CN106999355A - 用于获得氟化物掺杂的涂敷柠檬酸盐的无定形磷酸钙纳米颗粒的方法 - Google Patents
用于获得氟化物掺杂的涂敷柠檬酸盐的无定形磷酸钙纳米颗粒的方法 Download PDFInfo
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- CN106999355A CN106999355A CN201580050650.XA CN201580050650A CN106999355A CN 106999355 A CN106999355 A CN 106999355A CN 201580050650 A CN201580050650 A CN 201580050650A CN 106999355 A CN106999355 A CN 106999355A
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- Prior art keywords
- fluoride
- weight
- citrate
- calcium phosphate
- doped
- 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.)
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 27
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 27
- 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 title claims abstract description 27
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 25
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 title claims abstract description 21
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims abstract description 22
- 239000000463 material Substances 0.000 claims abstract description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000011248 coating agent Substances 0.000 claims abstract description 10
- 238000000576 coating method Methods 0.000 claims abstract description 10
- 239000001110 calcium chloride Substances 0.000 claims abstract description 7
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 7
- 229940112822 chewing gum Drugs 0.000 claims abstract description 6
- 235000015218 chewing gum Nutrition 0.000 claims abstract description 6
- 239000001509 sodium citrate Substances 0.000 claims abstract description 6
- 229940034610 toothpaste Drugs 0.000 claims abstract description 6
- 239000000606 toothpaste Substances 0.000 claims abstract description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 16
- 239000011575 calcium Substances 0.000 claims description 12
- 229910052791 calcium Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
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- 239000012620 biological material Substances 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000013049 sediment Substances 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 229910001634 calcium fluoride Inorganic materials 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical group [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 230000004087 circulation Effects 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 239000006228 supernatant Substances 0.000 claims description 3
