or any value therebetween.
In some embodiments, the mass ratio of the drug to the amorphous calcium carbonate nanoparticle prepared in step 1 is 0-100:1, and the drug encapsulation amount has an upper limit depending on the specific drug type, given the limited sites in the particle for binding to the drug.
The drug solution refers to a dispersion of a drug in water, alcohol, or dimethylsulfoxide.
In some embodiments, the above preparation method further comprises the steps of: and (3) mixing the amorphous calcium carbonate-polyphenol hollow nano particles prepared in the step (2) or the step (S) with a metal ion solution, and centrifuging to obtain a precipitate to obtain the amorphous calcium carbonate-polyphenol hollow nano particles loaded by metal ions.
The amorphous calcium carbonate-polyphenol hollow nano particles can also load metal ions, and the particles which encapsulate or not encapsulate the drugs can also load the metal ions, so that the problem of single loading function in the existing carrier is solved.
In some embodiments, the metal ions comprise any one or more metal ions of magnesium, aluminum, scandium, titanium, vanadium, chromium, manganese, cobalt, nickel, copper, zinc, gallium, germanium, molybdenum, barium, silver, cadmium, barium, gold, platinum, lanthanoid;
preferably, the metal ions include manganese, cobalt, nickel, copper, zinc and gallium, which have weaker binding capacities than calcium ions and do not damage the particle structure.
The metal ion solution comprises any one or more of water, methanol, ethanol or propanol solution of soluble metal salt; the soluble metal salt includes any one of metal chloride, nitrate, sulfate and hydrate thereof.
In some embodiments, the mass ratio of the metal ion to the amorphous calcium carbonate-polyphenol hollow nanoparticle prepared in step 2 or step S is 0-10:1, and the metal ion is not 0.
In some embodiments, the mass ratio of the metal ion to the amorphous calcium carbonate-polyphenol hollow nanoparticle produced in step 2 or step S is 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or any value therebetween.
In some embodiments, the mass ratio of the metal ion to the amorphous calcium carbonate-polyphenol hollow nanoparticle prepared in step 2 or step S is 0-10:1, and the metal ion loading has an upper limit depending on the specific metal ion species in view of the limited sites in the particle to which the metal ion is bound.
In some embodiments, the mixing time is 5 seconds or more. The reaction process is very rapid, and in some embodiments, the mixing time is 10s-2 hours; such as 15s, 20s, 30s, 60s, 2min, 5min, 10min, 30min, 1h, 1.5h, etc., or any value therebetween. Preferably, the reaction time is 30 seconds.
In some embodiments, the precipitate obtained by centrifugation at each step is typically subjected to a washing treatment, such as washing with any one or more solvents of water, methanol, ethanol, to remove impurities.
In some embodiments, each step of centrifugation is aimed at separating off the precipitated product, e.g., at a speed of no less than 5000 rpm; the centrifugation time is more than 60 seconds. Preferably, the centrifugation speed is 10000 revolutions per minute and the centrifugation time is 90 seconds.
The invention also provides amorphous calcium carbonate-polyphenol hollow nano particles prepared by the preparation method, wherein the amorphous calcium carbonate-polyphenol hollow nano particles have a hollow spherical structure, the average particle size is 100-300 nanometers, and the diameter of a cavity is 20-200 nanometers.
The invention also provides application of the amorphous calcium carbonate-polyphenol hollow nano particles in preparing daily chemical products, medical drugs or biological devices. Such as in the fields of preparation of drug delivery drugs, surface modification of implant devices and the like.
Compared with the prior art, the invention has the following beneficial effects:
(1) The amorphous calcium carbonate-polyphenol hollow nano-particles prepared by the invention can encapsulate various hydrophobic micromolecular medicaments and various macromolecular bioactive molecules and can also load metal ions; the method has high encapsulation efficiency and load rate, and solves the problem of single load function in the existing carrier. In addition, the amorphous calcium carbonate-polyphenol hollow nano particles for encapsulating the drug or loading the metal ions can respond to the release of the loaded drug or ions in an acidic way, and have good controllable loading-release capacity.
(2) The preparation method of amorphous calcium carbonate-polyphenol hollow nano particles has the advantages of simple process, rapid and stable reaction, high yield and strong expansibility; the obtained amorphous calcium carbonate-polyphenol hollow nano particles have uniform size and are stably dispersed in water.
Drawings
FIG. 1 shows transmission electron microscopy and ultraviolet absorption curves of amorphous calcium carbonate nanoparticles, amorphous calcium carbonate-tannic acid nanoparticles obtained in example 1, (a) amorphous calcium carbonate nanoparticles, (b) amorphous calcium carbonate-tannic acid hollow nanoparticles, and (c) ultraviolet absorption curves of tannic acid and both particles.
FIG. 2 is a transmission electron microscope of amorphous calcium carbonate nanoparticle (a) and amorphous calcium carbonate-tannic acid nanoparticle (b) obtained in example 2.
