CN114099700A - 一种基于酞菁锌纳米微球的制备 - Google Patents
一种基于酞菁锌纳米微球的制备 Download PDFInfo
- Publication number
- CN114099700A CN114099700A CN202111454748.5A CN202111454748A CN114099700A CN 114099700 A CN114099700 A CN 114099700A CN 202111454748 A CN202111454748 A CN 202111454748A CN 114099700 A CN114099700 A CN 114099700A
- Authority
- CN
- China
- Prior art keywords
- zinc
- phthalocyanine
- zinc phthalocyanine
- solution
- nano
- 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
- 239000011701 zinc Substances 0.000 title claims abstract description 45
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 45
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 44
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000004005 microsphere Substances 0.000 title claims abstract description 13
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 28
- 239000005017 polysaccharide Substances 0.000 claims abstract description 28
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000004676 glycans Chemical class 0.000 claims abstract description 24
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229920000669 heparin Polymers 0.000 claims abstract description 15
- 229960002897 heparin Drugs 0.000 claims abstract description 15
- 239000002243 precursor Substances 0.000 claims abstract description 14
- 239000000693 micelle Substances 0.000 claims abstract description 11
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 8
- ANYWGXDASKQYAD-UHFFFAOYSA-N 5-nitroisoindole-1,3-dione Chemical compound [O-][N+](=O)C1=CC=C2C(=O)NC(=O)C2=C1 ANYWGXDASKQYAD-UHFFFAOYSA-N 0.000 claims abstract description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- 239000011609 ammonium molybdate Substances 0.000 claims abstract description 6
- 235000018660 ammonium molybdate Nutrition 0.000 claims abstract description 6
- 229940010552 ammonium molybdate Drugs 0.000 claims abstract description 6
- 239000004202 carbamide Substances 0.000 claims abstract description 6
- ICXVJVVYSULERR-UHFFFAOYSA-L dichlorozinc hexahydrate Chemical compound O.O.O.O.O.O.Cl[Zn]Cl ICXVJVVYSULERR-UHFFFAOYSA-L 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 5
- -1 ammonium molybdate compound Chemical class 0.000 claims abstract description 4
- VEDOGGMXXKDNHS-UHFFFAOYSA-N methylsulfinylmethane;zinc Chemical compound [Zn].CS(C)=O VEDOGGMXXKDNHS-UHFFFAOYSA-N 0.000 claims abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000002086 nanomaterial Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 230000004913 activation Effects 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000502 dialysis Methods 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 238000005303 weighing Methods 0.000 claims description 8