- 239000012901 Milli-Q water Substances 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
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- 150000002222 fluorine compounds Chemical class 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 abstract description 6
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 abstract description 3
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- 229910019142 PO4 Inorganic materials 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
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- NQTSTBMCCAVWOS-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3-phenoxypropan-2-one Chemical compound COP(=O)(OC)CC(=O)COC1=CC=CC=C1 NQTSTBMCCAVWOS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 238000003917 TEM image Methods 0.000 description 2
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- 210000000963 osteoblast Anatomy 0.000 description 2
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical group [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- -1 phosphate anion Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000000101 transmission high energy electron diffraction Methods 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000004846 x-ray emission Methods 0.000 description 2
- OQUFOZNPBIIJTN-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;sodium Chemical compound [Na].OC(=O)CC(O)(C(O)=O)CC(O)=O OQUFOZNPBIIJTN-UHFFFAOYSA-N 0.000 description 1
- 101000878581 Aplysia californica Feeding circuit activating peptides Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241001609030 Brosme brosme Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 235000019738 Limestone Nutrition 0.000 description 1
- 101150113959 Magix gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 108010001441 Phosphopeptides Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- JXBAVRIYDKLCOE-UHFFFAOYSA-N [C].[P] Chemical compound [C].[P] JXBAVRIYDKLCOE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000675 anti-caries Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 210000000481 breast Anatomy 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- FFUMCSDSJNSMQH-HEXQVDJKSA-K chromoxane cyanin R Chemical compound [Na+].[Na+].[Na+].C1=C(C([O-])=O)C(=O)C(C)=C\C1=C(C=1C(=CC=CC=1)S([O-])(=O)=O)\C1=CC(C)=C(O)C(C([O-])=O)=C1 FFUMCSDSJNSMQH-HEXQVDJKSA-K 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 230000003013 cytotoxicity Effects 0.000 description 1