FIG. 3 is a transmission electron microscope of amorphous calcium carbonate nanoparticle (a) and amorphous calcium carbonate-gallic acid nanoparticle (b) obtained in example 3.
FIG. 4 is a transmission electron microscope of amorphous calcium carbonate nanoparticle (a) and amorphous calcium carbonate-epigallocatechin gallate nanoparticle (b) obtained in example 4.
FIG. 5 is a transmission electron microscope of the manganese ion-supported amorphous calcium carbonate-tannic acid nanoparticle obtained in example 5.
FIG. 6 shows the transmission electron microscope (a) of the zinc ion-supported amorphous calcium carbonate-tannic acid nanoparticle obtained in example 6 and the ion release behavior (b) thereof in different pH environments in application example 1.
FIG. 7 shows the transmission electron microscope (a) of the copper ion-supported amorphous calcium carbonate-tannic acid nanoparticle obtained in example 7 and the ion release behavior (b) thereof in different pH environments in application example 2.
FIG. 8 shows the transmission electron microscope (a) of doxorubicin-encapsulated amorphous calcium carbonate-tannic acid nanoparticles obtained in example 8 and the ion release behavior (b) in application example 3 in different pH environments.
Fig. 9 shows transmission electron microscopy (a) of curcumin-encapsulated amorphous calcium carbonate-tannic acid nanoparticles obtained in example 9 and their ion release behavior (b) in different pH environments in application example 4.
FIG. 10 shows the transmission electron microscope (a) of rapamycin encapsulated amorphous calcium carbonate-tannic acid nanoparticles obtained in example 10 and the ion release behavior (b) in different pH environments in application example 5.
FIG. 11 shows transmission electron microscopy (a) of ribonuclease-encapsulated amorphous calcium carbonate-tannic acid nanoparticles obtained in example 11 and the property (b) of ribonuclease transfer into cells in application example 6.
FIG. 12 shows a transmission electron microscope (a) of glucose oxidase-encapsulated amorphous calcium carbonate-tannic acid nanoparticles obtained in example 12 and a property (b) of storing glucose oxidase in application example 7.
FIG. 13 is a transmission electron micrograph of amorphous calcium carbonate-tannic acid nanoparticles obtained in example 13 using different amorphous calcium carbonate and tannic acid mass ratios.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. Modifications and equivalents will occur to those skilled in the art upon understanding the present teachings without departing from the spirit and scope of the present teachings.
The raw materials used in the following embodiments are commercially available unless otherwise specified.
Example 1
150mg of calcium chloride dihydrate is dissolved in 1mL of water, the solution is added into a 250mL beaker, 50mL of absolute ethyl alcohol is added into the beaker, two layers of breathable square tissues are covered on a beaker cover, 200mg of ammonium bicarbonate is paved on the square tissues, and finally, the mouth of the beaker is wrapped by tin paper. The whole beaker was placed in an oven preheated at 60 ℃ and stirred for 1 hour, and the liquid in the beaker was seen to turn white from clear. The product was centrifuged at 7000 rpm for 3 minutes, and the precipitate was collected and washed with absolute ethanol to obtain amorphous calcium carbonate nanoparticles.
The amorphous calcium carbonate nanoparticles obtained above were resuspended in 20mL of absolute ethanol, 80 mL of an aqueous tannic acid solution having a concentration of 0.5 mmol/l was rapidly poured therein, at which time the mass ratio of amorphous calcium carbonate nanoparticles to tannic acid was about 1:1, and left to stand at room temperature for 1min, the product was centrifuged at 10000 rpm for 3 min, the precipitate was collected, washed with deionized water, and lyophilized to obtain amorphous calcium carbonate-tannic acid hollow nanoparticles of about 108mg.
The transmission electron microscope of the obtained amorphous calcium carbonate nanoparticle and amorphous calcium carbonate-tannic acid hollow nanoparticle is shown in figure 1, wherein (a) is amorphous calcium carbonate nanoparticle and (b) is amorphous calcium carbonate-tannic acid hollow nanoparticle; the size of the prepared amorphous calcium carbonate nanoparticle is about 150nm, and the size distribution is uniform; the size of the amorphous calcium carbonate-tannic acid hollow nano particle is about 200nm, the pore diameter is about 100nm, and the size distribution is uniform.
The ultraviolet absorption curves of pure tannic acid and the above-obtained amorphous calcium carbonate nanoparticles and amorphous calcium carbonate-tannic acid hollow nanoparticle solution were tested, and as a result, as shown in (c) of fig. 1, it was seen that the obtained amorphous calcium carbonate-tannic acid hollow nanoparticles were very close in composition to tannic acid, and were greatly different from the original amorphous calcium carbonate nanoparticles.
Example 2
150mg of calcium chloride dihydrate is dissolved in 1mL of water, the solution is added into a 250mL beaker, 50mL of absolute ethyl alcohol is added into the beaker, two layers of breathable square tissues are covered on a beaker cover, 100mg of ammonium bicarbonate is paved on the square tissues, and finally, the mouth of the beaker is wrapped by tin paper. The whole beaker was placed in an oven preheated at 50 ℃ and stirred for 1 hour, and the liquid in the beaker was seen to turn white from clear. The product was centrifuged at 10000 rpm for 3 minutes, the precipitate was collected and washed with absolute ethanol to obtain amorphous calcium carbonate nanoparticles.
