CN108283718A - 一种镁离子掺杂纳米磷酸钙颗粒、其制备方法及用途 - Google Patents
一种镁离子掺杂纳米磷酸钙颗粒、其制备方法及用途 Download PDFInfo
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- CN108283718A CN108283718A CN201711406296.7A CN201711406296A CN108283718A CN 108283718 A CN108283718 A CN 108283718A CN 201711406296 A CN201711406296 A CN 201711406296A CN 108283718 A CN108283718 A CN 108283718A
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- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 47
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 47
- 239000002245 particle Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000002105 nanoparticle Substances 0.000 claims abstract description 57
- 239000003814 drug Substances 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 28
- 238000013268 sustained release Methods 0.000 claims abstract description 7
- 239000012730 sustained-release form Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 35
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 229960004343 alendronic acid Drugs 0.000 claims description 14
- 230000009514 concussion Effects 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 238000010348 incorporation Methods 0.000 claims description 12
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 12
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 12
- 239000012498 ultrapure water Substances 0.000 claims description 12
- 239000011575 calcium Substances 0.000 claims description 11
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 238000005119 centrifugation Methods 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 239000007853 buffer solution Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 159000000007 calcium salts Chemical class 0.000 claims description 6
- 159000000003 magnesium salts Chemical class 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- -1 rhodamine isothiocyanate Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 230000002045 lasting effect Effects 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 239000004575 stone Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 229960002319 barbital Drugs 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 claims description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 2