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- 230000008021 deposition Effects 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000002524 electron diffraction data Methods 0.000 description 1
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- IPCAPQRVQMIMAN-UHFFFAOYSA-L zirconyl chloride Chemical compound Cl[Zr](Cl)=O IPCAPQRVQMIMAN-UHFFFAOYSA-L 0.000 description 1
Classifications
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Abstract
本发明提供了用于获得氟化物掺杂的柠檬酸盐涂敷的无定形磷酸钙纳米颗粒的方法。由于该材料的可生物降解性和生物活性而在生物医学中具有应用；其还促进细胞附着和骨骼生成。在牙医学中，其可以作为牙本质和牙釉质的再矿化剂而用于牙膏、漱口剂、口香糖、凝胶以及氟化物涂膜中。本发明基于2种溶液，一方面是由氯化钙和柠檬酸钠形成的，而另一方面是由磷酸氢二钠和碳酸钠与氟化物形成的，这2种溶液在室温下混合。所述的方法是具有生态效益的并且是生态友好的，因为其不会残留任何酸的残留物；该方法由单阶段组成，其首次获得柠檬酸盐涂敷的且氟化物掺杂的无定形磷酸钙，其会增强材料的再矿化作用。
Description
技术领域和目的
在生物医学(即，药品传递纳米载体和骨再生)和牙医学中所关注的生物材料。
本发明的目的是用于获得柠檬酸盐(形成骨的有机相的一部分的分子)涂敷的并且掺杂有氟化物的无定形磷酸钙纳米颗粒的方法。由于该材料除了促进细胞附着和骨骼生成以外，还具有优异的生物降解能力和生物活性，所以其在生物医学(即，药品传递纳米载体和骨再生)领域中具有广泛的应用。同样，所述的材料在牙医学中具有多种应用，其中其作为牙本质和牙釉质的再矿化剂可以用于牙膏、漱口剂、氟化物涂膜、口香糖以及凝胶中。
所述的方法是基于两种溶液：一方面，通过氯化钙和柠檬酸钠形成的溶液；另一方面，通过磷酸氢二钠和碳酸钠与氟化物形成的溶液，将它们在室温下混合。关于现有技术，有利的是由于所述的方法不残留任何酸性残余物(在所述的合成中未使用强酸)，在单一的阶段中合成(在合成中使用柠檬酸钠作为反应试剂)，并且首次获得柠檬酸盐涂敷的并且掺杂氟化物的无定形磷酸钙(因此具有比无定形磷酸钙具有更强的再矿化活性)，所以其是生态高效的并且是生态友好的。
背景技术
在活的有机体中，无定形相是矿物质磷酸钙(CaP)不常见的形式。无定形磷酸钙(ACP)在真核细胞和原核细胞的线粒体中发现，并且被认为是骨的矿物质相(纳米晶体碳磷灰石)的形成过程中的前体阶段。近来发现，这种骨磷灰石的表面涂敷由柠檬酸盐。在使用不同方法制备多种CaP的过程中，ACP还起到中间相的作用。由于这种材料的受关注的性质，例如优异的生物活性，促进细胞附着，还有利于骨骼传导性和骨骼生成，所以其在生物医学领域中具有广泛的应用。同样，所述的材料在牙医学中具有多种应用，其中其作为牙本质和牙釉质的再矿化剂可以用于牙膏、漱口剂、口香糖、凝胶以及氟化物涂膜中。
WO98/40406公开了一种产物，其是由使用酪蛋白稳定的无定形磷酸钙(一种在乳液中存在的磷蛋白)构成的。该产物目前在牙膏、口香糖和牙齿美白治疗后用作研磨材料。但是，尚未证实其在预防龋齿和再矿化受损的涂膜中的效力。在齿状物(dental piece)的制备中，ACP还作为填充材料而用于复合的聚合材料中。特别是由于以下事实，ACP刺激牙齿修复：Ca和磷酸根离子响应于酸性pH而被释放，其中所述的酸性pH是由牙菌斑产生的，牙菌斑以羟磷灰石形式沉积在牙齿结构上，从而形成珐琅质(主要由羟磷灰石结晶构成)。表1概括了ACP作为生物材料的主要用途。
表1.用作生物材料的无定形磷酸钙。
这些用途中的一些用途在J.Zhao et al.,Amorphous calcium phosphate andits application in dentistry；Chemistry Central Journal(2011),5:40(doi:10.1186/1752-153X-5-40)中有所描述。
关于ACP的制备，已知在足以沉淀的pH下由可溶性Ca2+和PO4 3-前体获得多种形式，其中通常使用其阳离子不会产生其他物质的可溶性前体，其中所述的其他物质会后验干扰终产物的组成，例如Ca(OH)2,H3PO4,磷酸盐或磷酸氢铵。通常使用Ca(NO3)2。