The amorphous calcium carbonate nanoparticles obtained above were resuspended in 20mL of absolute ethanol, 80 mL of an aqueous tannic acid solution having a concentration of 0.3 mmol/l was rapidly poured therein, at which time the mass ratio of amorphous calcium carbonate nanoparticles to tannic acid was about 1:1, and left to stand at room temperature for 1min, the product was centrifuged at 10000 rpm for 3 min, the precipitate was collected, washed with deionized water, and lyophilized to obtain amorphous calcium carbonate-tannic acid hollow nanoparticles of about 98mg.
The transmission electron microscope of the obtained amorphous calcium carbonate nanoparticle and amorphous calcium carbonate-tannic acid hollow nanoparticle is shown in fig. 2, wherein (a) is amorphous calcium carbonate nanoparticle and (b) is amorphous calcium carbonate-tannic acid hollow nanoparticle; the size of the prepared amorphous calcium carbonate nanoparticle is about 100nm, and the size distribution is uniform; the size of the amorphous calcium carbonate-tannic acid hollow nano particle is about 120nm, the pore diameter is about 60nm, and the size distribution is uniform.
It can be seen from examples 1 and 2 that the size distribution of the obtained amorphous calcium carbonate nanoparticles can be controlled by adjusting the process, thereby adjusting the size distribution of the obtained amorphous calcium carbonate-tannic acid hollow nanoparticles.
Example 3
150mg of calcium chloride dihydrate is dissolved in 1mL of water, the solution is added into a 250mL beaker, 50mL of absolute ethyl alcohol is added into the beaker, two layers of breathable square tissues are covered on a beaker cover, 200mg of ammonium bicarbonate is paved on the square tissues, and finally, the mouth of the beaker is wrapped by tin paper. The whole beaker was placed in an oven preheated at 60 ℃ and stirred for 1 hour, and the liquid in the beaker was seen to turn white from clear. The product was centrifuged at 7000 rpm for 3 minutes, and the precipitate was collected and washed with absolute ethanol to obtain amorphous calcium carbonate nanoparticles.
The amorphous calcium carbonate nanoparticles obtained above were resuspended in 20mL of absolute ethanol, 80 mL of gallic acid aqueous solution with a concentration of 1 mmol/l was rapidly poured therein, at which time the mass ratio of amorphous calcium carbonate nanoparticles to gallic acid was about 1:0.1, and allowed to stand at room temperature for 1min, the product was centrifuged at 10000 rpm for 3 min, the precipitate was collected, washed with deionized water, and lyophilized to obtain amorphous calcium carbonate-gallic acid hollow nanoparticles of about 85mg.
The transmission electron microscope of the obtained amorphous calcium carbonate nanoparticle and amorphous calcium carbonate-gallic acid hollow nanoparticle is shown in figure 3, wherein (a) is amorphous calcium carbonate nanoparticle and (b) is amorphous calcium carbonate-gallic acid hollow nanoparticle; the prepared amorphous calcium carbonate particles have the size of about 80nm and uniform size distribution; the size of the amorphous calcium carbonate-gallic acid hollow nano particle is about 100nm, the pore diameter is about 80nm, and the size distribution is uniform.
Example 4
150mg of calcium chloride dihydrate is dissolved in 1mL of water, the solution is added into a 250mL beaker, 50mL of absolute ethyl alcohol is added into the beaker, two layers of breathable square tissues are covered on a beaker cover, 100mg of ammonium bicarbonate is paved on the square tissues, and finally, the mouth of the beaker is wrapped by tin paper. The whole beaker was placed in an oven preheated at 50 ℃ and stirred for 1 hour, and the liquid in the beaker was seen to turn white from clear. The product was centrifuged at 10000 rpm for 3 minutes, the precipitate was collected and washed with absolute ethanol to obtain amorphous calcium carbonate nanoparticles.
The amorphous calcium carbonate nanoparticles obtained above were resuspended in 20mL of absolute ethanol, 80 mL of an aqueous epigallocatechin gallate solution having a concentration of 0.6 mmol/L was rapidly poured therein, at which time the mass ratio of amorphous calcium carbonate nanoparticles to epigallocatechin gallate was about 1:0.2, and the mixture was allowed to stand at room temperature for 1min, the product was centrifuged at 10000 rpm for 3 min, the precipitate was collected, washed with deionized water, and lyophilized to obtain amorphous calcium carbonate-epigallocatechin gallate hollow nanoparticles of about 98mg.
