CN111840573A - 一种还原敏感性纳米胶束及其制备方法和应用 - Google Patents
一种还原敏感性纳米胶束及其制备方法和应用 Download PDFInfo
- Publication number
- CN111840573A CN111840573A CN202010835611.3A CN202010835611A CN111840573A CN 111840573 A CN111840573 A CN 111840573A CN 202010835611 A CN202010835611 A CN 202010835611A CN 111840573 A CN111840573 A CN 111840573A
- Authority
- CN
- China
- Prior art keywords
- sensitive
- reduction
- lipoic acid
- taurine
- 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.)
- Pending
Links
- 239000000693 micelle Substances 0.000 title claims abstract description 58
- 230000009467 reduction Effects 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000003814 drug Substances 0.000 claims abstract description 39
- 229940079593 drug Drugs 0.000 claims abstract description 37
- 229960003080 taurine Drugs 0.000 claims abstract description 29
- 150000002148 esters Chemical class 0.000 claims abstract description 28
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims abstract description 15
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 claims abstract description 14
- 235000019136 lipoic acid Nutrition 0.000 claims abstract description 14
- 229960002663 thioctic acid Drugs 0.000 claims abstract description 14
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims abstract description 6
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims abstract description 6
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims description 8
- 238000000502 dialysis Methods 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 7
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 6
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- 229960002918 doxorubicin hydrochloride Drugs 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 3
- 239000012498 ultrapure water Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 abstract description 19
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 abstract description 14