除了(例如)其他多聚羧酸(例如酒石酸)以外，柠檬酸作为Ca2+阳离子复合体的功能也是已知的，就制药观点而言，其也是可接受的。鉴于此，这些酸也用于稳定ACP的无定形组合物。这在公开专利WO03059304的权利要求书中列出，其中在具有Ca2+阳离子的其他螯合剂前体中，建议柠檬酸，其占制备物的0.1重量％至5重量％，其中所述的制备物包含与磷肽结合的ACP。
JP2001169121提出柠檬酸作为ACP的稳定剂的用途，其中所述的ACP已经通过以下过程形成：由磷酸和氢化钙沉淀，在上述柠檬酸存在下使其经历随后的磨制。
因此，这些公开文献均未提及制备，例如本发明的方法主题，其中柠檬酸盐作为用于ACP沉淀的反应试剂加入(在单阶段方法中)，并且在沉淀后并非作为相中的稳定剂加入(在二阶段方法中)。
由Dorozhkin S.V.[Nanosized and nanocrystalline calciumorthophsphates,Acta Biomaterialia(2010),No.6(3),715-734]；Combes C.and Rey C.[Amorphous calcium phosphates:synthesis,properties and uses in biomaterials,Acta Biomaterialia(2010),No.6(9),3362-3378]进行的修改以及由Dorozhkin S.V.[Amorphous calcium phosphates,Acta Biomaterialia(2010),No.6(12),4457-4475进行的另一种修改公开了多种湿法，但是其中未采用本发明的方法主题的相同的条件、方法阶段和反应试剂。事实上，在这些制备中，柠檬酸通常被设想为分散剂，并且偶尔被设想为具有相似功能的碳酸根阴离子。
J.M.Delgado-López et al.Crystallization of bioinspired citrate-functionalized nanoapatite with tailored carbonate content(Acta Biomaterialia(2012)No.8,page 3491)的公开物建立了磷灰石和柠檬酸盐涂敷的纳米晶体碳磷灰石的沉淀方法。在本领域的状态下，本发明的方法主题与上述文件之间的主要差异如下：
(1)沉淀温度。
(2)柠檬酸盐涂敷的且氟化物掺杂的ACP纳米颗粒作为稳定相的沉淀。
(3)不具有完备的沉淀方法。
(4)在沉淀物中未形成磷酸钙的磷灰石或任何其他的晶体相。
发明概述
本发明的第一个目的是用于会的氟化物掺杂的柠檬酸盐涂敷的无定形磷酸钙(FACP)的方法，其包括：
-浓度为0.08M至0.12M的CaCl2溶液以及浓度为0.35M至0.50M的Na3C6H5O7(柠檬酸钠)的制备；
-第二溶液的制备，该第二溶液是由浓度为0.10M至0.15M的Na2HPO4与Na2CO3 0.2M和氟化物形成；
-将之前阶段中制备的2种溶液在pH为8.3至8.7(例如使用HCl调节)和室温下以1:1v/v的比例搅拌少于2分钟的时间进行混合；
-通过离心进行3次连续的沉降循环，除去上清液，并使用超纯水洗涤沉淀物；以及
-将湿态的沉淀物冷冻干燥。
在本发明的优选的实施方案中，在第一溶液中使用的反应试剂的浓度如下：CaCl2，0.1M；Na3C6H5O7，0.4M；而用于第二溶液的浓度如下：Na2HPO4，0.12M；Na2CO3，0.2M。
所述的氟化物选自CaF2,NaF或KF，并且以浓度为0.01M至0.1M加入。在优选的实施方案中，氟化物为CaF2，并且以浓度为0.05M加入。
本发明的另一个目由通过之前的方法获得的氟化物掺杂的无定形磷酸钙纳米颗粒以及Na、Ca、P、柠檬酸盐、碳酸盐、氟化物和结构水内含物构成，其中所述的颗粒具有球形，大小为30nm至80nm，其中所述的内含物由以下构成：
-3.1重量％至3.5重量％的Na；
-27.0重量％至27.4重量％的Ca；
-37.0重量％至37.8重量％的P；
-3.5重量％至5.0重量％的柠檬酸盐；
-5.4重量％至7.0重量％的碳酸盐；
-6重量％至10重量％的水；
-2重量％至5重量％的氟化物。
在本发明的所述的方面中，术语“水”是指吸附水和结构水。
在第三个方面中，本发明的另一个目的是纳米颗粒在以下应用中的用途，例如：
-生物分子和/或药品的运输；
-生物材料用于整形外科应用中。
-在牙医学中，优选地作为用于制备填充和/或密封根管和牙齿修复的胶合剂的材料，或者作为牙膏、口香糖、漱口剂、氟化物涂膜、以及凝胶，从而通过磷酸钙和氟化物离子的逐渐释放而有利于珐琅质的再矿化。
附图简述
图1示出柠檬酸盐涂敷的ACP(a)和FACP(b)纳米颗粒的透射电子显微镜(TEM)图像。针对各个纳米颗粒所获得的所选区域的电子衍射图案(SAED)也以插入物的方式示出。A中左侧的插入物显示单个纳米颗粒的TEM图像。面板c和d分别代表ACP和FACP X-射线能量色散(EDS)光谱。
图2示出纳米颗粒的X-射线衍射图(a)和Raman光谱(b)。
图3示出与ACP纳米颗粒(100μg/mL,500μg/mL,1,000μg/mL)温育1、3和7天的人类成骨细胞上实施的MTT细胞增殖测试。*p≤0:05；***p≤0:001；n＝3。
本发明的实施方案
通过将2种溶液混合，通过沉淀方法而获得ACP纳米颗粒，其中所述的2种溶液包含：
(i)0.1M CaCl2+0.4M Na3C6H5O7；以及