The transmission electron microscope of the obtained amorphous calcium carbonate nanoparticle and amorphous calcium carbonate-epigallocatechin gallate hollow nanoparticle is shown in figure 4, wherein (a) is amorphous calcium carbonate nanoparticle and (b) is amorphous calcium carbonate-epigallocatechin gallate hollow nanoparticle; the size of the prepared amorphous calcium carbonate particles is about 100nm, and the size distribution is uniform; the amorphous calcium carbonate-epigallocatechin gallate hollow nano particle has the size of about 180nm, the pore diameter of about 120nm and uniform size distribution.
Example 5
Amorphous calcium carbonate-tannic acid hollow nanoparticles prepared as described in example 1 were dispersed in water to prepare a dispersion of 2 mg/mL.
9mg of manganese sulfate monohydrate was dissolved in 1mL of water to prepare a manganese ion solution of 3 mg/mL. Mixing amorphous calcium carbonate-tannic acid hollow nanoparticle dispersion liquid with the manganese ion solution in an equal volume, wherein the mass ratio of amorphous calcium carbonate-tannic acid hollow nanoparticle to manganese ion is 2:3; shaking, standing for 30 seconds, centrifuging the product at a speed of 5000 rpm for 3 minutes, collecting precipitate, and cleaning with deionized water to obtain the manganese ion-loaded amorphous calcium carbonate-tannic acid nanoparticles. The transmission electron microscope is shown in fig. 5.
Example 6
Amorphous calcium carbonate-tannic acid hollow nanoparticles prepared as described in example 1 were dispersed in water to prepare a dispersion of 2 mg/mL.
12mg of anhydrous zinc acetate was dissolved in 1mL of water to prepare a zinc ion solution of 3 mg/mL. Mixing amorphous calcium carbonate-tannic acid hollow nanoparticle dispersion liquid with the zinc ion solution in an equal volume, wherein the mass ratio of amorphous calcium carbonate-tannic acid hollow nanoparticle to zinc ion is 2:3; shaking, standing for 30 seconds, centrifuging the product at 8000 rpm for 3 minutes, collecting precipitate, and cleaning with deionized water to obtain amorphous calcium carbonate-tannic acid nanoparticle loaded with zinc ions. The transmission electron microscope is shown in fig. 6 (a).
Example 7
Amorphous calcium carbonate-tannic acid hollow nanoparticles prepared as described in example 1 were dispersed in water to prepare a dispersion of 2 mg/mL.
12mg of copper sulfate pentahydrate was dissolved in 1mL of water to prepare a copper ion solution of 3mg/mL, and then a small amount of ammonia water-ammonium chloride buffer was added to adjust the pH of the copper ion solution to 9. Mixing amorphous calcium carbonate-tannic acid hollow nanoparticle dispersion liquid with the copper ion solution in an equal volume, wherein the mass ratio of amorphous calcium carbonate-tannic acid hollow nanoparticle to copper ion is 2:3; shaking, standing for 30 seconds, centrifuging the product at a speed of 5000 rpm for 3 minutes, collecting precipitate, and cleaning with deionized water to obtain the copper ion-loaded amorphous calcium carbonate-tannic acid nanoparticles. The transmission electron microscope is shown in fig. 7 (a).
Example 8
10mg of doxorubicin hydrochloride was dissolved in 1mL of dimethyl sulfoxide to prepare a 10mg/mL doxorubicin solution.
The amorphous calcium carbonate nanoparticles obtained according to the preparation method described in example 1 were resuspended in 20mL of absolute ethanol, the above 200 μl of the above doxorubicin solution was added and shaken well, then 80 mL of a tannic acid aqueous solution having a concentration of 0.5 mmol/l was rapidly poured therein, the mass ratio of amorphous calcium carbonate nanoparticles to doxorubicin was 6:1, the mass ratio to tannic acid was 1:1, the mixture was allowed to stand at room temperature for 1min, the product was centrifuged at 10000 rpm for 3 minutes, and the precipitate was collected and washed with deionized water to obtain doxorubicin-encapsulated amorphous calcium carbonate-tannic acid hollow nanoparticles. The transmission electron microscope is shown in fig. 8 (a).
Example 9
10mg of curcumin was dissolved in 1mL of dimethyl sulfoxide to prepare a curcumin solution of 10 mg/mL.
The amorphous calcium carbonate nanoparticles obtained according to the preparation method described in example 1 were resuspended in 20mL of absolute ethanol, the above 200 μl of the above curcumin solution was added and shaken well, then 80 mL of tannic acid aqueous solution with a concentration of 0.5 mmol/l was rapidly poured therein, the mass ratio of amorphous calcium carbonate nanoparticles to curcumin was 6:1, the mass ratio to tannic acid was 1:1, and the mixture was left to stand at room temperature for 1min, and the product was centrifuged at 10000 rpm for 3 min, and the precipitate was collected and washed with deionized water to obtain curcumin-encapsulated amorphous calcium carbonate-tannic acid hollow nanoparticles. The transmission electron microscope is shown in fig. 9 (a).
Example 10
10mg of rapamycin was dissolved in 1mL of absolute ethanol and a 10mg/mL rapamycin solution was prepared.