- GHXRKGHKMRZBJH-UHFFFAOYSA-N boric acid Chemical compound OB(O)O.OB(O)O GHXRKGHKMRZBJH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000337 buffer salt Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
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- 230000003139 buffering effect Effects 0.000 claims 1
- 239000002367 phosphate rock Substances 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 11
- 235000011010 calcium phosphates Nutrition 0.000 abstract description 8
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 abstract description 8
- 230000015556 catabolic process Effects 0.000 abstract description 7
- 238000006731 degradation reaction Methods 0.000 abstract description 7
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- 239000008187 granular material Substances 0.000 abstract description 6
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- 125000003368 amide group Chemical group 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 235000013339 cereals Nutrition 0.000 description 7
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- 238000011026 diafiltration Methods 0.000 description 6
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 239000012930 cell culture fluid Substances 0.000 description 4
- 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 4
- 239000000203 mixture Substances 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 3
- 239000012901 Milli-Q water Substances 0.000 description 3
- 241000209094 Oryza Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910001425 magnesium ion Inorganic materials 0.000 description 3
- CVPJXKJISAFJDU-UHFFFAOYSA-A nonacalcium;magnesium;hydrogen phosphate;iron(2+);hexaphosphate Chemical compound [Mg+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Fe+2].OP([O-])([O-])=O.OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O CVPJXKJISAFJDU-UHFFFAOYSA-A 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229910052591 whitlockite Inorganic materials 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000004271 bone marrow stromal cell Anatomy 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005253 cladding Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 208000016261 weight loss Diseases 0.000 description 2