- 238000011068 loading method Methods 0.000 abstract description 10
- 229960003180 glutathione Drugs 0.000 abstract description 9
- 230000009471 action Effects 0.000 abstract description 6
- 229940009456 adriamycin Drugs 0.000 abstract description 6
- 239000003937 drug carrier Substances 0.000 abstract description 5
- 108010024636 Glutathione Proteins 0.000 abstract description 4
- 238000013270 controlled release Methods 0.000 abstract description 4
- 229920001577 copolymer Polymers 0.000 abstract description 4
- 238000007334 copolymerization reaction Methods 0.000 abstract description 2
- 238000009826 distribution Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 29
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 8
- 239000002245 particle Substances 0.000 description 6
- 239000002105 nanoparticle Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000000542 sulfonic acid group Chemical group 0.000 description 5
- 230000005540 biological transmission Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UFQDKRWQSFLPQY-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound Cl.C1CN=CN1 UFQDKRWQSFLPQY-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000000695 excitation spectrum Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002356 laser light scattering Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- MLIBNPMNPWTZHR-CMSHZVMTSA-N (2S,3S)-1,4-bis(sulfanyl)butane-1,2,3,4-tetrol Chemical compound SC([C@@H](O)[C@H](O)C(O)S)O MLIBNPMNPWTZHR-CMSHZVMTSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- RWSXRVCMGQZWBV-PHDIDXHHSA-N L-Glutathione Natural products OC(=O)[C@H](N)CCC(=O)N[C@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-PHDIDXHHSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000020774 essential nutrients Nutrition 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000000790 scattering method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- -1 sulfonate anion Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000000733 zeta-potential measurement Methods 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