The amorphous calcium carbonate nanoparticles obtained according to the preparation method described in example 1 were resuspended in 20mL of absolute ethanol, the above 200 μl of rapamycin solution was added and shaken well, then 80 mL of tannic acid aqueous solution with a concentration of 0.5 mmol/l was rapidly poured therein, the mass ratio of amorphous calcium carbonate nanoparticles to rapamycin was 6:1, the mass ratio of amorphous calcium carbonate nanoparticles to tannic acid was 1:1, and the mixture was allowed to stand at room temperature for 1min, and the product was centrifuged at 10000 rpm for 3 min, and the precipitate was collected and washed with deionized water to obtain rapamycin-encapsulated amorphous calcium carbonate-tannic acid hollow nanoparticles. The transmission electron microscope is shown in fig. 10 (a).
Example 11
10mg of ribonuclease was dissolved in 1mL of water to prepare a 10mg/mL ribonuclease solution.
The amorphous calcium carbonate nanoparticles obtained according to the preparation method described in example 1 were resuspended in 20mL of absolute ethanol, the above 200. Mu.l of the above ribonuclease solution was added and shaken well, then 80 mL of an aqueous tannic acid solution with a concentration of 0.5 mmol/l was rapidly poured therein, the mass ratio of amorphous calcium carbonate nanoparticles to ribonuclease was 6:1, the mass ratio of amorphous calcium carbonate nanoparticles to tannic acid was 1:1, and the mixture was left to stand at room temperature for 1min, and the product was centrifuged at 10000 rpm for 3 minutes, and the precipitate was collected and washed with deionized water to obtain ribonuclease-encapsulated amorphous calcium carbonate-tannic acid hollow nanoparticles. The transmission electron microscope is shown in fig. 11 (a).
Example 12
10mg of glucose oxidase was dissolved in 1mL of water to prepare a 10mg/mL glucose oxidase solution.
The amorphous calcium carbonate nanoparticles obtained according to the preparation method described in example 1 were resuspended in 20mL of absolute ethanol, the above 200. Mu.l of the above glucose oxidase solution was added and shaken well, then 80 mL of an aqueous tannic acid solution having a concentration of 0.5 mmol/l was rapidly poured thereinto, the mass ratio of amorphous calcium carbonate nanoparticles to glucose oxidase was 6:1, the mass ratio of amorphous calcium carbonate nanoparticles to tannic acid was 1:1, and the mixture was left to stand at room temperature for 1min, and the product was centrifuged at 10000 rpm for 3 minutes, and the precipitate was collected and washed with deionized water to obtain amorphous calcium carbonate-tannic acid hollow nanoparticles encapsulated with glucose oxidase. The transmission electron microscope is shown in fig. 12 (a).
Application example 1
To investigate the ion release behavior of zinc ion loaded amorphous calcium carbonate-tannic acid nanoparticles in different pH environments:
the different pH environments were simulated by using PBS phosphate buffer solution, amorphous calcium carbonate-tannic acid nano particles loaded with zinc ions prepared in example 6 were respectively added into different solutions (water, phosphate buffer solution PBS with pH value of 7.4 and phosphate buffer solution PBS with pH value of 6.0), the solutions were centrifuged at different time points, and the supernatant was taken to determine the content of the released zinc ions.
The results are shown in fig. 6 (b), which shows that the zinc ion-loaded amorphous calcium carbonate-tannic acid nanoparticles hardly decompose in water and phosphate buffer solution PBS of pH 7.4, which simulates physiological environment, showing their excellent physiological environment stability; in a phosphate buffer solution with a low pH value in a microenvironment simulating bacterial infection, amorphous calcium carbonate-tannic acid nano particles loaded by zinc ions can be rapidly decomposed, and the zinc ions are released to clear the bacterial infection.
Application example 2
To investigate the ion release behavior of copper ion loaded amorphous calcium carbonate-tannic acid nanoparticles in different pH environments:
the pH environments were simulated by using PBS phosphate buffer solution, the amorphous calcium carbonate-tannic acid nanoparticles loaded with copper ions prepared in example 7 were respectively added into different solutions (water, phosphate buffer solution PBS with pH value of 7.4 and phosphate buffer solution PBS with pH value of 6.0), the solutions were centrifuged at different time points, and the supernatant was taken to determine the content of the released copper ions.
The results are shown in fig. 7 (b), which shows that the copper ion-loaded amorphous calcium carbonate-tannic acid nanoparticles hardly decompose in water and phosphate buffer solution PBS at a simulated physiological environment pH of 7.4, showing excellent physiological environment stability; in a phosphate buffer solution with a low pH value in a microenvironment simulating bacterial infection, the amorphous calcium carbonate-tannic acid nano particles loaded by copper ions can be rapidly decomposed to release the copper ions to clear the bacterial infection.
Application example 3
To investigate the ion release behavior of doxorubicin encapsulated amorphous calcium carbonate-tannic acid nanoparticles in different pH environments:
the different pH environments were simulated by PBS phosphate buffer solution, the doxorubicin-encapsulated amorphous calcium carbonate-tannic acid nanoparticles prepared in example 8 were added to different solutions (water, phosphate buffer solution PBS with pH value of 7.4, phosphate buffer solution PBS with pH value of 6.0) respectively, the solutions were centrifuged at different time points, and the supernatant was taken to determine the released doxorubicin content.