(ii)0.12M Na2HPO4+0.2M Na2CO3，
其中所述的2种溶液以1:1v/v的比例混合，总计200ml，并且使用HCl在环境温度下将pH调节至8.5。
当混合物呈现乳白色外观(在混合物后大约30s)时，通过离心使颗粒经历3次连续的沉降循环，除去上清液，并使用超纯水(Millipore)洗涤沉淀物。随后，将湿态的沉淀物冷冻干燥，并随后对该颗粒进行表征。
为了获得这些氟化物掺杂的颗粒，将CaF2 0.05M加入溶液(ii)中。
表征技术
使用Scanning Transmission Electron Microscope(STEM Philips CM 20)在80kV下操作来分析纳米颗粒。该设备还允许获取所选区域的电子衍射(SAED)图案和X-射线能量色散(EDS)光谱。就这些分析而言，冷冻干燥的样品分散于超纯水中，然后少量的这种悬液滴沉积在传统的铜光栅上。
使用Liberty 200(Varian,Australia)光谱仪，使用发射光谱法(ICP-OES)来定量Ca和P的量。为此，将冷冻干燥的样品溶解于浓缩的超纯的硝酸(1％v/v)中。
使用SDT Q 600系统(TA Instruments,New Castle,DE,USA)在氮气的恒定流动(100mL.min-1)下并将温度以10℃.min-1的间隔升高至1,200℃进行热重量分析(TGA)。
使用装配有PIXcel检测器(在45kV和40mA下操作，并具有入射Cu Kα辐射)的X-Pert PRO(PANalytical)衍射仪。使用辐射长度为10mm的可变光谱带宽(反散射)。2θ范围为5°至70°，并且2θ的增量为0.039。
使用LabRAMHR光谱仪(Jobin-Yvon,Horiba,Japan)获得Raman光谱。该单元装配有二极管激光器作为激发源(λ＝532nm)，以及Peltier-冷却的CCD检测器(1026x 256像素)。使用3cm-1的光谱分辨率来获得光谱。
使用PHILIPS Magix Pro(PW-2440)光谱仪，通过X-射线荧光光谱(XRF)来定量样品中氟化物的量。此外，还通过复合有氯化氧锆和铬花青R的分光光度测定法并在570mm下测量复合物的吸光率来测定氟化物的含量。
体外细胞培养物的分析
使用人类成骨细胞的细胞系(MG-63,Lonza,Italy)来评价纳米颗粒的生物应答。将该细胞在DMEM/F12培养基(PAA,Austria)中在37℃及CO2气氛(5％)中培养，其中所述的培养基包含10％胎牛血清(FBS)和青霉素-链霉素(100U/mL-100μg/mL)。随后，通过胰蛋白酶化使细胞与它们的培养基分离，然后离心并再悬浮。使用台盼蓝不相容检验来计数活细胞(细胞活力检验)。将细胞沉积在96孔板上，并且密度为3.0x103细胞/孔。24小时后，将3种不同浓度的柠檬酸盐涂敷的ACP纳米颗粒(事先通过25kGyγ辐射灭菌)加入至细胞培养物(100μg/mL,500μg/mL,1,000μg/mL)中。将该细胞在标准的条件(37℃，5％CO2)温育1、3和7天。每3天更新培养物的培养基。所有这些测试都是在操作箱(laminar flow cabinet)中实施的。
MTT细胞毒性和细胞活力
MTT方法[3-(4.5-二甲基噻唑-2-基)-2.5-二苯基四唑溴化物]用于测定纳米颗粒的可能毒性作用。这测试是基于在蓝色化合物(甲瓒)中通过线粒体酶的琥珀酸脱氢酶对3-(4.5-二甲基噻唑-2-基)-2.5-二苯基四唑溴化物(MTT)(其浓度可以通过比色法测定)的代谢还原作用，从而可以测定所处理细胞的线粒体的功能性。
在37℃下，将与纳米颗粒接触1、3和7天后的细胞以1:10的比例在溶解于PBS(5mgmL-1)中的MTT中温育2小时。然后，将该细胞与200μl二甲基亚砜(Sigma)温育15min，从而溶解甲瓒晶体。Multiskan FC Microplate(Thermo Scientific)光谱仪用于测量吸光率，其在570nm下与代谢活细胞的数量成正比。对于各个所研究的时间间隔(1、3和7天)来分析3种样品。
结果
TEM图像(图1)表明未掺杂的样品ACP(A)和掺杂样品FCAP(B)均为大小为30nm至80nm的球形纳米颗粒。此外，SAED图案中的衍射点的吸光率表明它们的无定形本性。相应地，EDS光谱证明它们仅由Ca和P组成。在掺杂的颗粒光谱中未观察到F峰(其应该在大约0.68KeV处出现)，可能是因为其被氧气峰(0.2KeV)(其是更强烈的)重叠。X-射线衍射图案中峰的缺乏证明这些材料的不定性本性(图2A)。Raman光谱也是无定形磷酸钙的特征，其在952cm-1处出现主峰，相对于晶体羟磷灰石的主峰(961cm-1)稍微迁移。通过TGA,ICP和X-射线荧光获得的ACP和FACP材料的化学组成之前已经描述。
使用成骨细胞(MG-63)来研究纳米颗粒的生物应答。将3种不同浓度的纳米颗粒(100,500和1,000μg/ml)加入至培养物培养基中，并且在某段温育时期(1、3或7天)后，通过MTT测试来定量代谢活细胞的数量(图3)。在温育1至7天后在所有情况下均观察到细胞增殖增加(甚至最高浓度也是如此)。此外，对于所研究的最低浓度，细胞生长相当于在缺乏纳米颗粒(对照)下通过细胞所观察的情况。然而，增加所述的浓度，细胞生长未必对照显著，可能是由于这样的事实：它们的纳米颗粒的浓度过高。尽管如此，对于所研究的所有浓度而言，细胞活力和形态学测试(未示出)均获得极相似的结果。这些结果清楚地表明所述的纳米颗粒在与所述的人类成骨细胞的细胞系接触时是完全生物相容的。