- A61K47/6905—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 colloid or an emulsion
- A61K47/6907—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 colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
- C08F220/382—Esters containing sulfur and containing oxygen, e.g. 2-sulfoethyl (meth)acrylate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-(meth)acryloylmorpholine
- C08F220/585—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-(meth)acryloylmorpholine and containing other heteroatoms, e.g. 2-acrylamido-2-methylpropane sulfonic acid [AMPS]
Abstract
本发明提供一种还原敏感性纳米胶束及其制备方法和应用,属于生物医用材料技术领域。首先将牛磺酸与丙烯酰氯反应制备N‑丙烯酰牛磺酸;再将硫辛酸与甲基丙烯酸羟乙酯制备硫辛酸‑甲基丙烯酰氧基乙基酯;然后N‑丙烯酰牛磺酸与硫辛酸‑甲基丙烯酰氧基乙基酯进行共聚反应,得到共聚物;最后用二硫苏糖醇与上述共聚物反应制备核交联的还原敏感性纳米胶束。该纳米胶束形貌规整,分布均匀,用作药物载体,可吸附正电荷的药物分子阿霉素,提高载药率;在谷胱甘肽作用下,交联结构破坏,可实现药物在还原条件下的控制释放。
Description
技术领域
本发明属于生物医用材料技术领域,具体涉及一种还原敏感性纳米胶束及其制备方法和应用,尤其适用于作为抗癌药物载体使用。
背景技术
恶性肿瘤是全球一个主要死亡原因。目前治疗癌症的方法主要包括外科手术切除、化学药物治疗和辐射治疗。但是这些治疗手段都存在很大缺陷,例如药物具有毒副作用,损伤正常组织器官,对于患者而言都是极大的痛苦。
纳米药物载体在输送化疗药物方面具有特殊的优势。将抗癌药物通过物理/化学方式包裹入载体内部,可减小药物的毒副作用并提高药物的生物利用度。
牛磺酸是人体健康必不可少的营养素,牛磺酸分子中同时含有氨基和磺酸基团,牛磺酸分子中的磺酸基是带负电荷的强电离基团,高度亲水,可以位于纳米胶束的外层,维持胶束的稳定性,同时带负电荷的基团对正电荷药物有吸附作用,如果将该基团引入到药物载体中,可以提高对抗癌药物盐酸阿霉素的载药率。
硫辛酸是一种重要的人体内源性物质,能清除体内致病与加速老化的自由基,被称为“万能抗氧化剂”。硫辛酸具有含硫五元环结构,在催化量的1,4-二巯基苏糖醇(DTT)作用下形成双硫键结构,使药物载体交联,这种交联结构在肿瘤细胞内的还原条件下破坏,双硫键断裂。谷胱甘肽在肿瘤细胞内的浓度比在体液内高100~1000倍。载药纳米颗粒进入肿瘤细胞内,在谷胱甘肽作用下聚合物交联结构破坏,释放出药物,因此可实现药物在还原条件下的控制释放。
目前纳米胶束研究报道虽然较多,但是多数体系是通过物理吸附方法载药,容易发生药物泄露,而且载药率不高,影响药物的生物利用度。
发明内容
针对现有技术存在的问题,本发明提供一种还原敏感性纳米胶束及其制备方法和应用,以获得亲水性较强,胶束稳定的还原敏感性纳米胶束,并将其应用于吸附/释放抗癌药物分子。
作为本发明的第一个方面,提供一种含有磺酸基团和双硫键的还原敏感性纳米胶束的制备方法,首先制备分子中同时含有磺酸基团和C=C双键的小分子;再将硫辛酸分子官能团化,将C=C双键引入到硫辛酸;然后依次通过共聚反应和核交联反应制备还原敏感性纳米胶束。
在具体方法步骤中,
1)在250ml单口烧瓶中,将牛磺酸溶于蒸馏水,添加氢氧化钠溶液,将烧瓶置于0℃的冰水混合物中搅拌30分钟;将预先精制好的丙烯酰氯与二氯甲烷混合成溶液,通过恒压滴液漏斗滴加到单口烧瓶中,在40min内滴加完毕,控制反应在25℃下反应5h,将产物过滤、用去离子水洗3次,再用乙酸乙酯重结晶,真空干燥24h,得到N-丙烯酰牛磺酸,备用;