- XJGIDGNLXAJIOA-UHFFFAOYSA-N 2,11,20,29,37,38,39,40-octazanonacyclo[28.6.1.13,10.112,19.121,28.04,9.013,18.022,27.031,36]tetraconta-1(36),2,4,6,8,10(40),11,13,15,17,19,21(38),22,24,26,28,30,32,34-nonadecaen-37-amine Chemical compound Nn1c2nc3nc(nc4[nH]c(nc5nc(nc1c1ccccc21)c1ccccc51)c1ccccc41)c1ccccc31 XJGIDGNLXAJIOA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 5
- 239000002077 nanosphere Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 239000012265 solid product Substances 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 241000588724 Escherichia coli Species 0.000 claims description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 claims description 3
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 claims description 3
- 125000000600 disaccharide group Chemical group 0.000 claims description 3
- 238000001338 self-assembly Methods 0.000 claims description 3
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 claims description 3
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 claims description 2
- 238000000227 grinding Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940097042 glucuronate Drugs 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 229950006780 n-acetylglucosamine Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000008685 targeting Effects 0.000 abstract description 5
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 230000002776 aggregation Effects 0.000 abstract description 4
- 238000004220 aggregation Methods 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 4
- 230000000149 penetrating effect Effects 0.000 abstract description 4
- 229910000071 diazene Inorganic materials 0.000 abstract description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000003504 photosensitizing agent Substances 0.000 description 6
- 238000003917 TEM image Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 238000002428 photodynamic therapy Methods 0.000 description 3
- 238000009210 therapy by ultrasound Methods 0.000 description 3
- 229940045136 urea Drugs 0.000 description 3
- 238000000134 MTT assay Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- OUCMTIKCFRCBHK-UHFFFAOYSA-N 3,3-dibenzylcyclooctyne Chemical compound C1CCCCC#CC1(CC=1C=CC=CC=1)CC1=CC=CC=C1 OUCMTIKCFRCBHK-UHFFFAOYSA-N 0.000 description 1
- XCVHLJMNYNLKBZ-UHFFFAOYSA-N [Zn]N Chemical compound [Zn]N XCVHLJMNYNLKBZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000011089 mechanical engineering Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000014207 opsonization Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