The results are shown in fig. 8 (b), which shows that doxorubicin-encapsulated amorphous calcium carbonate-tannic acid nanoparticles hardly decompose in water and phosphate buffer solution PBS at a simulated physiological environment pH of 7.4, showing their excellent physiological environment stability; in phosphate buffer solution simulating tumor acidic microenvironment (pH 6.0), the amorphous calcium carbonate-tannic acid nanoparticle encapsulated by the doxorubicin can be rapidly decomposed to release the doxorubicin to kill tumor cells.
Application example 4
To investigate the ion release behavior of curcumin encapsulated amorphous calcium carbonate-tannic acid nanoparticles in different pH environments:
the pH environment was simulated with PBS phosphate buffer, the curcumin-encapsulated amorphous calcium carbonate-tannic acid nanoparticles prepared in example 9 were added to different solutions (water, phosphate buffer solution PBS with pH 7.4, phosphate buffer solution PBS with pH 6.0) respectively, the solutions were centrifuged at different times, and the supernatant was taken to determine the content of curcumin released.
The results are shown in fig. 9 (b), which shows that curcumin encapsulated amorphous calcium carbonate-tannic acid nanoparticles hardly decompose in water and phosphate buffer solution PBS at simulated physiological environment pH 7.4, showing their excellent physiological environment stability; in a phosphate buffer solution with low pH value in an acidic microenvironment simulating a bacterial biofilm, the curcumin-encapsulated amorphous calcium carbonate-tannic acid nanoparticles can be rapidly decomposed to release curcumin to damage the bacterial biofilm.
Application example 5
To investigate the ion release behavior of rapamycin encapsulated amorphous calcium carbonate-tannic acid nanoparticles in different pH environments:
the rapamycin encapsulated amorphous calcium carbonate-tannic acid nanoparticles prepared in example 10 were added to different solutions (water, phosphate buffered saline PBS at pH 7.4, phosphate buffered saline PBS at pH 6.0) respectively, the solutions were centrifuged at different time points, and the supernatant was taken to determine the released rapamycin content.
The results are shown in fig. 10 (b), which shows that the rapamycin encapsulated amorphous calcium carbonate-tannic acid nanoparticles hardly decompose in water and phosphate buffer solution PBS at a simulated physiological environment pH of 7.4, showing their excellent physiological environment stability; in a phosphate buffer solution with a low pH value in an acidic microenvironment simulating inflammation, the rapamycin encapsulated amorphous calcium carbonate-tannic acid nano particles can be rapidly decomposed, and rapamycin is released to relieve inflammation.
Application example 6
To investigate the properties of ribonuclease-encapsulated amorphous calcium carbonate-tannic acid nanoparticles to intracellular delivery enzymes:
l-929 was finely inoculated in 96-well plates with a cell number of 5X 10 per well 4 After cell attachment (overnight), amorphous calcium carbonate-tannic acid nanoparticles (pure carrier), ribonuclease and the encapsulated ribonuclease prepared in example 11 were added to each group for incubation, each group was provided with 6 multiple wells, and at 37℃5% CO 2 Cell viability was determined by CCK-8 after 24h incubation in an incubator.
The results are shown in FIG. 11 (b), which shows that pure vector and free ribonuclease show little cytotoxicity, whereas encapsulated ribonuclease shows stronger cytotoxicity due to its ability to be efficiently endocytosed into cells. This result shows that enzymes can be encapsulated by amorphous calcium carbonate-tannic acid nanoparticles to increase their intracellular delivery efficiency.
Application example 7
To investigate the change in enzyme activity of glucose oxidase before and after encapsulation of amorphous calcium carbonate-tannic acid nanoparticles:
the enzyme activity of free glucose oxidase, amorphous calcium carbonate-tannic acid nanoparticles (neat carrier), the encapsulated glucose oxidase prepared in example 12, was measured with a glucose oxidase activity kit under different pH environments.
The results are shown in FIG. 12 (b), which shows that the encapsulated glucose oxidase will decompose at pH 6.0, and that the released glucose oxidase activity is better retained. This result demonstrates that preservation of enzymes can be performed by amorphous calcium carbonate-tannic acid nanoparticles.
Example 13
According to the preparation process of example 1, only the concentrations of tannic acid were adjusted to be 0.25, 2 and 5 mmoles/liter, respectively, i.e., the mass ratio of amorphous calcium carbonate nanoparticles to tannic acid was 1:0.5, 1:4 and 1:10, respectively, and the results of the transmission electron microscopy of the obtained amorphous calcium carbonate-tannic acid nanoparticles are shown in fig. 13. The particles obtained at a tannic acid concentration of 0.5,2 mmol/l were found to have a uniform morphology and good dispersibility.