2):在装有回流和分水装置的三口烧瓶中,将硫辛酸溶于甲苯,再加入甲基丙烯酸羟乙酯,添加催化剂,搅拌30分钟,氮气保护,升温到85℃反应6小时,冷却后用1.0M的氢氧化钠溶液洗涤产物,分液弃去水层,减压蒸馏除去甲苯,得到硫辛酸-甲基丙烯酰氧基乙基酯,备用;
3)在三口烧瓶中,将N-丙烯酰牛磺酸和硫辛酸-甲基丙烯酰氧基乙基酯溶入二甲亚砜,室温下搅拌均匀,添加引发剂,搅拌使之完全溶解,通氮气20分钟后升温至60~65℃,反应5小时,冷却后得聚合物溶液;将上述聚合物溶液缓缓滴入到去离子水中,添加二硫苏糖醇,25~30℃反应24h,然后移入到透析袋中,透析72小时,将纳米胶束溶液冷冻干燥,得到还原敏感性纳米胶束。
在一种实施例中,在步骤1)中,所加入的牛磺酸与氢氧化钠的摩尔比为1:1。
在一种实施例中,在步骤1)中,牛磺酸与丙烯酰氯的摩尔比为1:1.1~1.2。
在一种实施例中,在步骤2)中,硫辛酸与甲基丙烯酸羟乙酯的摩尔比为1.2~1.4:1。
在一种实施例中,在步骤2)中,所述催化剂为对甲苯磺酸、浓硫酸、高氯酸、三氯乙酸中的一种或几种,其用量为硫辛酸重量的1~3%。
在一种实施例中,在步骤3)中,N-丙烯酰牛磺酸与硫辛酸-甲基丙烯酰氧基乙基酯的重量比为1:1~2。
在一种实施例中,在步骤3)中,所述引发剂为偶氮二异丁咪唑啉盐酸盐、偶氮二异丁腈、偶氮二异庚腈中的一种或几种,其用量为N-丙烯酰牛磺酸和硫辛酸-甲基丙烯酰氧基乙基酯重量之和的0.5~1%。
在一种实施例中,在步骤3)中,硫辛酸-甲基丙烯酰氧基乙基酯与二硫苏糖醇的重量比为17:1~6:1。
作为本发明的第二个方面,还提供一种由上述制备方法所制得的还原敏感性纳米胶束。
作为本发明的第三个方面,还提供一种还原敏感性纳米胶束作为抗癌药物载体的应用,包括:
称10mg盐酸阿霉素溶于10mL二甲基亚砜,搅拌下加入0.1mL三乙胺,反应1h,再加入10mg还原敏感性纳米胶束,搅拌溶解,再滴加80mL超纯水,搅拌2h,将溶液转入截留分子量为3500的透析袋中透析8h,获得载药胶束溶液,冷冻干燥后得到一种载药还原敏感性纳米胶束。
本发明的有益效果:
1.通过本发明提供的还原敏感性纳米胶束的制备方法所合成的纳米胶束以亲水性的牛磺酸为壳,结构单元中含有负电荷的磺酸基团,一方面使胶束稳定,另一方面可吸附正电荷的药物分子阿霉素,提高载药率。
2.本发明所合成的还原敏感性纳米胶束内层是疏水性的硫辛酸,经过与二硫苏糖醇反应后,内核发生交联,保证了纳米胶束在非还原条件下的稳定性;而在肿瘤细胞内谷胱甘肽作用下,交联结构破坏,释放出药物,因此可实现药物在还原条件下的控制释放。
3.本发明提供的还原敏感性纳米胶束形貌规整,分布均匀,用作药物载体,使用性能优良。
附图说明:
图1为N-丙烯酰牛磺酸的合成反应式
图2为硫辛酸-甲基丙烯酰氧基乙基酯的合成反应式
图3为还原敏感性纳米胶束的合成路线
图4为硫辛酸-甲基丙烯酰氧基乙基酯的核磁共振氢谱
图5为还原敏感性纳米胶束的透射电镜图
图6为还原敏感性纳米胶束的在10mmol/L GSH作用下荧光强度的变化
图7负载阿霉素药物的还原敏感性纳米胶束的药物释放曲线
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
以下结合具体实施例和附图对本发明作进一步说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
还需要说明的是,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、商品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、商品或者设备所固有的要素。
实施例1
1)N-丙烯酰牛磺酸的制备:在250mL单口烧瓶中,将6.25g(0.05mol)牛磺酸溶于50mL蒸馏水,添加浓度为2.0mol/L氢氧化钠溶液25mL,将烧瓶置于0℃的冰水混合物中搅拌30分钟;将预先精制好的5.0g丙烯酰氯与20mL二氯甲烷混合成溶液,通过恒压滴液漏斗滴加到单口烧瓶中,在40min内滴加完毕,控制反应在25℃下反应5h;将产物过滤、用去离子水洗3次,再用乙酸乙酯重结晶,在真空干燥箱中干燥24h,得到N-丙烯酰牛磺酸,备用。
2)硫辛酸-甲基丙烯酰氧基乙基酯的制备:在装有回流和分水装置的250mL三口烧瓶中,将硫辛酸12.4g(0.06mol)溶于100mL甲苯,再加入甲基丙烯酸羟乙酯6.5g(0.05mol),添加对甲苯磺酸0.25克,搅拌30分钟,氮气保护,升温到85℃反应6小时,冷却后用1.0M的氢氧化钠溶液洗涤产物,分液弃去水层,减压蒸馏除去甲苯,得到硫辛酸-甲基丙烯酰氧基乙基酯,备用。