Claims (11)
1.一种用于获得氟化物掺杂的柠檬酸盐涂敷的无定形磷酸钙纳米颗粒的方法，其包括：
-浓度为0.08M至0.12M的CaCl2溶液以及浓度为0.35M至0.50M的Na3C6H5O7的制备；
-第二溶液的制备，该第二溶液是由浓度为0.10M至0.15M的Na2HPO4与Na2CO3 0.2M和氟化物形成；
-将之前所述的阶段中制备的所述的2种溶液在pH为8.3至8.7和环境温度下以1:1v/v的比例搅拌少于2分钟的时间进行混合；
-通过离心进行3次连续的沉降循环，除去上清液，并使用超纯水洗涤沉淀物；以及
-将湿态的沉淀物冷冻干燥。
2.根据权利要求1所述的方法，其特征在于用于所述的第一溶液的所述的反应试剂的浓度如下：CaCl2，0.1M；以及Na3C6H5O7，0.4M。
3.根据权利要求1和2的任意一项所述的方法，其特征在于用于所述的第二溶液的浓度如下：Na2HPO4，0.12M；Na2CO3，0.2M。
4.根据权利要求1至3的任意一项所述的方法，其特征在于所述的氟化物选自CaF2,NaF和KF，并且以浓度为0.01M至0.1M加入。
5.根据权利要求4所述的方法，其特征在于所述的氟化物为CaF2，其以浓度为0.05M加入。
6.通过权利要求1至5所定义的方法而获得的柠檬酸盐涂敷的且氟化物掺杂的无定形磷酸钙纳米颗粒，其特征在于它们为球形，大小为30nm至80nm，并且具有Na,Ca,P,柠檬酸盐,碳酸盐,氟化物和水内含物，其中它们分别为：
-3.1重量％至3.5重量％的Na；
-27.0重量％至27.4重量％的Ca；
-37.0重量％至37.8重量％的P；
-3.5重量％至5.0重量％的柠檬酸盐；
-5.4重量％至7.0重量％的碳酸盐；
-6重量％至10重量％的水；
-2重量％至5重量％的氟化物。
7.通过权利要求6所定义的柠檬酸盐涂敷的且氟化物掺杂的无定形磷酸钙纳米颗粒作为用于生物分子和/或药品的媒介物的用途。
8.通过权利要求6所定义的氟化物掺杂的柠檬酸盐涂敷的无定形磷酸钙纳米颗粒作为成骨细胞应用中的生物材料的用途。
9.通过权利要求6所定义的氟化物掺杂的柠檬酸盐涂敷的无定形磷酸钙纳米颗粒用于牙医学应用的用途。
10.根据权利要求9所述的作为用于制备填充和/或密封根管和牙齿修复的胶合剂的材料的用途。
11.根据权利要求9所述的作为牙膏、口香糖、漱口剂、氟化物涂膜以及凝胶的成分的用途，其中所述的成分是通过磷酸钙和氟化物离子的逐渐释放而有利于珐琅质的再矿化。
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| CN111714385A (zh) * | 2020-06-03 | 2020-09-29 | 温州医科大学 | 一种复合微纳米颗粒配方及其应用 |
| CN112384187A (zh) * | 2018-06-28 | 2021-02-19 | 库拉赛普特抗变色系统有限公司 | 掺杂氟离子的稳定化无定形磷酸钙以及用于产生其的工艺 |
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| CN110251733A (zh) * | 2019-07-17 | 2019-09-20 | 成都理工大学 | 高生物矿化活性的无定型磷酸钙/柠檬酸钙复合粉体及其制备方法 |
| WO2021059215A2 (en) | 2019-09-25 | 2021-04-01 | Church & Dwight Co., Inc. | Oral care composition |
| ES2879098B2 (es) | 2020-05-18 | 2022-10-14 | Univ Granada | Extracto etanólico de semillas de Euphorbia lathyris, método para obtenerlo, composición farmacéutica que lo contiene y su uso como agente antitumoral |
| CN115974543B (zh) * | 2022-11-17 | 2023-10-27 | 苏州大学 | 一种仿生酸性非晶磷酸钙铁纳米颗粒及其制备方法和应用 |
| WO2024134524A1 (en) | 2022-12-22 | 2024-06-27 | Consiglio Nazionale Delle Ricerche | Composite material based on bioactive glass and amorphous calcium phosphate, and the process for producing the same |
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| CN112384187A (zh) * | 2018-06-28 | 2021-02-19 | 库拉赛普特抗变色系统有限公司 | 掺杂氟离子的稳定化无定形磷酸钙以及用于产生其的工艺 |
| CN111714385A (zh) * | 2020-06-03 | 2020-09-29 | 温州医科大学 | 一种复合微纳米颗粒配方及其应用 |
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