Images
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
- A61K47/6927—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 a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—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 a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6939—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 a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种基于酞菁锌纳米微球的制备方法，包括：将4‑硝基邻苯二甲酰亚胺、氯化锌六水合物，尿素和钼酸铵化合物混合，于高温下反应获得四氨基酞菁锌；将制得的四氨基酞菁锌二甲基亚砜溶液、肝素前体多糖甲酰胺溶液和1‑乙基‑(3‑二甲基氨基丙基)碳酰二亚胺/N‑羟基琥珀酰亚胺溶液混合，进行酰化反应获得两性胶束，两性胶束即可自组装形成纳米微球。本发明提供的酞菁锌纳米微球的制备方法步骤简单便捷，在一定程度上改善酞菁锌溶解性、稳定性、聚集倾向性和吸收特性等，从而调节药物在体内的转运和穿透癌细胞的能力、肿瘤组织对药物的摄取及识别靶向等问题。
Description
技术领域
本发明涉及两性胶束纳米材料制备技术，具体而言，涉及一种基于酞菁锌纳米微球的制备方法。
背景技术
1.纳米材料是新兴的材料，是指在三维空间中至少有一维处于纳米尺寸或由它们作为基本单元构成的材料。纳米材料在电子设备、机械工程、环境治理、化妆品、涂料、成像以及生物医药等诸多领域得到了广泛应用。
2.靶向抗肿瘤纳米材料指通过不同途径给药后，纳米粒子可吸收进入体循环系统，经数次循环后可相对定向到达肿瘤病灶组织。靶向抗肿瘤纳米材的料制备原料有很多，大致分为有机纳米材料以及无机纳米材料两种。无机材料一般无需自组装即是纳米材料，包括超顺磁材料、介孔二氧化硅纳米粒，金纳米粒等。有机材料一般是长链且不具有两性，需要接枝亲水分子或疏水分子形成两性胶束后才能自组装形成纳米材料，主要包括人工合成高分子和天然生物大分子材料。天然生物大分子具有应用优越性，其生物相容性好、天然无毒，且具有羟基、羧基等化学修饰位点，有利于接枝疏水分子形成自组装胶束，是作为胶束亲水端很好的选择。
3.天然生物大分子材料中的肝素前体多糖(heparosan)，是大肠杆菌K5(E.coliK5)的荚膜多糖主要成分，由GlcUA与GlcNAc通过β-1，4糖苷键连接形成二糖单元，二糖单元间通过α-1，4糖苷键连接而成。由于其天然无毒，带负电荷的性质避免了调理作用并提供了有利的血液循环半衰期。基于肝素前提多糖固有的溶解性和生物相容性，它很可能用作药物载体并提供改进的药代动力学和药物性能特性。
4.ZnPc作为光敏剂，其发挥抗肿瘤活性的机制是通过光动力疗法PDT，即注射一定剂量光敏剂后，以一定波长激发光照射病变部位(通常为近红外光)，光敏剂与病变部位相互作用，产生大量活性氧簇(ROS)，促使细胞死亡。影响PDT效果的关键因素之一是光敏剂，能作为光敏剂的酞菁锌以其高效低毒的优点成为人们研究抗肿瘤药物的焦点。然而，酞菁锌溶解性不好，不利于在体内运输。目前其通过纳米材料作为给药途径得到了科研工作者的广泛研究。通过将其制备成纳米材料，来改善其溶解性、稳定性、聚集倾向性和吸收特性等，从而调节药物在体内的转运和穿透癌细胞的能力、肿瘤组织对药物的摄取及识别靶向等问题。
5.本发明通过对酞菁锌的结构进行改造，在其表面添加氨基修饰位点，利于和亲水性的肝素前体多糖羧基进行酰化反应，自组装形成两性纳米胶束。
发明内容
1.本发明提供一种基于酞菁锌纳米微球制备方法，旨在于改善酞菁锌溶解性、稳定性、聚集倾向性和吸收特性等，从而调节药物在体内的转运和穿透癌细胞的能力、肿瘤组织对药物的摄取及识别靶向等问题。
2.为解决上述问题，本发明提供一种基于酞菁锌纳米微球制备方法，包括如下步骤：
3.步骤S100将4-硝基邻苯二甲酰亚胺、氯化锌六水合物，尿素和钼酸铵混合物混合，于高温下反应获得四氨基酞菁锌。
4.步骤S200将四氨基酞菁锌与肝素前体多糖通过酰化反应获得两性胶束，两性胶束自组装形成纳米材料。
5.优选的，所述的步骤S100中包括：
6.步骤S110，将4-硝基邻苯二甲酰亚胺、氯化锌六水合物，尿素以物质的量4∶1∶20混合，加入少量的钼酸铵，研磨均匀，混合物在180-220℃下回流6-8h。
7.步骤S120，趁热将步骤S110中固体产物倒入1-2mol/l盐酸中，于90℃水浴加热搅拌1-2h，过滤并用水洗涤至中性。
8.步骤S130，经步骤S120处理的产物再分散于1-2mol/l氢氧化钠溶液中，同样90℃水浴加热搅拌1-2h，过滤并用水洗涤至中性，并在真空下脱水，得到蓝紫色产物。
9.步骤S140，将上述步骤S130中获得的产物(1mol)和九水合硫化钠(12mol)与二甲基甲酰胺混合，并在剧烈搅拌下在三颈烧瓶中加热至60℃。1小时后，混合物用水洗涤至中性，真空干燥，得到深绿色固体物质(ZnPc，有4个残留胺基)。
10.优选的，步骤S200包括：
11.步骤S210，肝素多糖肝素前体多糖羧基的活化；称取适量的肝素前体多糖(0.1mmol)，溶于甲酰胺(FA)中，继而加入2-5倍羧基摩尔量的酰化试剂1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)及N-羟基琥珀酰亚胺(NHS)，室温下(20-30℃)避光搅拌2h，得到肝素前体多糖活化液。
11.步骤S220，肝素前体多糖接枝氨基酞菁锌：称取适量的氨基酞菁锌(0.01-0.1mmol)溶于DMSO，继而向瓶中加入步骤S210所制备的肝素前体多糖活化液，继续反应24h。反应结束后，将反应液转移至3500Da透析袋中，先DMSO透析2天后，更换至蒸馏水中透析3天，冻干。
12.步骤S230，取适量步骤S220中所制样品，复水溶，超声，即可得基于酞菁锌的纳米微球混悬液。
13.本发明提供一种基于酞菁锌纳米微球制备方法，通过对酞菁锌结构进行改造，得到带有四个氨基的酞菁锌，将其溶于二甲基亚砜溶液，与肝素前体多糖甲酰胺溶液、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)/N-羟基琥珀酰亚胺(NHS)溶液混合进行酰化反应，从而完成基于酞菁锌的纳米微球的制备。本发明提供的纳米微球制备方法操作步骤简单便捷，在一定程度上改善其溶解性、稳定性、聚集倾向性和吸收特性等，从而调节药物在体内的转运和穿透癌细胞的能力以及肿瘤组织对药物的摄取及识别靶向等问题。
14.为使本发明的上述目的、特征和优点能更明显易懂，下文特举较佳实施例，作详细说明如下。
附图说明
图1为实施例1氨基酞菁锌的核磁图谱
图2为实施例2粒径分布图
图3为实施例2在100及200nm下的透射电镜图
图4为实施例2MTT实验细胞存活率图
图5为实施例3粒径分布图
图6为实施例3在100及200nm下的透射电镜图
图7为实施例3MTT实验细胞存活率图
具体实施方式
实施例1：四氨基酞菁锌的合成
1.将4-硝基邻苯二甲酰亚胺(4.1g)、氯化锌六水合物(1.2g)，尿素(10g)和钼酸铵(0.05g)混合物混合，研磨均匀，于195℃下回流6个小时。
2.趁热将固体产物倒入300ml 1mol/l盐酸中，于水浴(90°)加热搅拌2h，过滤并用水洗涤至中性。
3.经酸处理的产物再分散于300ml1mol/l氢氧化钠溶液中，同样水浴(90°)加热搅拌2h，过滤并用水洗涤至中性，并在真空下脱水，得到蓝紫色产物。
4.将上述获得的产物(1mol)和九水合硫化钠(12mol)与二甲基甲酰胺(15ml)混合，并在剧烈搅拌下在三颈烧瓶中加热至60℃。1小时后，混合物用水洗涤至中性，真空干燥，得到深绿色固体物质(ZnPc，有4个残留胺基)。其核磁图谱见附图1。
实施例2：基于酞菁锌纳米材料的制备1
1.肝素前体多糖肝素前体多糖羧基的活化：称取40mg的肝素前体多糖，溶于甲酰胺(FA)10ml中，继而加入5倍羧基摩尔量的酰化试剂1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(96mg)及N-羟基琥珀酰亚胺(58mg)，室温下(20-30℃)避光搅拌2h，得到肝素前体多糖肝素前体多糖活化液。
2.肝素前体多糖接枝氨基酞菁锌：称取6mg的氨基酞菁锌溶于5ml DMSO，继而向瓶中加入上述所制备的肝素前体多糖活化液，继续反应24h。反应结束后，将反应液转移至3500Da透析袋中，先DMSO透析2天后，更换至蒸馏水中透析3天，冻干。
3.取适量上述所制样品，复水溶，超声，即可得基于酞菁锌的纳米微球混悬液。其粒径为136nm，粒径分布图及TEM图见附图2、3。
4.将B16细胞以5000细胞/孔接种于96孔板中，保持12小时，将细胞与200μL纳米材料(1mg/ml)一起温育。孵育12小时后，使用730nm激光照射20分钟。孵育12小时后，向所有细胞添加50μL MTT(2mg/mL)并放置4小时。然后用150μL DMSO置换培养基溶解甲臜结晶。使用酶标仪在570nm处检测吸光度。见附图4。
实施例3：基于酞菁锌纳米材料的制备2
1.前体多糖肝素前体多糖羧基的活化：称取40mg的肝素前体多糖，溶于甲酰胺(FA)10ml中，继而加入5倍羧基摩尔量的酰化试剂，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(96mg)及N-羟基琥珀酰亚胺(58mg)，室温下(20-30℃)避光搅拌2h，得到肝素前体多糖肝素前体多糖活化液。
2.肝素前体多糖接枝氨基酞菁锌：称取6mg的氨基酞菁锌溶于5ml DMSO，继而向瓶中加入上述所制备的肝素前体多糖活化液，继续反应24h。反应结束后，将反应液转移至3500Da透析袋中，先DMSO透析2天后，更换至蒸馏水中透析3天，冻干。
3.酞菁锌纳米材料接枝二苄基环辛炔(DBCO-NH2)：称取40mg酞菁锌纳米材料，溶于甲酰胺(FA)10ml中，继而加入5倍羧基摩尔量的酰化试剂，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(96mg)及N-羟基琥珀酰亚胺(58mg)，室温下(20-30℃)避光搅拌2h，得到酞菁锌纳米材料活化液。称取DBCO-NH250mg溶于5ml的DMSO中，继而向瓶中加入酞菁锌纳米材料活化液，继续反应24h。反应结束后，将反应液转移至3500Da透析袋中，先用DMSO透析2天后，更换至蒸馏水中透析3天，冻干。
4.取适量上述所制样品，复水溶，超声，即可得基于酞菁锌的纳米微球混悬液。其粒径为178nm，粒径分布图及TEM图见附图5、6。
5.将B16细胞以5000细胞/孔接种于96孔板中，保持12小时，将细胞与200μL 1mg/ml为终浓度的纳米材料一起温育。孵育12小时后，使用730nm激光照射20分钟。孵育12小时后，向所有细胞添加50μL MTT(2mg/mL)并放置4小时。然后用150μL DMSO置换培养基溶解甲臜结晶。使用酶标仪在490nm处检测吸光度。见附图7。
Claims (6)
1.一种基于酞菁锌纳米微球制备方法，其特征在于，包括以下步骤：
步骤S100，将4-硝基邻苯二甲酰亚胺、氯化锌六水合物，尿素和钼酸铵化合物混合，于高温下反应获得四氨基酞菁锌。
步骤S200，将四氨基酞菁锌二甲基亚砜溶液、肝素前体多糖甲酰胺溶液以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)/N-羟基琥珀酰亚胺(NHS)溶液混合，通过酰化反应获得两性胶束，两性胶束自组装形成纳米材料。
2.根据权利要求1所述的一种基于酞菁锌纳米微球制备方法，其特征在于，所述步骤S100，包括：
步骤S110，将4-硝基邻苯二甲酰亚胺、氯化锌六水合物，尿素和钼酸铵，研磨均匀，混合物在180-220℃下回流6个小时。
步骤S120，趁热将固体产物倒入盐酸中，于90℃水浴加热搅拌，过滤并用水洗涤至中性。
步骤S130，经步骤S120处理的产物再分散于氢氧化钠溶液中，同样90℃水浴加热搅拌，过滤并用水洗涤至中性，并在真空下脱水，得到蓝紫色产物。
