CN114099436A - 一种活性氧响应的纳米血小板载药胶束及其制备方法和应用 - Google Patents
一种活性氧响应的纳米血小板载药胶束及其制备方法和应用 Download PDFInfo
- Publication number
- CN114099436A CN114099436A CN202111541756.3A CN202111541756A CN114099436A CN 114099436 A CN114099436 A CN 114099436A CN 202111541756 A CN202111541756 A CN 202111541756A CN 114099436 A CN114099436 A CN 114099436A
- Authority
- CN
- China
- Prior art keywords
- drug
- platelet
- active oxygen
- loaded
- loaded micelle
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 84
- 229940079593 drug Drugs 0.000 title claims abstract description 77
- 239000000693 micelle Substances 0.000 title claims abstract description 69
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 25
- 239000001301 oxygen Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002064 nanoplatelet Substances 0.000 title claims abstract description 14
- 230000004044 response Effects 0.000 title claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 37
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 27
- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000843 powder Substances 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 17
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 17
- 239000000725 suspension Substances 0.000 claims abstract description 17
- 239000012528 membrane Substances 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 15
- 239000011780 sodium chloride Substances 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 230000000379 polymerizing effect Effects 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 238000010257 thawing Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- QXJQHYBHAIHNGG-UHFFFAOYSA-N trimethylolethane Chemical compound OCC(C)(CO)CO QXJQHYBHAIHNGG-UHFFFAOYSA-N 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 210000003743 erythrocyte Anatomy 0.000 claims description 2
- 210000000265 leukocyte Anatomy 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 230000008685 targeting Effects 0.000 abstract description 4
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- 241000700159 Rattus Species 0.000 description 28
- 210000005013 brain tissue Anatomy 0.000 description 13