3)还原敏感性纳米胶束的制备:在150mL三口烧瓶中加入二甲亚砜20mL,N-丙烯酰牛磺酸2.5g,硫辛酸-甲基丙烯酰氧基乙基酯2.5g,室温下搅拌均匀,添加引发剂偶氮二异丁咪唑啉盐酸盐0.05g,搅拌使之完全溶解,通氮气20min后升温至60~65℃,反应5小时,冷却后得到聚合物溶液;冷却后将聚合物溶液缓缓滴入到250mL去离子水中,添加二硫苏糖醇(DTT)0.15g,25~30℃反应24h,然后将溶液移入透析袋中,透析袋的截留分子量为3500,透析72小时,将纳米胶束溶液冷冻干燥,得到还原敏感性纳米胶束,标记为NLD-1。
实施例2
步骤1)、2)与实施例1相同;但是在步骤3)中,改变硫辛酸-甲基丙烯酰氧基乙基酯的重量为3.0克,偶氮二异丁咪唑啉盐酸盐0.055g,DTT的重量为0.3克,其余步骤相同,得到还原敏感性纳米胶束,标记为NLD-2。
实施例3
步骤1)、2)与实施例1相同;但是在步骤3)中,改变硫辛酸-甲基丙烯酰氧基乙基酯的重量为3.5克,偶氮二异丁咪唑啉盐酸盐0.06g,DTT的重量为0.45克,其余步骤相同,得到还原敏感性纳米胶束,标记为NLD-3。
实施例4
步骤1)、2)与实施例1相同;但是在步骤3)中,改变硫辛酸-甲基丙烯酰氧基乙基酯的重量为4.0克,偶氮二异丁咪唑啉盐酸盐0.065g,DTT的重量为0.6克,其余步骤相同,得到还原敏感性纳米胶束,标记为NLD-4。
实施例5
步骤1)、2)与实施例1相同;但是在步骤3)中,改变硫辛酸-甲基丙烯酰氧基乙基酯的重量为5.0克,偶氮二异丁咪唑啉盐酸盐0.075g,DTT的重量为0.8克,其余步骤相同,得到还原敏感性纳米胶束,标记为NLD-5。
表1还原敏感性纳米胶束的制备实施例配方一览表
说明:NAT:N-丙烯酰牛磺酸;LAMHE:硫辛酸-甲基丙烯酰氧基乙基酯;引发剂:偶氮二异丁咪唑啉盐酸盐;DTT:二硫苏糖醇
实施例6
硫辛酸-甲基丙烯酰氧基乙基酯的核磁共振氢谱表征:将硫辛酸-甲基丙烯酰氧基乙基酯溶于CDCl3,浓度为20mg/mL,以四甲基硅烷为内标物,用AVANCE III HD 400MHz型核磁共振谱仪测定硫辛酸-甲基丙烯酰氧基乙基酯的核磁共振氢谱,结果见图4。分析如下:化学位移δ:3.5~3.7(2H,-SS-CH2-),δ:1.56~1.75(2H,-CH2-),δ:3.6~3.7(1H,-SS-CH-),δ:1.7~1.9(6H,-CH2--CH2--CH2-),δ:1.5~1.6(3H,CH3),δ:2.4~2.5(2H,CH2=);δ:6.1~6.3(4H,-CH2-CH2-),δ:5.2~5.3(-CH2-C=O),氢的化学位移值、峰的积分面积与理论值相同,证明硫辛酸-甲基丙烯酰氧基乙基酯的合成。
实施例7
纳米胶束的Zeta电位分析:采用ZetaPALS型Zeta电位及纳米粒度分析仪对纳米颗粒的Zeta电位进行分析,测试温度为25℃,pH 7.4。从表2看到:纳米胶束具有较高的负Zeta电位,说明纳米胶束外层带负电荷,为磺酸根负离子SO3 -,来源于牛磺酸。还可以观察到,从NLD-1到NLD-5,Zeta电位绝对值下降,这是因为从NLD-1到NLD-5,LAMHE含量增加,NAT相对含量减少,其中的磺酸根负离子SO3 -依次减少,因而Zeta电位绝对值下降。
表2还原敏感性纳米胶束的性能
a)动态激光光散射法(pH=7.2,25℃);b):DLR:载药率
实施例8
纳米胶束的粒径分析:配置1.0mg/mL的纳米胶束溶液,用0.45μm过滤器过滤除尘,采用ALV/DLS/SLS-5022F型动态激光光散射仪测定胶束的粒径及其分布,测试温度25℃,结果见表2。形成胶束后,胶束的尺寸在92~197nm之间。随着合成时硫辛酸-甲基丙烯酰氧基乙基酯的含量增加,共聚物粒径变大,这是因为硫辛酸-甲基丙烯酰氧基乙基酯是疏水部分,当其含量增加时,由于链段之间的相互作用,将形成较大的颗粒团聚,因而粒径变大。
实施例9
纳米胶束的形貌观察:将1.5mg/mL的纳米颗粒溶液30μL滴到铜网上,然后往铜网上滴加一滴1.0wt%磷钨酸溶液进行染色,铜网在室温下自然干燥,用透射电子显微镜在高真空状态下观察NLD-1和NLD-5纳米颗粒的形貌,透射电镜加速电压为120kV。通过透射电镜观察纳米胶束的形貌,图5中(a)(b)分别是样品NLD-1和NLD-5的透射电镜图,可以观察到,纳米胶束呈球形、形貌比较规整,粒径尺寸与动态激光光散射法测试所得结果相符,即随着硫辛酸-甲基丙烯酰氧基乙基酯的含量增加,共聚物粒径变大。
实施例10