步骤S140，经步骤S130获得的产物和九水合硫化钠与二甲基甲酰胺混合，并在剧烈搅拌下在三颈烧瓶中加热至60℃。1小时后，混合物用水洗涤至中性，真空干燥，得到深绿色固体物质(ZnPc，有4个残留胺基)。
3.根据权利要求1所述的一种基于酞菁锌纳米微球制备方法，其特征在于，所述步骤S200，包括：
步骤S210，肝素前体多糖羧基的活化：称取适量的肝素前体多糖，溶于甲酰胺(FA)中，继而加入酰化试剂1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)及N-羟基琥珀酰亚胺(NHS)，室温下(20-30℃)避光搅拌2h，得到肝素前体多糖活化液。
步骤S220，肝素前体多糖接枝氨基酞菁锌：称取适量的氨基酞菁锌溶于DMSO，继而向瓶中加入肝素前体多糖活化液，继续反应24h。反应结束后，将反应液转移至3500Da透析袋中，先DMSO透析2天后，更换至蒸馏水中透析3天，冻干。
步骤S230，取适量步骤S220所制得的样品，复水溶，即可得到基于酞菁锌的纳米微球悬浮液。
4.权利要求3所述的肝素前体多糖是从大肠杆菌K5提取出来的，其结构是由葡萄糖醛酸GlcUA和氮乙酰葡萄糖胺GlcNAc通过β-1，4糖苷键连接形成二糖单元，分子量为12171Da，纯度为96.12％。
5.根据权利要求1-4任一项所述的制备方法得到的基于酞菁锌纳米微球，粒径在100-180nm。
6.根据权利要求5所述制备的纳米微球对黑色素瘤细胞(B16)具有一定的抗肿瘤活性，其杀伤率可达90％左右。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111454748.5A CN114099700A (zh) | 2021-12-01 | 2021-12-01 | 一种基于酞菁锌纳米微球的制备 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111454748.5A CN114099700A (zh) | 2021-12-01 | 2021-12-01 | 一种基于酞菁锌纳米微球的制备 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114099700A true CN114099700A (zh) | 2022-03-01 |
Family
ID=80369758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111454748.5A Pending CN114099700A (zh) | 2021-12-01 | 2021-12-01 | 一种基于酞菁锌纳米微球的制备 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114099700A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115490696A (zh) * | 2022-09-23 | 2022-12-20 | 青岛科技大学 | 一种纳米化酞菁及其制备方法和应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112402625A (zh) * | 2020-11-19 | 2021-02-26 | 健进制药有限公司 | 负载光敏剂的peg化肝素纳米胶束及其制备方法 |
| CN112791186A (zh) * | 2021-04-14 | 2021-05-14 | 江苏艾洛特医药研究院有限公司 | 一种多糖纳米复合材料及其制备与应用 |
-
2021
- 2021-12-01 CN CN202111454748.5A patent/CN114099700A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112402625A (zh) * | 2020-11-19 | 2021-02-26 | 健进制药有限公司 | 负载光敏剂的peg化肝素纳米胶束及其制备方法 |
| CN112791186A (zh) * | 2021-04-14 | 2021-05-14 | 江苏艾洛特医药研究院有限公司 | 一种多糖纳米复合材料及其制备与应用 |
Non-Patent Citations (2)
| Title |
|---|
| 尹彦冰等: "两类四氨基酞菁的合成及其性质研究", 《东北师大学报(自然科学版)》 * |
| 邵宇飞等: "羧基酞菁锌与壳聚糖偶联物的制备", 《福州大学学报 （自然科学版 ）》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115490696A (zh) * | 2022-09-23 | 2022-12-20 | 青岛科技大学 | 一种纳米化酞菁及其制备方法和应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Eivazzadeh-Keihan et al. | A novel biocompatible core-shell magnetic nanocomposite based on cross-linked chitosan hydrogels for in vitro hyperthermia of cancer therapy | |
| Anirudhan et al. | Graphene oxide based functionalized chitosan polyelectrolyte nanocomposite for targeted and pH responsive drug delivery | |
| Abrica-González et al. | Gold nanoparticles with chitosan, N-acylated chitosan, and chitosan oligosaccharide as DNA carriers | |