- 210000004556 brain Anatomy 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 238000010186 staining Methods 0.000 description 7
- 230000002490 cerebral effect Effects 0.000 description 5
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 229960004580 glibenclamide Drugs 0.000 description 4
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 206010061216 Infarction Diseases 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000007574 infarction Effects 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000000635 electron micrograph Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
- C08G63/698—Polyesters containing atoms other than carbon, hydrogen and oxygen containing boron
- C08G63/6982—Polyesters containing atoms other than carbon, hydrogen and oxygen containing boron derived from hydroxy carboxylic acids
-
- 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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nanotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Polymers & Plastics (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- General Physics & Mathematics (AREA)
- Manufacturing & Machinery (AREA)
- Physics & Mathematics (AREA)
- General Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Diabetes (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Biotechnology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种活性氧响应的纳米血小板载药胶束及其制备方法，包括以下步骤：将甲氧基聚乙二醇、4‑羧基苯硼酸和ε‑己内酯聚合形成聚合物粉末；将药物和聚合物粉末溶解于溶剂中，然后向体系中滴加氯化钠溶液，搅拌至溶剂挥发，制得载药胶束；将载药胶束与血小板膜混悬液混合，搅拌，制得。该载药胶束可有效解决现有的注射给药存在的药物使用剂量大、无靶向作用的问题。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种活性氧响应的纳米血小板载药胶束及其制备方法和应用。
背景技术
缺血性脑卒中已经成为我国国民主要的死亡原因，脑卒中具有发病率高、高致死率、高致残率等特点。目前，脑卒中临床上最佳治疗方案是静脉注射抗血栓药物溶栓治疗，但较短的窗口时间和再灌注损伤等风险使这种方案使用范围受限。缺血性脑卒中患者脑病灶部位进行无氧代谢产生大量的活性氧自由基，基于活性氧的靶向释药开关能使药物降低在非梗死区域的释放量。
血脑屏障是存在于脑组织和血液循环系统之间的生理屏障，能够有效阻挡有毒物质入脑，为脑实质组织维持了相对稳定生理环境，但同时也阻断大部分药物进入脑部发挥治疗作用。因此，发明一种新兴的纳米仿生载药技术用于透过血脑屏障靶向递送药物到脑卒中病灶部位，已经迫在眉睫。
发明内容
针对现有技术中存在的上述问题，本发明提供一种活性氧响应的纳米血小板载药胶束及其制备方法和应用，该载药胶束可有效解决现有的注射给药存在的药物使用剂量大、无靶向作用的问题。
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
一种活性氧响应的纳米血小板载药胶束的制备方法，包括以下步骤：
(1)将甲氧基聚乙二醇、4-羧基苯硼酸和ε-己内酯聚合形成聚合物载体粉末；
(2)将药物和步骤(1)中聚合物载体粉末溶解于溶剂中，然后向体系中滴加氯化钠溶液，搅拌至溶剂挥发，制得载药胶束；
(3)将步骤(2)中的载药胶束与血小板膜混悬液混合，搅拌，制得。
进一步地，步骤(1)中聚合物载体粉末通过如下方法制得：将甲氧基聚乙二醇和4-羧基苯硼酸溶解于二氯甲烷/四氢呋喃混合溶液中，然后在冰浴条件下依次向其中加入4-二甲氨基吡啶和二环己基碳二亚胺溶液，室温反应后去除二环己基脲，然后依次加入石油醚和乙酸乙酯进行沉淀，得甲氧基聚乙二醇/4-羧基苯硼酸聚合物；
将甲氧基聚乙二醇/4-羧基苯硼酸聚合物、三羟甲基乙烷和无水甲苯于100-140℃条件下反应，冷却至室温后向其中加入冰乙醚，真空干燥得到羟基化甲氧基聚乙二醇/4-羧基苯硼酸聚合物，将羟基化甲氧基聚乙二醇/4-羧基苯硼酸聚合物与ε-己内酯于120-160℃真空条件下反应，制得聚合物载体。
进一步地，步骤(2)中溶剂为四氢呋喃或丙酮。
进一步地，步骤(2)中所述氯化钠溶液中氯化钠与载药胶束的质量比为1:10-20。
进一步地，步骤(2)中聚合物粉末与药物的质量比为1:10-20。
进一步地，步骤(3)中载药胶束与血小板膜混悬液按照质量体积比为10:2-5的比例混合，然后以20-50r/min的速度搅拌6-10h，制得。
进一步地，步骤(3)中所述血小板膜混悬液的制备方法如下：将新鲜血液离心去除红细胞和白细胞，然后向其中加入防血小板激活剂，然后在超低温和常温条件下反复冻融，最后经离心、洗涤，超声分散，制得血小板混悬液。
进一步地，反复冻融次数为5-10次，然后于2-6℃、7000-13000g的离心力条件下离心8-15min，用去离子水反复洗涤，得血小板混悬液。
一种活性氧响应的纳米血小板载药胶束。
一种活性氧响应的纳米血小板载药胶束在脑梗死药物中的应用。
本发明所产生的有益效果为：
本发明中的载药胶束以包封药物的短棒状聚合物胶束作为内核，其外层包裹血小板膜，因血小板膜的包裹，使得该载药胶束具有良好的生物相容性、血液清除率低、天然的靶向血栓作用等特点，可通过外层的血小板膜可将药物靶向递送至脑内缺血部位，短棒状的聚合物载药胶束细胞摄取量高，能更好地穿透血脑屏障，提供更高的载药量和载药效率；该载药胶束通过4-羧基苯硼酸作为药物的释放开关，其与脑内缺血部位过表达的活性氧自由基结合，使药物迅速在缺血半暗带区域释放神经保护剂，缓解缺血再灌注损伤；通过该载药胶束可将药物靶向作用于缺血部位，以降低药物的使用剂量，降低药物对身体其他部位的影响。
本申请中通过向聚合物胶束溶液中滴加盐水，对聚合物胶束的形貌进行优化，促进聚合物胶束转变成短棒状结构，以增加载药率和载药量，提高细胞摄取的药物量。本申请中使用的聚乙烯、聚己内酯的生物相容性好的有点。
附图说明
图1为加氯化钠溶液之前聚合物载体的电镜图；
图2为加氯化钠溶液之前聚合物载体的电镜图；
图3为大鼠MCAO建模的流程图；
图4为空白组大鼠脑组织染色后的照片；
图5为对照组大鼠脑组织染色后的照片；
图6为实验组1大鼠脑组织染色后的照片；
图7为实验组2大鼠脑组织染色后的照片；
图8为大鼠脑部血管双光子共聚焦显微镜显示图；
图9为大鼠脑部血管双光子共聚焦显微镜显示图。
具体实施方式
下面结合附图对本发明的具体实施方式做详细的说明。
以下实施例中，聚合物粉末的制备方法如下：
1、将甲氧基聚乙二醇(0.50g,0.01mmol)和4-羧基苯硼酸(0.09g,0.54mmol)溶解于二氯甲烷-四氢呋喃(体积比1:1)混合液中，在0℃下冰浴然后加入4-二甲氨基吡啶(0.025g,0.2mmol)，然后，在30min内向体系中滴加二环己基碳二亚胺(0.21g,0.10mmol)的二氯甲烷溶液5mL，于室温下继续反应2天，过滤除去二环己基脲，再用石油醚、乙酸乙酯沉淀，重复三次真空干燥，得到；
2、称取甲氧基聚乙二醇/4-羧基苯硼酸聚合物(0.66g,0.13mmol)、三羟甲基乙烷(0.08g,0.67mmol)和120mL无水甲苯在120℃下冷凝除水过夜，冷却至室温后，将反应液加入到冰乙醚中，洗涤过滤、真空干燥得到羟基化甲氧基聚乙二醇/4-羧基苯硼酸聚合物；
3、称取羟基化甲氧基聚乙二醇/4-羧基苯硼酸聚合物(0.3g)、ε-己内酯(0.7mmol)和SnCl2(0.1g)置于真空活塞单口瓶中在磁力搅拌器下搅拌，在真空下抽气并加热至140℃持续反应6h，反应后在室温下冷却，溶解于15mL二氯甲烷中，再加入无水乙醇将反应物沉淀出，用离心机在5000r/min离心15min，真空干燥得到白色粉末。
血小板膜混悬液的制备方法如下：取新鲜血液，于500g离心力作用下离心10min，用生理盐水洗去血浆，向离心管中等体积的含1mM EDTA和2μM前列腺素E1，抑制血小板的激活，之后继续100g离心力离心20min，得到分离的血小板，将血小板在-80℃～室温下反复冻融7次，在4℃下8000g离心力离心10min，用去离子水洗涤，反复3次得到血小板膜悬液。
实施例1
一种活性氧响应的纳米血小板载药胶束，其制备方法包括以下步骤：
(1)将甲氧基聚乙二醇、4-羧基苯硼酸和ε-己内酯聚合形成聚合物载体粉末；
(2)将10mg Glyburide药物和1mg步骤(1)中聚合物粉末溶解于5ml四氢呋喃中，然后在磁力搅拌器上搅拌，同时向体系中滴加10ml浓度为0.05M的氯化钠溶液，搅拌至溶剂挥发，此过程中自发形成胶束，制得载药胶束；
(3)将10mg步骤(2)中的载药胶束与3ml血小板膜混悬液混合，搅拌8h，制得。