Claims (10)
1. A method for preparing amorphous calcium carbonate-polyphenol hollow nano-particles, which is characterized by comprising the following steps:
step 1, reacting a calcium ion solution with ammonium carbonate or ammonium bicarbonate, centrifuging, and taking out precipitates to obtain amorphous calcium carbonate nano particles;
step 2, adding a polyphenol aqueous solution into the alcohol dispersion liquid of the amorphous calcium carbonate nano particles prepared in the step 1, mixing, centrifuging and taking out precipitate to obtain amorphous calcium carbonate-polyphenol hollow nano particles;
or, step 2 is replaced with the following step S:
and S, sequentially or simultaneously adding a drug solution and a polyphenol water solution into the alcohol dispersion liquid of the amorphous calcium carbonate nano particles prepared in the step 1, mixing, centrifuging and taking out precipitate to obtain the drug-encapsulated amorphous calcium carbonate-polyphenol hollow nano particles.
2. The method for preparing amorphous calcium carbonate-polyphenol hollow nanoparticles according to claim 1, further comprising the steps of: and (3) mixing the amorphous calcium carbonate-polyphenol hollow nano particles prepared in the step (2) or the step (S) with a metal ion solution, and centrifuging to obtain a precipitate to obtain the amorphous calcium carbonate-polyphenol hollow nano particles loaded by metal ions.
3. The method for preparing amorphous calcium carbonate-polyphenol hollow nanoparticles according to claim 1, wherein the calcium ion solution comprises any one or more solutions of water, methanol, ethanol or propanol of soluble calcium salt; the soluble calcium salt comprises any one or more of calcium chloride, calcium sulfate, calcium nitrate and hydrates thereof;
and/or the molar concentration of calcium ions in the calcium ion solution is 10mmol/L-1mol/L;
and/or the reaction temperature of the step 1 is 50-80 ℃ and the reaction time is 0.5-24h.
4. The method for preparing amorphous calcium carbonate-polyphenol hollow nanoparticles according to claim 1, wherein the polyphenols comprise one or more of tannins or tea polyphenols, flavonoids, gossypols, anthocyans;
and/or the molar concentration of polyphenol in the aqueous polyphenol solution is 5 mu mol/L to 5mmol/L;
and/or the drug comprises a small molecule drug and/or a large molecule drug.
5. The method for preparing amorphous calcium carbonate-polyphenol hollow nanoparticles according to claim 1, wherein in step 2 or step S, the mass ratio of amorphous calcium carbonate nanoparticles prepared in step 1 to polyphenols is 1:0.1-10; and/or the mixing time is 5s or more.
6. The method for preparing amorphous calcium carbonate-polyphenol hollow nanoparticles according to claim 1, wherein in the step S, the mass ratio of the drug to the amorphous calcium carbonate nanoparticles prepared in the step 1 is 0-100:1, and the drug is not 0.
7. The method of preparing shaped calcium carbonate-polyphenol hollow nanoparticles according to claim 2, wherein the metal ions comprise any one or more of magnesium, aluminum, scandium, titanium, vanadium, chromium, manganese, cobalt, nickel, copper, zinc, gallium, germanium, molybdenum, barium, silver, cadmium, barium, gold, platinum, lanthanoid.
8. The method for preparing the shaped calcium carbonate-polyphenol hollow nanoparticle according to claim 2, wherein the mass ratio of the metal ion to the amorphous calcium carbonate-polyphenol hollow nanoparticle prepared in step 2 or step S is 0-10:1, and the metal ion is not 0; and/or the mixing time is 5s or more.
9. Amorphous calcium carbonate-polyphenol hollow nanoparticle prepared by the preparation method according to any one of claims 1 to 8, wherein the amorphous calcium carbonate-polyphenol hollow nanoparticle has a hollow spherical structure, an average particle diameter of 100 to 300 nanometers, and a cavity diameter of 20 to 200 nanometers.