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- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- 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
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- VWDWKYIASSYTQR-YTBWXGASSA-N sodium;dioxido(oxo)azanium Chemical compound [Na+].[O-][15N+]([O-])=O VWDWKYIASSYTQR-YTBWXGASSA-N 0.000 description 1
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Classifications
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- 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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B25/00—Phosphorus; Compounds thereof
- C01B25/16—Oxyacids of phosphorus; Salts thereof
- C01B25/26—Phosphates
- C01B25/45—Phosphates containing plural metal, or metal and ammonium
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
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- C01P2004/00—Particle morphology
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种镁离子掺杂纳米磷酸钙颗粒,纳米颗粒本体外形为球形或椭球形结构,纳米颗粒本体的直径在60‑300nm之间,其内部为中空结构,纳米颗粒本体外壳上分布有若干通孔,通孔均与外界相通,中空结构的孔径30‑100nm之间,通孔的孔径在2‑50nm之间。本发明还提供了上述镁离子掺杂纳米磷酸钙颗粒的制备方法及其在载药缓释领域的应用。本发明极大地提高了磷酸钙颗粒的载药效率,并实现了药物的缓释。镁离子掺杂调控了材料的降解速率,使材料的降解和药物的释放表现出显著的酸碱环境依赖性。此外,通过对材料表面进行的氨基修饰,纳米颗粒易于进一步连接活性基团,应用于不同需求。
Description
技术领域
本发明属于生物医药材料技术领域,尤其是涉及一种镁离子掺杂纳米磷酸钙颗粒、其制备方法及用途。
背景技术
多孔结构的镁离子掺杂纳米磷酸钙颗粒具有包覆各类治疗性药物(如阿仑膦酸钠)的能力,并实现局部缓释效果,维持有效药物作用浓度。Chao Qi等人利用调控水热反应前体中钙盐及镁盐的比例,并引入磷酸肌酸二钠盐,制备出镁离子掺杂空心多孔结构磷酸钙小球,但所合成小球为微米级别。纳米颗粒具有与人体骨骼、牙齿等硬组织相似的和化学组成,具有良好的生物相容性,其降解产物不但可作为硬组织再生的无机盐来源,微量释放的钙、镁离子还可促进骨形成细胞的增殖、分化、矿化活动,加速硬组织缺损的愈合。
发明内容
有鉴于此,本发明旨在提出一种镁离子掺杂纳米磷酸钙颗粒,在常规沉淀法的基础上,通过镁离子与表面活性剂十二烷基硫酸钠,对磷酸钙材料结晶过程进行调控制备出具有空心介孔结构的纳米磷酸钙颗粒,纳米级介孔结构极大地提高磷酸钙颗粒的载药效率,并实现了药物的缓释。另外,本发明还系统研究了该纳米颗粒的体外降解速率,以及负载、释放阿仑膦酸钠药物的能力。通过体外生物学实验,测试了镁离子掺杂磷酸钙颗粒的生物相容性以及细胞对该纳米颗粒的吞噬性能。
为达到上述目的,本发明的技术方案是这样实现的:
一种镁离子掺杂纳米磷酸钙颗粒,包括纳米颗粒本体,所述纳米颗粒本体外形为球形或椭球形结构,纳米颗粒本体的直径在60-300nm之间,纳米颗粒本体的内部为中空结构,纳米颗粒本体的外壳上分布有若干通孔,通孔均与外界相通,部分所述通孔与中空结构连通,另一部分通孔不与中空结构连通。
优选的,所述中空结构的孔径30-100nm之间,通孔的孔径在2-50nm之间。
优选的,所述纳米颗粒本体含有的主要元素为Ca、P、O、Mg,且各元素均匀分布于纳米颗粒本体。
优选的,所述纳米颗粒本体的主要成分为化学式为Ca18Mg2H2(PO4)14的白磷石。
优选的,所述纳米颗粒本体还含有碳酸根及氨基成分。
本发明的另一目的在于提出一种上述镁离子掺杂纳米磷酸钙颗粒的制备方法,包括如下步骤:
A、将钙盐溶液和镁盐溶液混合,并加入与混合液等体积的十二烷基磷酸钠溶液,搅拌使其全部混合均匀;
B、在上述混合液中加入磷酸盐溶液,调节使其pH不小于10.0,持续搅拌且恒温24小时以上,确保液体温度保持在60℃,恒温期间不断调试pH值,确保其不小于10.0;
C、将步骤B中的液体离心得到纳米颗粒,并依次用超纯水和无水乙醇反复洗涤纳米颗粒,将所得产物于120℃下干燥,干燥时间不小于24小时,并于干燥环境中保存;
D、罗丹明标记:将步骤C中得到的固体研磨成粉末,并将粉末分散于pH值为7.4的缓冲溶液中,加入罗丹明异硫氰酸盐溶液,混合均匀并持续搅拌,在不小于9000rpm的转速下离心收集产物,经超纯水和无水乙醇先后洗涤多次,干燥后即得到罗丹明标记的纳米颗粒;
E、载药过程:将步骤D中得到的纳米颗粒粉末重悬于阿仑膦酸钠溶液中,于37℃,300rpm的摇床中避光震荡24小时,经超纯水快速洗涤后,离心获得载阿仑膦酸钠的白磷钙石纳米颗粒。
优选的,所述步骤A中钙盐溶液和镁盐溶液按照3:1的摩尔比进行混合,加入的十二烷基磷酸钠溶液的浓度为4.66mg/mL。
优选的,所述步骤B中的磷酸盐溶液包括磷酸二氢盐、可溶的磷酸一氢盐和可溶的磷酸正盐。
优选的,所述步骤D缓冲盐溶液为磷酸缓冲盐溶液、巴比妥钠-盐酸缓冲液、Tris-HCl缓冲液或者硼酸-硼砂缓冲液中的一种。
本发明的另一目的在于提出一种上述镁离子掺杂纳米磷酸钙颗粒载药缓释领域的应用。
相对于现有技术,本发明所述的镁离子掺杂纳米磷酸钙颗粒的纳米级介孔结构极大地提高了磷酸钙颗粒的载药效率,并实现了药物的缓释。镁离子掺杂调控了材料的降解速率,使材料的降解和药物的释放表现出显著的酸碱环境依赖性。此外,通过对材料表面进行的氨基修饰,纳米颗粒易于进一步连接活性基团(如罗丹明染料等),应用于不同需求。
具体的,本发明所述的镁离子掺杂纳米磷酸钙颗粒、其制备方法及用途具有以下优势:
(1)通过调节磷酸钙材料重沉淀前体溶液中钙盐和镁盐的比例,并引入表面活性剂(十二烷基硫酸钠,SDS),制备出镁离子掺杂且具有空心介孔结构的纳米磷酸钙颗粒;
(2)纳米级介孔结构极大地提高了磷酸钙颗粒的载药效率,实现了对常规难以通过吸附方式结合于磷酸钙类材料的阿仑膦酸钠的高效负载;同时,该纳米颗粒可达到在不同酸碱环境中以不同速率缓释阿仑膦酸钠药物效果;
(3)纳米颗粒具有良好的生物相容性,对人骨间充质干细胞不存在细胞毒性,且可被细胞内吞进入胞内实现药物的高效投放;
(4)纳米颗粒表面修饰有氨基,可方便高效地结合包括荧光染料在内的各種活性成分,实现对纳米颗粒的体内/体外失踪等功能。
附图说明
图1为实施例1中纳米磷酸钙颗粒的透射电镜图;
图2为实施例1中纳米磷酸钙颗粒的扫描电镜低倍图;
图3为实施例1中纳米磷酸钙颗粒的扫描电镜高倍图;
图4为实施例1中纳米磷酸钙颗粒的傅氏转换红外线光谱图;
图5为实施例1中纳米磷酸钙颗粒的X射线衍射谱图;
图6为实施例1中纳米磷酸钙颗粒的粒径分布统计图;
图7为实施例1中纳米磷酸钙颗粒的氮吸附曲线及孔径分布图;
图8为实施例1中纳米磷酸钙颗粒的热重分析曲线;
图9为实施例1中纳米磷酸钙颗粒的元素分布分析;
图10为实施例1中纳米磷酸钙颗粒于细胞培养液中镁、钙离子释放量;
图11为实施例1-9中不同药物浓度载药包覆率;
图12为实施例1中纳米磷酸钙颗粒在不同pH下的药物释放曲线;
图13为实施例1中纳米磷酸钙颗粒体外降解曲线(失重法);
图14为实施例1中纳米磷酸钙颗粒的不同浓度对人骨髓间充质干细胞活性的影响柱状图;
图15为实施例1中纳米磷酸钙颗粒进入人骨髓间充质干细胞的图像(激光共聚焦显微镜):a.细胞骨架;b.细胞核。
具体实施方式
除有定义外,以下实施例中所用的技术术语具有与本发明所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。
下面结合实施例及附图来详细说明本发明。
实施例1
A、将750mL、0.2mol/L的氯化钙溶液和250mL 0.2mol/L的氯化镁溶液混合,并加入与500mL、4.66mg/mL的十二烷基磷酸钠溶液,搅拌使其全部混合均匀;
B、在上述混合液中加入磷酸氢二铵溶液,控制元素摩尔比为(Ca+Mg)/P=1.67,用33%的氨水调节使其pH为10.0,持续搅拌且在60℃下恒温24小时,恒温期间不断调试pH值,确保其不小于10.0;
C、将步骤B中的液体离心得到纳米颗粒,先用超纯水洗涤5次,再用无水乙醇洗涤3次,将所得产物于120℃下干燥24小时,并于干燥环境中保存;