实施例2
一种活性氧响应的纳米血小板载药胶束，其制备方法包括以下步骤：
(1)将甲氧基聚乙二醇、4-羧基苯硼酸和ε-己内酯聚合形成聚合物载体粉末；
(2)将20mg Glyburide药物和1mg步骤(1)中聚合物粉末溶解于5ml四氢呋喃中，然后在磁力搅拌器上搅拌，同时向体系中滴加10ml浓度为0.05M的氯化钠溶液，搅拌至溶剂挥发，此过程中自发形成胶束，制得载药胶束；
(3)将10mg步骤(2)中的载药胶束与2ml血小板膜混悬液混合，搅拌6h，制得。
实施例3
一种活性氧响应的纳米血小板载药胶束，其制备方法包括以下步骤：
(1)将甲氧基聚乙二醇、4-羧基苯硼酸和ε-己内酯聚合形成聚合物载体粉末；
(2)将15mg Glyburide药物和1mg步骤(1)中聚合物粉末溶解于5ml四氢呋喃中，然后在磁力搅拌器上搅拌，同时向体系中滴加10ml浓度为0.05M的氯化钠溶液，搅拌至溶剂挥发，此过程中自发形成胶束，制得载药胶束；
(3)将10mg步骤(2)中的载药胶束与5ml血小板膜混悬液混合，搅拌10h，制得。
对比例1
一种活性氧响应的纳米血小板载药胶束，其制备方法包括以下步骤：
(1)将甲氧基聚乙二醇、4-羧基苯硼酸和ε-己内酯聚合形成聚合物载体粉末；
(2)将10mg Glyburide药物和1mg步骤(1)中聚合物粉末溶解于5ml四氢呋喃中，然后在磁力搅拌器上搅拌至溶剂挥发，制得药物胶束；
(3)将10mg步骤(2)中的载药胶束与3ml血小板膜混悬液混合，搅拌8h，制得。
试验例
取大鼠，分为实验组1、实验组2、对照组和空白组，对实验组1、实验组2和对照组大鼠采用线栓法建立大鼠MCAO模型，具体操作方法见附图3，然后对实验组1大鼠通过尾静脉注射实施例1中制得的载药胶束，对实验组2大鼠通过尾静脉注射对比例1中制得的载药胶束，对对照组和空白组大鼠通过尾静脉注射生理盐水，2天后，获取实验组、对照组和空白组大鼠的脑组织，然后分别对脑组织进行TTC染色，具体结果见附图4-7。
对空白组大鼠采用双光子共聚焦显微镜进行活体拍摄，具体操作为：采用罗丹明对载体胶束进行标记，采用FITC-Dextran对脑部血管进行标记，葡聚糖分子量为200KDa，然后在大鼠颅骨表面开一个大小在1平方厘米的孔洞，通过尾静脉价格上述标记了的载药胶束注射进入大鼠体内，具体结果见图8和图9。
附图4为空白组大鼠脑组织染色后的照片，通过照片可以看出，正常大鼠脑组织呈现完整的红色，并未出现梗死区域。
附图5为对照组大鼠脑组织染色后的照片，通过照片可以看出，对照组大鼠脑组织呈现出大面积的梗死。
附图6为实验组1大鼠脑组织染色后的照片，通过照片可以看出，实验组大鼠经过本申请中的载体药物治疗后，其脑组织梗死面积相对于对照组明显减小，证明本申请中的载体药物可透过血脑屏障作用于脑部缺血区域，实现脑梗死的治疗。
附图7为实验组2大鼠脑组织染色后的照片，通过照片可以看出，未加氯化钠溶液后，制得的纳米血小板为非棒状结构，其治疗脑梗死的效果差于实施例1中的治疗效果，证明载药载体的形状对于治疗效果有较大的影响。
图8和图9均为大鼠脑部血管组织，通过图8和9可明显看出载药纳米粒子靶向作用于大鼠脑部血管内，证明本申请中的载药胶束具有靶向作用。
Claims (10)
1.一种活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，包括以下步骤：
(1)将甲氧基聚乙二醇、4-羧基苯硼酸和ε-己内酯聚合形成聚合物载体粉末；
(2)将药物和步骤(1)中聚合物载体粉末溶解于溶剂中，然后向体系中滴加氯化钠溶液，搅拌至溶剂挥发，制得载药胶束；
(3)将步骤(2)中的载药胶束与血小板膜混悬液混合，搅拌，制得。
2.如权利要求1所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，步骤(1)中聚合物载体粉末通过如下方法制得：将甲氧基聚乙二醇和4-羧基苯硼酸溶解于二氯甲烷/四氢呋喃混合溶液中，然后在冰浴条件下依次向其中加入4-二甲氨基吡啶和二环己基碳二亚胺溶液，室温反应后去除反应产物二环己基脲，然后依次加入石油醚和乙酸乙酯进行沉淀，得甲氧基聚乙二醇/4-羧基苯硼酸聚合物；
将甲氧基聚乙二醇/4-羧基苯硼酸聚合物、三羟甲基乙烷和无水甲苯于100-140℃条件下反应，冷却至室温后向其中加入冰乙醚，真空干燥得到羟基化甲氧基聚乙二醇/4-羧基苯硼酸聚合物，将羟基化甲氧基聚乙二醇/4-羧基苯硼酸聚合物与ε-己内酯于120-160℃真空条件下反应，制得聚合物载体。
3.如权利要求1所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，步骤(2)中溶剂为四氢呋喃或丙酮。
4.如权利要求1所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，步骤(2)中所述氯化钠溶液中氯化钠与载药胶束的质量比为1:10-20。
5.如权利要求1所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，步骤(2)中聚合物粉末与药物的质量比为1:10-20。
6.如权利要求1所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，步骤(3)中载药胶束与血小板膜混悬液按照质量体积比为10:2-5的比例混合，然后以20-50r/min的速度搅拌6-10h，制得。
7.如权利要求1所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，步骤(3)中所述血小板膜混悬液的制备方法如下：将新鲜血液离心去除红细胞和白细胞，然后向其中加入防血小板激活剂，然后在超低温和常温条件下反复冻融，最后经离心、洗涤，超声分散，制得血小板混悬液。
8.如权利要求7所述的活性氧响应的纳米血小板载药胶束的制备方法，其特征在于，反复冻融次数为5-10次，然后于2-6℃、7000-13000g的离心力条件下离心8-15min，用去离子水反复洗涤，得血小板混悬液。
9.一种活性氧响应的纳米血小板载药胶束，其特征在于，采用权利要求1-8中任一项所述的方法制得。
10.一种活性氧响应的纳米血小板载药胶束在脑梗死药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111541756.3A CN114099436B (zh) | 2021-12-16 | 2021-12-16 | 一种活性氧响应的纳米血小板载药胶束及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111541756.3A CN114099436B (zh) | 2021-12-16 | 2021-12-16 | 一种活性氧响应的纳米血小板载药胶束及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114099436A true CN114099436A (zh) | 2022-03-01 |
| CN114099436B CN114099436B (zh) | 2022-08-02 |
Family
ID=80364985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111541756.3A Expired - Fee Related CN114099436B (zh) | 2021-12-16 | 2021-12-16 | 一种活性氧响应的纳米血小板载药胶束及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114099436B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115477741A (zh) * | 2022-09-14 | 2022-12-16 | 浙江中医药大学 | 一种可降解聚合物及其制备方法与应用 |
| CN118059219A (zh) * | 2024-04-19 | 2024-05-24 | 西南交通大学 | 一种肥胖相关乳腺癌的个性化核酸疫苗及其制备方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428008A (en) * | 1989-04-14 | 1995-06-27 | Prp, Inc. | Therapeutic composition of micellar structures capable of promoting hemotasis |
| CN109364263A (zh) * | 2018-10-31 | 2019-02-22 | 南京医科大学 | 一种功能化的血小板仿生智能载体及其抗缺血性脑卒中应用 |
| CN109568600A (zh) * | 2019-01-25 | 2019-04-05 | 南开大学 | 一种具有双配体可逆互屏蔽的靶向纳米胶束的结构及载药系统 |
| CN112898579A (zh) * | 2021-02-04 | 2021-06-04 | 四川大学 | 一种高分子材料、混合胶束及其制备方法和应用 |
-
2021
- 2021-12-16 CN CN202111541756.3A patent/CN114099436B/zh not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428008A (en) * | 1989-04-14 | 1995-06-27 | Prp, Inc. | Therapeutic composition of micellar structures capable of promoting hemotasis |
| CN109364263A (zh) * | 2018-10-31 | 2019-02-22 | 南京医科大学 | 一种功能化的血小板仿生智能载体及其抗缺血性脑卒中应用 |
| CN109568600A (zh) * | 2019-01-25 | 2019-04-05 | 南开大学 | 一种具有双配体可逆互屏蔽的靶向纳米胶束的结构及载药系统 |
| CN112898579A (zh) * | 2021-02-04 | 2021-06-04 | 四川大学 | 一种高分子材料、混合胶束及其制备方法和应用 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115477741A (zh) * | 2022-09-14 | 2022-12-16 | 浙江中医药大学 | 一种可降解聚合物及其制备方法与应用 |
| CN115477741B (zh) * | 2022-09-14 | 2023-08-18 | 浙江中医药大学 | 一种可降解聚合物及其制备方法与应用 |
| CN118059219A (zh) * | 2024-04-19 | 2024-05-24 | 西南交通大学 | 一种肥胖相关乳腺癌的个性化核酸疫苗及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114099436B (zh) | 2022-08-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114099436B (zh) | 一种活性氧响应的纳米血小板载药胶束及其制备方法和应用 | |
| Gao et al. | In situ formation of injectable hydrogels for chronic wound healing | |
| CN111440253B (zh) | 立方形环糊精骨架-rgd组合物及其制备方法 | |
| CN109846856B (zh) | 一种生物酶催化产气抗肿瘤仿生纳米粒及其制备方法 | |
| CA3016655C (en) | Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared thereby and use thereof | |
| CN112089704A (zh) | 一种仿生纳米载体及其制备方法和应用 | |
| CN112957521B (zh) | 一种载青蒿素脂质体的海藻酸盐-丝素蛋白复合水凝胶的制备方法 | |
| CN111035625A (zh) | 阿司匹林在血小板靶向载药系统制备中的用途 | |
| Wang et al. | Two novel nanoscale preparations of micelle and thermosensitive hydrogel for docetaxel to treat malignant tumor | |
| CN107432951A (zh) | 一种负载四氢姜黄素纳米颗粒的海藻酸钠‑壳聚糖敷料及其制备方法 | |
| CN106389355A (zh) | 一种紫杉烷类抗肿瘤药物的聚合物胶束冻干制剂及其制备方法和应用 | |
| CN108904446B (zh) | 一种动脉斑块微环境响应的载药纳米胶束的制备方法及应用 | |
| CN113730599A (zh) | 一种功能丝素蛋白药物载体及其制备方法 | |
| CN113813445A (zh) | 一种丝素蛋白复合多孔支架及其制备方法 | |
| CN107441547B (zh) | 一种创伤修复材料及其制备方法和用途 | |
| WO2012142328A2 (en) | Polymer microsphere compositions for localized delivery of therapeutic agents | |
| CN102836147B (zh) | 一种包载紫杉醇的生物可降解纳米复合物及其制备方法 | |
| Huang et al. | Black phosphorus assisted polyionic micelles with efficient PTX loading for remotely controlled release and synergistic treatment of drug-resistant tumors | |
| CN116063389B (zh) | 递送核酸药物的多肽载体、治疗肿瘤的核酸药物及其制备方法 | |
| CN114159393B (zh) | 一种载汉防己甲素的杂化纳米粒子、载汉防己甲素的可溶性微针递药系统及其制备方法 | |
| CN107163255B (zh) | 氧化还原和pH双重响应的无规-接枝型药物载体及方法 | |
| CN114917360B (zh) | 一种小分子药物与siRNA共输送的小粒径纳米体系的构建方法及应用 | |
| CN1709224A (zh) | 以超临界co2抗溶剂过程制备聚合物磁性载药微粒的方法 | |
| CN114146050B (zh) | 一种可溶性微针基质材料及其制备方法和应用 | |
| CN113262309B (zh) | 一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体及其制备方法和应用 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220802 |