10. Use of amorphous calcium carbonate-polyphenol hollow nanoparticles according to claim 9 in the preparation of daily chemicals, medical drugs or biological devices.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310414753.6A CN116495763A (en) | 2023-04-18 | 2023-04-18 | Amorphous calcium carbonate-polyphenol hollow nanoparticle as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310414753.6A CN116495763A (en) | 2023-04-18 | 2023-04-18 | Amorphous calcium carbonate-polyphenol hollow nanoparticle as well as preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116495763A true CN116495763A (en) | 2023-07-28 |
Family
ID=87317668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310414753.6A Pending CN116495763A (en) | 2023-04-18 | 2023-04-18 | Amorphous calcium carbonate-polyphenol hollow nanoparticle as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116495763A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130036948A1 (en) * | 2011-04-28 | 2013-02-14 | Miguel Fernandez | Methods and compositions using calcium carbonate and stabilizer |
| WO2021171088A1 (en) * | 2020-02-25 | 2021-09-02 | <<Qr.Bio>>, Limited Liability Company | Nanocarriers for delivery of molecules to clinically relevant cell types |
| WO2022144136A1 (en) * | 2020-12-30 | 2022-07-07 | Luxembourg Institute Of Science And Technology (List) | Stabilisation of carbonate calcium nanoparticles |
| CN115043420A (en) * | 2022-07-13 | 2022-09-13 | 西安交通大学 | Porous hollow calcium carbonate nanosphere and preparation method and application thereof |
-
2023
- 2023-04-18 CN CN202310414753.6A patent/CN116495763A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130036948A1 (en) * | 2011-04-28 | 2013-02-14 | Miguel Fernandez | Methods and compositions using calcium carbonate and stabilizer |
| WO2021171088A1 (en) * | 2020-02-25 | 2021-09-02 | <<Qr.Bio>>, Limited Liability Company | Nanocarriers for delivery of molecules to clinically relevant cell types |
| WO2022144136A1 (en) * | 2020-12-30 | 2022-07-07 | Luxembourg Institute Of Science And Technology (List) | Stabilisation of carbonate calcium nanoparticles |
| CN115043420A (en) * | 2022-07-13 | 2022-09-13 | 西安交通大学 | Porous hollow calcium carbonate nanosphere and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| ZILIANG DONG: "Synthesis of Hollow Biomineralized CaCO3−Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity", JACS, 28 January 2018 (2018-01-28), pages 2165 - 2178 * |
| 李亮;朱英杰;曹少文;马明燕;: "碳酸钙纳米结构多孔空心微球的制备及其药物缓释性能研究", 无机材料学报, no. 01, 15 January 2009 (2009-01-15) * |
| 董自亮: "肿瘤微环境响应性纳米材料的可控制备与肿瘤治疗增敏研究", 中国知网优秀博士学位伦数据库, 15 June 2021 (2021-06-15), pages 105 - 135 * |
| 韩熠楷: "新型碳酸钙基生物材料用于肿瘤化疗增敏研究", 万方学位论文数据库, 12 January 2023 (2023-01-12), pages 29 - 60 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Metal-organic frameworks for stimuli-responsive drug delivery | |
| Zhang et al. | Hydrothermal synthesis of Ag nanoparticles on the nanocellulose and their antibacterial study | |
| Qi et al. | Preparation and antibacterial activity of chitosan nanoparticles | |
| Rastogi et al. | Highly stable, protein capped gold nanoparticles as effective drug delivery vehicles for amino-glycosidic antibiotics | |
| Zhao et al. | Microwave-assisted synthesis of silver nanoparticles using sodium alginate and their antibacterial activity | |
| Geisberger et al. | Synthesis, characterisation and cytotoxicity of polyoxometalate/carboxymethyl chitosan nanocomposites | |
| KR101117177B1 (en) | Method for synthesizing silver nanoparticles by solid-state reaction process and silver nanoparticles synthesized by the same | |
| CN106880593B (en) | Nano antibacterial agent simultaneously loaded with nano silver and curcumin and preparation method and application thereof | |
| CN102604115B (en) | Carboxymethyl chitosan quaternary ammonium salt/PAMAM(Polyamidoamine) core-shell nanoparticles and preparation method | |
| LU502502B1 (en) | Preparation method and characteristic of novel multifunctional janus-type mesoporous silica nano-pesticide fertilizer | |
| Qiu et al. | Triple-stimuli (protease/redox/pH) sensitive porous silica nanocarriers for drug delivery | |
| CN103563983A (en) | Nano-silver peroxide composite antibacterial solution and preparation method thereof | |
| CN111202091A (en) | Nano-silver loaded mesoporous silica antibacterial material and preparation method and application thereof | |
| Wang et al. | Chitosan-modified halloysite nanotubes as a controlled-release nanocarrier for nitrogen delivery | |
| Malathi et al. | Green synthesis of gold nanoparticles for controlled delivery | |
| Qin et al. | Green synthesis of biocompatible trypsin-conjugated Ag nanocomposite with antibacterial activity | |
| Luo et al. | An NIF-doped ZIF-8 hybrid membrane for continuous antimicrobial treatment | |
| Yilmaz et al. | Synthesis of taurine-Cu3 (PO4) 2 hybrid nanoflower and their peroxidase-mimic and antimicrobial properties | |
| CN115919801B (en) | Preparation method of tannic acid-zinc coordinated chitosan-selenium nanoparticle | |
| Zhang et al. | A redox and pH dual-triggered drug delivery platform based on chitosan grafted tubular mesoporous silica | |
| Moaness et al. | Novel zinc-silver nanocages for drug delivery and wound healing: Preparation, characterization and antimicrobial activities | |
| CN108096214B (en) | Magnetotactic bacteria quantum dot microcapsule and preparation method thereof | |
| Yang et al. | Biomineralization inspired synthesis of CaCO3-based DDS for pH-responsive release of anticancer drug | |
| Sathiyaseelan et al. | Research progress on chitosan-zinc oxide nanocomposites fabrication, characterization, biomedical and environmental applications | |
| CN113998679B (en) | Manganese phosphate nano material, and rapid preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |