CN111072976A - Controllable synthesis method for preparing HA-PEI targeted drug carrier with high yield - Google Patents
Controllable synthesis method for preparing HA-PEI targeted drug carrier with high yield Download PDFInfo
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- CN111072976A CN111072976A CN201911254087.4A CN201911254087A CN111072976A CN 111072976 A CN111072976 A CN 111072976A CN 201911254087 A CN201911254087 A CN 201911254087A CN 111072976 A CN111072976 A CN 111072976A
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- 239000003937 drug carrier Substances 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 69
- 238000000502 dialysis Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002243 precursor Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000009833 condensation Methods 0.000 claims abstract description 9
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- 238000010992 reflux Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims description 21
- 238000005303 weighing Methods 0.000 claims description 20
- 159000000000 sodium salts Chemical class 0.000 claims description 17
- 230000010355 oscillation Effects 0.000 claims description 15
- 230000005855 radiation Effects 0.000 claims description 15
- 239000008367 deionised water Substances 0.000 claims description 14
- 229910021641 deionized water Inorganic materials 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000012498 ultrapure water Substances 0.000 claims description 11
- 239000012266 salt solution Substances 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 6
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
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- 229940005574 sodium gluconate Drugs 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 230000002087 whitening effect Effects 0.000 claims description 3
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 claims description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 2
- 239000004115 Sodium Silicate Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229940047670 sodium acrylate Drugs 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000004317 sodium nitrate Substances 0.000 claims description 2
- 235000010344 sodium nitrate Nutrition 0.000 claims description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 2
- 239000004324 sodium propionate Substances 0.000 claims description 2
- 235000010334 sodium propionate Nutrition 0.000 claims description 2
- 229960003212 sodium propionate Drugs 0.000 claims description 2
- 229940048086 sodium pyrophosphate Drugs 0.000 claims description 2
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052911 sodium silicate Inorganic materials 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 235000019818 tetrasodium diphosphate Nutrition 0.000 claims description 2
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- NCPXQVVMIXIKTN-UHFFFAOYSA-N trisodium;phosphite Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])[O-] NCPXQVVMIXIKTN-UHFFFAOYSA-N 0.000 claims description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims 3
- 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 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- 229960003885 sodium benzoate Drugs 0.000 claims 1
- 235000013024 sodium fluoride Nutrition 0.000 claims 1
- 239000011775 sodium fluoride Substances 0.000 claims 1
- 229920002873 Polyethylenimine Polymers 0.000 abstract description 56
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 abstract description 4
- 229920002674 hyaluronan Polymers 0.000 abstract description 4
- 229960003160 hyaluronic acid Drugs 0.000 abstract description 4
- -1 Poly(ethylenimine) Polymers 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 abstract 6
- 239000011259 mixed solution Substances 0.000 abstract 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 abstract 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 abstract 1
- 231100000252 nontoxic Toxicity 0.000 abstract 1
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- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
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- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
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- 229960003668 docetaxel Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
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- 229920000573 polyethylene Polymers 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
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- 229920001282 polysaccharide Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
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- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
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- 238000001959 radiotherapy Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明专利涉及一种高产率制备HA‑PEI靶向药物载体的可控合成方法，其特征在于以NHS(英文名称：N‑hydroxysuccinimide，中文名称：N‑羟基丁二酰亚胺)、EDC(英文名称：1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimidehydrochloride，中文名称：1‑(3‑二甲氨基丙基)‑3‑乙基碳二亚胺)、HA(英文名称：Hyaluronic acid，中文名称：透明质酸)及PEI(英文名称：Poly(ethylenimine)，中文名称：聚乙烯亚胺)为原料，采用微波辐射法高产率制备HA‑PEI靶向药物载体。主要合成方法是：将NHS和EDC混合HA后，将PEI滴加到上述混合溶液，得到前驱体混合溶液，将上述前驱体混合溶液转移到带有冷凝回流装置的常压微波反应器中，将所得溶液冷却至室温，将溶液倒入透析袋，渗析12～24个小时，‑40～‑60低温冷冻干燥12～120小时，收集样品。此合成方法的优点是：原料无毒无害、成本低、合成效率高、形貌可控，合成的药物满足人体的吸收需求，有望投放于医疗行业取得良好效果。
The patent of the present invention relates to a controllable synthesis method for preparing HA-PEI targeted drug carrier with high yield, which is characterized in that NHS (English name: N-hydroxysuccinimide, Chinese name: N-hydroxysuccinimide), EDC ( English name: 1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimidehydrochloride, Chinese name: 1‑(3‑dimethylaminopropyl)‑3‑ethylcarbodiimide), HA (English name: Hyaluronic acid, Chinese Name: hyaluronic acid) and PEI (English name: Poly(ethylenimine), Chinese name: polyethyleneimine) as raw materials, and the HA-PEI targeted drug carrier was prepared by microwave irradiation method with high yield. The main synthesis method is as follows: after NHS and EDC are mixed with HA, PEI is added dropwise to the above mixed solution to obtain a precursor mixed solution, and the above precursor mixed solution is transferred to an atmospheric pressure microwave reactor with a condensation reflux device, and the mixture is mixed. The obtained solution was cooled to room temperature, poured into a dialysis bag, dialyzed for 12-24 hours, freeze-dried at -40--60 temperature for 12-120 hours, and the samples were collected. The advantages of this synthesis method are that the raw materials are non-toxic and harmless, the cost is low, the synthesis efficiency is high, and the morphology is controllable.