| Wang et al. | PEGylated chitosan nanoparticles with embedded bismuth sulfide for dual-wavelength fluorescent imaging and photothermal therapy | |
| Xu et al. | Curcumin polymer coated, self-fluorescent and stimuli-responsive multifunctional mesoporous silica nanoparticles for drug delivery | |
| Wang et al. | Multifunctional Fe 3 O 4–CdTe@ SiO 2–carboxymethyl chitosan drug nanocarriers: synergistic effect towards magnetic targeted drug delivery and cell imaging | |
| Kesavan et al. | Ulvan loaded graphene oxide nanoparticle fabricated with chitosan and d-mannose for targeted anticancer drug delivery | |
| CN110801431B (zh) | 一种核-壳型智能纳米递送系统的构建及应用 | |
| Bian et al. | Cu-based MOFs decorated dendritic mesoporous silica as tumor microenvironment responsive nanoreactor for enhanced tumor multimodal therapy | |
| Zhu et al. | Facile preparation of indocyanine green and tiny gold nanoclusters co-loaded nanocapsules for targeted synergistic sono-/photo-therapy | |
| CN108939071B (zh) | 一种近红外光热响应的功能化氧化石墨烯/透明质酸复合水凝胶的制备方法 | |
| Ahmed | Recruitment of various biological macromolecules in fabrication of gold nanoparticles: overview for preparation and applications | |
| Gao et al. | AuNRs@ MIL-101-based stimuli-responsive nanoplatform with supramolecular gates for image-guided chemo-photothermal therapy | |
| Duong et al. | Biocompatible chitosan-functionalized upconverting nanocomposites | |
| Liu et al. | In situ self-assembled biosupramolecular porphyrin nanofibers for enhancing photodynamic therapy in tumors | |
| CN114099700A (zh) | 一种基于酞菁锌纳米微球的制备 | |
| Emam | Clustering of photoluminescent carbon quantum dots using biopolymers for biomedical applications | |
| Qiu et al. | Self-assembled multifunctional core–shell highly porous metal–organic framework nanoparticles | |
| Kariminia et al. | Fluorescent folic acid-chitosan/carbon dot for pH-responsive drug delivery and bioimaging | |
| CN113384713A (zh) | 酶响应的超分子纳米粒子可控释放抗癌药物阿霉素体系及其制备方法 | |
| CN111202853B (zh) | 具有光声显影、光热治疗和载药多功能的纳米颗粒 | |
| Thankachan et al. | MnO2 nanoparticle encapsulated in polyelectrolytic hybrids from alkyl functionalized carboxymethyl cellulose and azide functionalized gelatin to treat tumors by photodynamic therapy and photothermal therapy | |
| Liu et al. | Self-assembled oleylamine grafted alginate aggregates for hydrophobic drugs loading and controlled release | |
| Xu et al. | A dual-sensitive poly (amino acid)/hollow mesoporous silica nanoparticle-based anticancer drug delivery system with a rapid charge-reversal property | |
| CN102940894A (zh) | 基于叶酸修饰的第二代聚酰胺-胺树状大分子稳定的金纳米颗粒的靶向ct造影剂的制备 |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220301 |