D、罗丹明标记:将步骤C中得到的固体研磨成粉末,并将10mg粉末分散于5mL、pH值为7.4的磷酸缓冲盐溶液中,再加入1mg/ml罗丹明异硫氰酸盐的甲醇溶液250μL,混合均匀并持续搅拌4小时,在9000rpm的转速下离心收集产物,先用超纯水滤洗2次,再用无水乙醇滤洗2次,干燥后即得到罗丹明标记的纳米颗粒;
E、载药过程:将步骤D中得到的纳米颗粒粉末重悬于0.6mg/mL阿仑膦酸钠溶液中,震荡15秒后,于37℃,300rpm的摇床中避光震荡24小时,经超纯水快速洗涤后,离心获得载阿仑膦酸钠的白磷钙石纳米颗粒。
从图1和图3中能够明显看到制备的纳米颗粒为具有中空结构的球体或椭球体,球体外壳具有与外界相连通的介孔结构;从图2和图6中能够明显看到所制备的纳米颗粒为均质的球体或椭球体结构,其中球体直径在60-300nm之间;从图4中可见所制得的纳米颗粒含有一定量的碳酸根和氨基成分;将图5中的X射线衍射谱图与标准卡片(JCPDS card#70-2064)对比可知,所制得的纳米颗粒的主要成分为化学式为Ca18Mg2H2(PO4)14的白磷石,同时含有少量碳酸钙成分;从图7的氮吸附曲线及孔径分布图可以看出制得的纳米颗粒的吸附曲线模式符合典型的介孔结构材料,孔径分布均匀,中空结构的孔径30-100nm之间,通孔的孔径在2-50nm之间;从图8中可以看出,所制得的纳米颗粒于100℃-445℃表现为平缓持续失重,而于445℃-657℃出现一显著失重,而657℃以上未见明显失重;从图9和表1我们可以看出制得的纳米颗粒主要成分为Ca、P、O、Mg,且各元素均匀分布于纳米颗粒上;我们将实施例1中制得的纳米颗粒投放72h,从图10中可以看到细胞培养液中镁离子含量显著增加,但对钙离子含量无明显影响。
实施例2
载药过程在300rpm的摇床中避光震荡48小时,其余制备方法与实施例1相同。
实施例3
载药过程在300rpm的摇床中避光震荡72小时,其余制备方法与实施例1相同。
实施例4
A、将750mL、0.2mol/L的硝酸钙溶液和250mL 0.2mol/L的硝酸镁溶液混合,并加入与500mL、4.66mg/mL的十二烷基磷酸钠溶液,搅拌使其全部混合均匀;
B、在上述混合液中加入磷酸二氢钠溶液,控制元素摩尔比为(Ca+Mg)/P=1.67,用33%的氨水调节使其pH为10.7,持续搅拌且在60℃下恒温28小时,恒温期间不断调试pH值,确保其不小于10.0;
C、将步骤B中的液体离心得到纳米颗粒,先用超纯水洗涤3次,再用无水乙醇洗涤3次,将所得产物于120℃下干燥32小时,并于干燥环境中保存;
D、罗丹明标记:将步骤C中得到的固体研磨成粉末,并将10mg粉末分散于5mL、pH值为7.4的Tris-HCl缓冲液中,再加入1mg/ml罗丹明异硫氰酸盐的甲醇溶液250μL,混合均匀并持续搅拌4小时,在9000rpm的转速下离心收集产物,先用超纯水滤洗2次,再用无水乙醇滤洗2次,干燥后即得到罗丹明标记的纳米颗粒;
E、载药过程:将步骤D中得到的纳米颗粒粉末重悬于1.5mg/ml阿仑膦酸钠溶液中,震荡15秒后,于37℃,300rpm的摇床中避光震荡24小时,经超纯水快速洗涤后,离心获得载阿仑膦酸钠的白磷钙石纳米颗粒。
实施例5
载药过程在300rpm的摇床中避光震荡48小时,其余制备方法与实施例4相同。
实施例6
载药过程在300rpm的摇床中避光震荡72小时,其余制备方法与实施例4相同。
实施例7
A、将750mL、0.2mol/L的氯化钙溶液和250mL 0.2mol/L的氯化镁溶液混合,并加入与500mL、4.66mg/mL的十二烷基磷酸钠溶液,搅拌使其全部混合均匀;
B、在上述混合液中加入磷酸钾溶液,控制元素摩尔比为(Ca+Mg)/P=1.67,用33%的氨水调节使其pH为11.0,持续搅拌且在60℃下恒温24小时,恒温期间不断调试pH值,确保其不小于10.0;
C、将步骤B中的液体离心得到纳米颗粒,先用超纯水洗涤5次,再用无水乙醇洗涤5次,将所得产物于120℃下干燥30小时,并于干燥环境中保存;
D、罗丹明标记:将步骤C中得到的固体研磨成粉末,并将10mg粉末分散于5mL、pH值为7.4的巴比妥钠-盐酸缓冲液中,再加入1mg/ml罗丹明异硫氰酸盐的甲醇溶液250μL,混合均匀并持续搅拌4小时,在9000rpm的转速下离心收集产物,先用超纯水滤洗3次,再用无水乙醇滤洗3次,干燥后即得到罗丹明标记的纳米颗粒;
E、载药过程:将步骤D中得到的纳米颗粒粉末重悬于5.0mg/ml阿仑膦酸钠溶液中,震荡15秒后,于37℃,300rpm的摇床中避光震荡24小时,经超纯水快速洗涤后,离心获得载阿仑膦酸钠的白磷钙石纳米颗粒。
实施例8
载药过程在300rpm的摇床中避光震荡48小时,其余制备方法与实施例7相同。
实施例9
载药过程在300rpm的摇床中避光震荡72小时,其余制备方法与实施例7相同。
载药量的计算:
在实施例1-9的载药过程中,抽取离心后得到的少量上清液与邻苯二醛,2-巯基乙醇混合物反应60分钟后,用高效液相色谱(HPLC)在波长333nm,等强度洗脱测定上清液中阿仑膦酸钠的含量,以此计算出载药量。结果如图11所示。由图11可知,纳米颗粒可高效包覆药物,包覆时间大于24小时后,延长包覆时间对包覆率无显著影响,而增加药物浓度可显著提高载药量。