Description
[ technical field ]: the invention relates to a synthesis method of a targeted drug, in particular to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield.
[ technical background ]: in the last two decades, nano-drugs have been playing a positive role in clinical practice of tumor and cancer therapy, and the purpose of the nano-drugs is to improve the curative effect and selectivity of traditional drug therapy, alleviate the pain of patients, and reduce the side effects (Sara Maiolino, Annapina Russo, Valentia Paglira, et al. biological degradable with polyethylene and hydrophilic for the targeted delivery of docetaxel to air cancer cells [ J ]. Journal of biological technology, 2015, 13 (1): 2-4). Through the use of targeted drugs, a protective shell can be provided for expensive active substances, and theoretically, degradation protection of the drugs can be provided, so that the interaction and side effects of the drugs and healthy cells are limited, and therefore, the targeted drugs become hot spots for research of people. The targeted medicine is a high-tech therapeutic medicine generated by the development of modern medicine, biomolecular science and biological cytology, and can prevent the growth of cancer cells through the action of specific molecular targets necessary for carcinogenesis and tumor growth. The common means for treating cancer is chemotherapy and radiotherapy, but the price is high, the side effect is great, and the last straw is often crushed. The targeted drugs are divided into antibody drugs and kinase inhibitors, the antibody drugs have extremely strong targeting property and long half-life, but the production cost is high, and the large-scale investment in the pharmaceutical industry is not easy; the kinase inhibitor has small relative molecular mass, can be orally taken, has short half life and low production cost.
The nano-drug and the intermediate are novel polymers and can be used for treating cancers. HA and PEI Polymers, PEls can produce Anti-cancer effects by electrostatic interaction with cell membranes (Huang Z, Yang Y, Jiang Y, et al, Anti-tumor biological responses of tumor-associated macrophages via toll-like receptors 4triggered by biological Polymers [ J ]. Biomaterials, 2013, 34 (3): 746. 755; Wang, Shengpeng; Zhang, Jinming; Wang, Yitao; et al, Hyaluronic acid-coated PEI-polymeric binders treated co-delivery of polynucleotide and miR-542-3p for triple hybrid fiber receptor, Nanodiological PEI and PEI-PEI, Saudi-biological technologies, Saudi-12, Saudi-biological technologies, Saudi-2016. 12, Saudi-biological technologies, Saudi-2016. multidigi-drug, Miyaura biological technologies, Miudi-molecular biological technologies, Miyaura-3 p, Miyaura molecular biological technologies, Miyaura, Polychairi-biological technologies, Miyaura, The shape is irregular, so that a quick, low-cost and slow targeting medicament with good effect is urgently needed to be found.
Aiming at the existing technical problems and urgent needs of anticancer drugs, the invention provides a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, the dosage of the targeted drug prepared by the method accords with the absorption rate of a human body, the targeted drug effect is strong, the cost is low, and the targeted drug is expected to be put into the pharmaceutical industry for batch production.
[ summary of the invention ]: the invention discloses a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, the method realizes controllable appearance of the targeted drug, can prolong the effective period of the drug, can slowly release the drug, HAs strong targeted drug, reduces the pain of patients, HAs low cost of the synthesized drug, is expected to be put into the pharmaceutical industry, and HAs good development prospect in the medical industry.
[ technical solution of the present invention ]: the invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, which comprises the following specific synthesis steps:
a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield is characterized in that NHS, EDC, HA and PEI are used as raw materials, the HA-PEI targeted drug carrier is prepared by a microwave radiation method, and the reaction steps are as follows:
firstly, weighing 0.1000 g-2.0000 g of sodium salt, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium salt solution;
secondly, respectively weighing 0.0100 g-1.8000 g of HA and 0.0010 g-1.0000 g of PEI into 2 beakers, respectively adding 5-20 ml of the prepared sodium salt solution, and ultrasonically vibrating for 5-120 min for later use after the ultrasonic treatment is finished;
thirdly, weighing 0.0100-0.2200 g of NHS and 0.0100-0.3550 g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 5-120 min for later use after the ultrasonic oscillation is finished;
fourthly, after mixing HA with NHS/EDC, adding PEI: firstly transferring 30 ml of NHS/EDC solution prepared in the third step into a 200ml round-bottom flask, then transferring 0.0100 g-1.8000 g of HA solution prepared in the second step into the round-bottom flask, and then quickly adding a solution containing 0.0010 g-1.0000 g of PEI to obtain a precursor solution;
fifthly, transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100-1200W, heating the solution to 10-100 ℃, and continuously reacting for 1-120 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature;
and sixthly, pouring the solution after the reaction into a dialysis bag with the aperture of 5-20 microns, placing the dialysis bag into constant-temperature circulating high-purity water at the temperature of 25 ℃, dialyzing for 12-24 hours at normal temperature, gradually whitening the color in the dialysis process, pouring the product into a sterilized clean 200ml beaker, freeze-drying for 12-120 hours at the low temperature of-40 to-60 when the impurity content in the dialysis bag is equal to the high-purity water value, and collecting a sample for later use.
2. The sodium salt according to claim 1, wherein the sodium salt is one, two or more of sodium sulfite, sodium phosphite, sodium bromate, sodium bromide, sodium nitrate, sodium bicarbonate, sodium carbonate, sodium gluconate, sodium chlorate, sodium chloride, sodium sulfate, sodium thiosulfate, sodium phosphate, sodium pyrophosphate, sodium formate, sodium persulfate, sodium silicate, sodium perchlorate, sodium iodide, sodium acetate, sodium hypochlorite, sodium acrylate, sodium propionate and sodium benzoate.
[ advantages and effects of the invention ]: the invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, the synthesis route is simple to operate, and raw materials are cheap and easy to obtain; the invention has the innovation points that the synthesized targeted drug has controllable appearance, is in a hollow spherical structure, delays the valid period of expensive active ingredients, can be slowly released for a long time, particularly has the release rate of the compound conforming to the rate absorbed by human bodies, has strong targeted drug, reduces the side effect of drug pairs, reduces the production cost, has high synthesis efficiency, improves the curative effect and lightens the economic burden of families of patients. The targeting drug synthesized by the invention can overcome the trouble that a patient takes medicines for a plurality of times a day; because the preparation process is simple and the curative effect is good, the material is expected to be put into the pharmaceutical industry and produced in batches, and multiple medical tests of mice and the like prove that the material has good effect.
Drawings
FIG. 1 shows the structural formula of HA as a raw material
FIG. 2 is a structural formula diagram of PEI as a raw material
FIG. 3 is a structural formula diagram of NHS as a raw material
FIG. 4 is a structural formula diagram of raw material EDC
FIG. 5 is the nuclear magnetic spectrum of HA as the raw material
FIG. 6 is a nuclear magnetic spectrum of PEI as a raw material
FIG. 7 is a nuclear magnetic spectrum diagram of HA-PEI as a synthetic target product, which shows obvious characteristic peaks
FIG. 8 is a scanning electron microscope photomicrograph of HA-PEI of the synthetic sample
FIG. 9 is a scanning electron microscope photomicrograph of HA-PEI as a synthesized sample
FIG. 10 shows an atmospheric microwave reactor with reflux condensation
[ embodiments ] of the present invention:
example 1: synthesis of targeted drug carrier by microwave radiation method with heating power of 100W and heating temperature of 20 DEG C
Weighing 0.1200g of sodium chloride, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium chloride solution; respectively weighing 0.0250g of HA and 0.0150g of PEI in 2 beakers, respectively adding 15ml of the prepared sodium salt solution, and carrying out ultrasonic oscillation for 15min for later use after the ultrasonic oscillation is finished; weighing 0.1800g of NHS and 0.0550g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 50min for later use after the ultrasonic oscillation is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.0250g HA into the round-bottom flask, and dropwise adding a solution containing 0.0150g PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100W, heating the solution to 20 ℃, and continuously reacting for 10 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 5 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 24 hours, pouring the product into a sterilized clean 200ml beaker, freezing and drying at the low temperature of 60 ℃ below zero for 100 hours when the color gradually turns white and the impurity content in the dialysis bag is equal to the number of the high-purity water in the dialysis bag, and collecting a sample for later use. The structural formulas of the raw materials HA, PEI, NHS and EDC are respectively shown in figures 1, 2, 3 and 4, the nuclear magnetic spectrograms of the raw materials HA and PEI are shown in figures 5 and 6, the nuclear magnetic spectrogram of the HA-PEI polymer synthesized by a microwave radiation method is shown in figure 7, the peak near the abscissa 2.75 can be obtained from figure 7 to show that the polymerization degree of HA and PEI is high, the controllable polymerization of a molecular chain is completed, the scanning electron microscope picture of the HA-PEI polymer is shown in figures 8 and 9, and the scanning electron microscope picture and the nuclear magnetic spectrogram can be obtained.
Example 2: synthesis of targeted drug carrier by microwave radiation method with heating power of 800W and heating temperature of 20 DEG C
Weighing 0.500g of sodium sulfate, dissolving the sodium sulfate in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium sulfate solution; respectively weighing 0.4000g of HA and 0.0500g of PEI in 2 beakers, respectively adding 5ml of the prepared sodium salt solution, ultrasonically vibrating for 15min, and standing by after the ultrasonic is finished; weighing 0.0100g of NHS and 0.0200g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 50min for later use after the ultrasonic oscillation is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml of NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.4000g of HA into the round-bottom flask, and dropwise adding a solution containing 0.0500g of PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor (as shown in figure 10) with normal pressure and reflux condensation, adjusting the microwave radiation power to 800W, heating the solution at the temperature of 20 ℃, and continuously reacting for 3 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 10 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 24 hours, pouring the product into a sterilized clean 200ml beaker, freeze-drying the product at the low temperature of minus 40 ℃ for 80 hours in the dialysis process, and collecting a sample for later use, wherein the scanning electron microscope image and the nuclear magnetic spectrum of the HA-PEI polymer synthesized under the conditions are the same as those in example 1, and good beneficial effects are obtained in medical experiments.
Example 3: synthesis of targeted drug carrier by microwave radiation method with heating power of 400W and heating temperature of 40 DEG C
Weighing 0.500g of sodium acetate, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium acetate solution; respectively weighing 0.2000g of HA and 0.0170g of PEI in 2 beakers, respectively adding 5ml of the prepared sodium salt solution, and ultrasonically oscillating for 5min for later use after the ultrasonic oscillation is finished; 0.0220g of NHS and 0.0350g of EDC are weighed, dissolved in 30 ml of deionized water, ultrasonically vibrated for 5min and reserved after the ultrasonic vibration is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.2000g HA into the round-bottom flask, and dropwise adding a solution containing 0.0170g PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to 400W, heating the solution to 40 ℃, and continuously reacting for 10 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 10 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 12 hours, pouring the product into a sterilized clean 200ml beaker, freeze-drying the product at the low temperature of minus 60 ℃ for 60 hours in the dialysis process, and collecting a sample for later use, wherein the scanning electron microscope image and the nuclear magnetic spectrum of the HA-PEI polymer synthesized under the conditions are the same as those in example 1, and good beneficial effects are obtained in medical experiments.