不同酸碱环境中药物释放实验:
(1)分别用pH值为4.1和7.4的磷酸缓冲盐溶液溶解载实施例1中载有药物的纳米颗粒;
(2)震荡15秒后,放在37℃摇床上,以200rpm匀度震荡2周;
(3)分别在6小时、24小时、48小时、72小时、5天、一周、两周后每组各取0.8mL取样待测;
(4)在每个样品中加入0.8mL对应pH值的磷酸缓冲盐溶液;
(5)抽取少量上清液与邻苯二醛,2-巯基乙醇混合物反应60分钟后,用高效液相色谱(HPLC)在波长333nm,等强度洗脱测定上清液中阿仑膦酸钠的含量,结果如图12所示,可见纳米颗粒在168h内缓慢释放所载药物,且药物释放率显著受环境酸碱度影响较大。
体外降解(失重法)实验:
(1)称取实施例1中制得的30mg的纳米磷酸钙颗粒,加入10毫升pH值为7.4的磷酸缓冲溶液,超声震荡摇匀。
(2)将样品横向放入37℃保温箱内,放置时间分别为一周、两周、三周、六周,高速离心,干燥,称量剩余的纳米磷酸钙颗粒,实验过程中每周为所有样品均更换新鲜的磷酸缓冲溶液。
实验结果如图13所示,可见本发明制得的纳米磷酸钙颗粒于中性环境下六周内失重约0.15%。
细胞毒性实验:
(1)在96孔板中每孔接种5000个人骨髓间充质干细;
(2)经过24小时的贴壁后,吸弃上清液,加入均匀悬浮有实施例1中制得的纳米颗粒的细胞培养液,加入的纳米颗粒的浓度分别为100mg/L、50mg/L、10mg/L和5mg/L;
(3)于37℃细胞培养箱内孵育三天后以CCK-8法[2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐]测试细胞活性;
(4)以不含纳米颗粒细胞培养液所培养的细胞活力作为参照,计算出不同浓度纳米颗粒对细胞活性的影响,结果如图14所示,可见当本发明制得的纳米颗粒浓度低于50mg/L时,对细胞无明显毒性作用。
通过激光共聚焦显微镜观察实施例1中的纳米磷酸钙颗粒进入人骨髓间充质干细胞的图像,如图15所示,可见细胞形态正常,细胞内可见大量罗丹明标记的纳米颗粒。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种镁离子掺杂纳米磷酸钙颗粒,其特征在于:包括纳米颗粒本体,所述纳米颗粒本体外形为球形或椭球形结构,纳米颗粒本体的直径在60-300nm之间,纳米颗粒本体的内部为中空结构,纳米颗粒本体的外壳上分布有若干通孔,通孔均与外界相通,部分所述通孔与中空结构连通,另一部分通孔不与中空结构连通。
2.根据权利要求1所述的镁离子掺杂纳米磷酸钙颗粒,其特征在于:所述中空结构的孔径30-100nm之间,通孔的孔径在2-50nm之间。
3.根据权利要求1所述的镁离子掺杂纳米磷酸钙颗粒,其特征在于:所述纳米颗粒本体含有的主要元素为Ca、P、O、Mg,且各元素均匀分布于纳米颗粒本体。
4.根据权利要求1所述的镁离子掺杂纳米磷酸钙颗粒,其特征在于:所述纳米颗粒本体的主要成分为化学式为Ca18Mg2H2(PO4)14的白磷石。
5.根据权利要求1所述的镁离子掺杂纳米磷酸钙颗粒,其特征在于:所述纳米颗粒本体还含有碳酸根及氨基成分。
6.权利要求1-5任一所述的镁离子掺杂纳米磷酸钙颗粒的制备方法,其特征在于:包括如下步骤:
A、将钙盐溶液和镁盐溶液混合,并加入与混合液等体积的十二烷基磷酸钠溶液,搅拌使其全部混合均匀;
B、在上述混合液中加入磷酸盐溶液,调节使其pH不小于10.0,持续搅拌且恒温24小时以上,确保液体温度保持在60℃,恒温期间不断调试pH值,确保其不小于10.0;
C、将步骤B中的液体离心得到纳米颗粒,并依次用超纯水和无水乙醇反复洗涤纳米颗粒,将所得产物于120℃下干燥,干燥时间不小于24小时,并于干燥环境中保存;
D、罗丹明标记:将步骤C中得到的固体研磨成粉末,并将粉末分散于pH值为7.4的缓冲溶液中,加入罗丹明异硫氰酸盐溶液,混合均匀并持续搅拌,在不小于9000rpm的转速下离心收集产物,经超纯水和无水乙醇先后洗涤多次,干燥后即得到罗丹明标记的纳米颗粒;
E、载药过程:将步骤D中得到的纳米颗粒粉末重悬于阿仑膦酸钠溶液中,于37℃,300rpm的摇床中避光震荡24小时以上,经超纯水快速洗涤后,离心获得载阿仑膦酸钠的白磷钙石纳米颗粒。
7.根据权利要求6所述的制备方法,其特征在于:所述步骤A中钙盐溶液和镁盐溶液按照3:1的摩尔比进行混合,加入的十二烷基磷酸钠溶液的浓度为4.66mg/mL。
8.根据权利要求6所述的制备方法,其特征在于:所述步骤B中的磷酸盐溶液包括磷酸二氢盐、可溶的磷酸一氢盐和可溶的磷酸正盐。
9.根据权利要求6所述的制备方法,其特征在于:所述步骤D缓冲盐溶液为磷酸缓冲盐溶液、巴比妥钠-盐酸缓冲液、Tris-HCl缓冲液或者硼酸-硼砂缓冲液中的一种。
10.一种如权利要求1所述的镁离子掺杂纳米磷酸钙颗粒在载药缓释领域的应用。
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