Example 4: synthesis of targeted drug carrier by microwave radiation method with heating power of 600W and heating temperature of 40 DEG C
0.6500g of sodium gluconate is weighed and dissolved in 20ml of deionized water, and the solution is heated to 30 ℃ to form sodium gluconate solution; respectively weighing 0.3500g of HA and 0.0400g of PEI in 2 beakers, respectively adding 5ml of the prepared sodium salt solution, and carrying out ultrasonic oscillation for 5min for later use after the ultrasonic oscillation is finished; weighing 0.0260g of NHS and 0.0500g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 25min for standby after the ultrasonic oscillation is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml of NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.3500g of HA into the round-bottom flask, and dropwise adding a solution containing 0.0400g of PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to 600W, heating the solution to 40 ℃, and continuously reacting for 10 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 10 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 12 hours, pouring the product into a sterilized clean 200ml beaker, freeze-drying the product at the low temperature of minus 60 ℃ for 70 hours in the dialysis process, and collecting a sample for later use, wherein the scanning electron microscope image and the nuclear magnetic spectrum of the HA-PEI polymer synthesized under the conditions are the same as those in example 1, and good beneficial effects are obtained in medical experiments.
Comparative example:
reference (Sahiner N, Sagbas S, Sahine)r M，et al.Polyethyleneimine modifiedpoly(Hyaluronic acid)particles with controllable antimicrobial and anticancereffects[J]Carbohydrate polymers, 2017, 159: 29-38.) provides a synthetic method for preparing the HA-PEI targeted drug: dispersing HA particles weighing 1g in a suspension containing 10 wt% NaIO4Is stirred at 500 rpm for 12 hours, then precipitated with excess acetone, washed with acetone by centrifugation at least 2 times and subjected to NalO4The treated 0.5g HA particles were placed in 20mL aqueous solutions containing different concentrations of PEI (0.5, 1 and 2mL) for 12 hours. The precipitation was carried out with HA: PEI particles in a weight ratio of 1: 1, 1: 1 and 1: 2, and an excess of acetone was added. The HA-PEl particles were washed at least 2 times with an acetone-water mixture, centrifuged for 10 minutes at 10000rpm, dried with a heat gun, and stored in closed containers for drug loading and release studies.
The invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, which is characterized in that NHS, EDC, HA and PEI are taken as raw materials, the HA-PEI targeted drug carrier is prepared by a microwave radiation method, and the reaction steps are as follows: weighing 0.1000 g-2.0000 g of sodium salt, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium salt solution; respectively weighing 0.0100 g-1.8000 g of HA and 0.0010 g-1.0000 g of PEI into 2 beakers, respectively adding 5-20 ml of the prepared sodium salt solution, and carrying out ultrasonic oscillation for 5-120 min for later use after the ultrasonic oscillation is finished; weighing 0.0100-0.2200 g of NHS and 0.0100-0.3550 g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 5-120 min for later use after the ultrasonic oscillation is finished; after NHS/EDC mixed HA, PEI: firstly transferring 30 ml of NHS/EDC solution prepared in the third step into a 200ml round-bottom flask, then transferring 0.0100 g-1.8000 g of HA solution prepared in the second step into the round-bottom flask, and then quickly adding a solution containing 0.0010 g-1.0000 g of PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100-1200W, heating the solution at the temperature of 10-100 ℃, and stopping the reaction for 1-120 minutes; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 5-20 microns, placing the dialysis bag into constant-temperature circulating high-purity water at the temperature of 25 ℃, dialyzing for 12-24 hours at normal temperature, gradually whitening the color in the dialysis process, pouring the product into a sterilized clean 200ml beaker, freeze-drying for 12-120 hours at the low temperature of-40-60 ℃ and collecting a sample for later use, wherein the impurity content in the dialysis bag is equal to the number of the high-purity water. The HA-PEI targeted drug carrier synthesized by the invention HAs controllable appearance, can delay the effective period of the drug, can be slowly released, HAs strong targeted drug, is not easy to damage normal cells and reduce the harm of side effects to human bodies, HAs strong targeting property, is not easy to damage normal cells, and HAs good effect in medical experiments, and can be produced in batches.
Claims (2)
1. A controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield is characterized in that NHS, EDC, HA and PEI are used as raw materials, the HA-PEI targeted drug carrier is prepared by a microwave radiation method, and the reaction steps are as follows:
firstly, weighing 0.1000 g-2.0000 g of sodium salt, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium salt solution;
secondly, weighing 0.0100 g-1.8000 g of HA and 0.0010 g-1.0000 g of PEI respectively in 2 beakers, adding 5-20 ml of the prepared sodium salt solution respectively, and carrying out ultrasonic oscillation for 5-120 min for later use after the ultrasonic oscillation is finished;
thirdly, weighing 0.0100-0.2200 g of NHS and 0.0100-0.3550 g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 5-120 min for later use after the ultrasonic oscillation is finished;
fourthly, after mixing HA with NHS/EDC, adding PEI: firstly transferring 30 ml of NHS/EDC solution prepared in the third step into a 200ml round-bottom flask, then transferring 0.0100 g-1.8000 g of HA solution prepared in the second step into the round-bottom flask, and then quickly adding a solution containing 0.0010 g-1.0000 g of PEI to obtain a precursor solution;
fifthly, transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100-1200W, heating the solution to 10-100 ℃, and continuously reacting for 1-120 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature;
and sixthly, pouring the solution after the reaction into a dialysis bag with the aperture of 5-20 microns, placing the dialysis bag into constant-temperature circulating high-purity water at the temperature of 25 ℃, dialyzing for 12-24 hours at normal temperature, gradually whitening the color in the dialysis process, pouring the product into a sterilized clean 200ml beaker, freeze-drying for 12-120 hours at the low temperature of-40 to-60 when the impurity content in the dialysis bag is equal to the high-purity water value, and collecting a sample for later use.
2. The sodium salt of claim 1, wherein the sodium salt is one, two or more of sodium sulfite, sodium phosphite, sodium bromate, sodium bromide, sodium nitrate, sodium bicarbonate, sodium carbonate, sodium gluconate, sodium fluoride, sodium chloride, sodium sulfate, sodium thiosulfate, sodium phosphate, sodium pyrophosphate, sodium formate, sodium persulfate, sodium silicate, sodium monofluoride, sodium iodide, sodium acetate, sodium hypofluoride, sodium acrylate, sodium propionate and sodium benzoate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2560694A1 (en) * | 2010-04-22 | 2013-02-27 | Nobil Bio Ricerche S.r.l. | Implanting device with antibacterial properties and multifunctional surface |
| CN103417992A (en) * | 2013-08-01 | 2013-12-04 | 东华大学 | Preparation method for ferroferric oxide nano particle targeted MRI contrast agent |
| CN109512784A (en) * | 2019-01-04 | 2019-03-26 | 青岛科技大学 | A kind of preparation of magnetic target preparation |
| CN110305253A (en) * | 2019-06-30 | 2019-10-08 | 海南师范大学 | Medical composite homogeneous scaffold of oxidized alginate/polyacrylamide interpenetrating network and preparation method thereof |
-
2019
- 2019-12-10 CN CN201911254087.4A patent/CN111072976A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2560694A1 (en) * | 2010-04-22 | 2013-02-27 | Nobil Bio Ricerche S.r.l. | Implanting device with antibacterial properties and multifunctional surface |
| CN103417992A (en) * | 2013-08-01 | 2013-12-04 | 东华大学 | Preparation method for ferroferric oxide nano particle targeted MRI contrast agent |
| CN109512784A (en) * | 2019-01-04 | 2019-03-26 | 青岛科技大学 | A kind of preparation of magnetic target preparation |
| CN110305253A (en) * | 2019-06-30 | 2019-10-08 | 海南师范大学 | Medical composite homogeneous scaffold of oxidized alginate/polyacrylamide interpenetrating network and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| 孙李平，等: "透明质酸纳米给药载体的研究进展 ", 《药学服务与研究》 * |
| 孟路华: "透明质酸靶向姜黄素脂质体的制备及细胞毒性研究", 《中国优秀硕士论文全文数据库医药卫生科技辑》 * |
| 王新位，等: "透明质酸修饰的pH敏感载多柔比星纳米粒的制备及初步评价", 《药物生物技术》 * |
| 袁玉姣，等: "透明质酸衍生物在生物药品传递方面的研究进展 ", 《沈阳药科大学学报》 * |
| 邱立朋，等: "透明质酸肿瘤靶向给药系统的研究进展 ", 《药学学报》 * |
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