纳米胶束的还原敏感性测试:将含有4.0×10-6mmol/L芘的胶束溶液(8mL,1mg/mL)在37℃的恒温振荡箱孵育一段时间,加入10mmol/L的谷胱甘肽(GSH)水溶液,利用荧光分光光度计测定溶液在不同的孵育时间时的激发光谱,发射波长为395nm,激发和发射狭缝宽度均为5nm,观察荧光强度的变化。芘是疏水性物质,会进入到胶束内腔中,显示激发光谱。当胶束破坏,芘进入极性介质中,荧光强度减弱。由图6看出,胶束在10mmol/L的GSH溶液中,随时间延长,荧光强度下降,这是因为胶束中的双硫键在GSH作用下断裂,交联结构破坏,芘释放到极性水介质中,导致其荧光强度下降。
实施例11
纳米胶束的药物负载:称10mg盐酸阿霉素溶于10mL二甲基亚砜,搅拌下加入0.1mL三乙胺,反应1h,再加入10mg纳米胶束,搅拌溶解,再滴加80mL超纯水,搅拌2h,将溶液转入截留分子量为3500的透析袋中透析8h,获得载药胶束溶液。移取2.0mL载药胶束溶液,冷冻干燥后用二甲基亚砜溶解、定容,用紫外分光光度计在483nm下测吸光度,根据标准曲线算出阿霉素的负载量,计算载药率(DLR):
DLR(%)=(WL/WN)×100
WL—载体中负载药物的质量,mg;
WN—载药胶束冻干后的质量,mg;
抗癌药物阿霉素在纳米胶束中有较高的载药率,五种纳米胶束样品的载药率在16.8%~21.5%范围内,见表2,载药率较高,这是因为纳米胶束中含有大量的SO3 -基团,可与阿霉素分子中正电荷的氨基快速作用,获得较高的载药率。
实施例12
药物控制释放:取5mL载药胶束溶液置于含10mmol/L GSH的ABS缓冲溶液中(pH5.5),于37℃恒温振荡器中振荡,在一定的时间取出4mL释放介质,用紫外分光光度计测量介质中的阿霉素浓度,计算药物累积释放率。该纳米胶束在10mmol/L的GSH溶液中控制释放,15小时累积释放71%,在48小时内,累积释放92.8%;而对比在缺乏GSH的溶液中、其他条件相同时的药物释放,15小时累积释放30%;48小时累积释放36.9%,说明纳米胶束具有还原条件控制释放。
以上仅以较佳实施例对本发明的技术方案进行介绍,但是对于本领域的一般技术人员,依据本发明实施例的思想,应能在具体实施方式上及应用范围上进行改变,故而,综上所述,本说明书内容不应该理解为本发明的限制,凡在本发明的精神和原理之内所作的任何修改、等同替换、改进等,均应包含在本发明的权利要求范围之内。
Claims (10)
1.一种还原敏感性纳米胶束的制备方法,其特征在于,包括以下步骤:
1)在250mL单口烧瓶中,将牛磺酸溶于蒸馏水,添加氢氧化钠溶液,将烧瓶置于0℃的冰水混合物中搅拌30分钟;将丙烯酰氯与二氯甲烷混合成溶液,通过恒压滴液漏斗滴加到单口烧瓶中,在40min内滴加完毕,控制反应在25℃下反应5h,将产物过滤、用去离子水洗3次,再用乙酸乙酯重结晶,真空干燥24h,得到N-丙烯酰牛磺酸;
2)在装有回流和分水装置的三口烧瓶中,将硫辛酸溶于甲苯,再加入甲基丙烯酸羟乙酯,添加催化剂,搅拌30分钟,氮气保护,升温到85℃反应6小时,冷却后用1.0M的氢氧化钠溶液洗涤产物,分液弃去水层,减压蒸馏除去甲苯,得到硫辛酸-甲基丙烯酰氧基乙基酯;
3)在三口烧瓶中,将N-丙烯酰牛磺酸和硫辛酸-甲基丙烯酰氧基乙基酯溶于二甲亚砜,室温下搅拌均匀,添加引发剂,搅拌使之完全溶解,通氮气20分钟后升温至60~65℃,反应5小时,冷却后得聚合物溶液;将上述聚合物溶液缓缓滴入到去离子水中,添加二硫苏糖醇,25~30℃反应24h,然后移入透析袋中,透析72小时,将纳米胶束溶液冷冻干燥,得到还原敏感性纳米胶束。
2.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤1)中,所加入的牛磺酸与氢氧化钠的摩尔比为1:1。
3.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤1)中,牛磺酸与丙烯酰氯的摩尔比为1:1.1~1.2。
4.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤2)中,硫辛酸与甲基丙烯酸羟乙酯的摩尔比为1.2~1.4:1。
5.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤2)中,所述催化剂为对甲苯磺酸、浓硫酸、高氯酸、三氯乙酸中的一种或几种,其用量为硫辛酸重量的1~3%。
6.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤3)中,N-丙烯酰牛磺酸与硫辛酸-甲基丙烯酰氧基乙基酯的重量比为1:1~2。
7.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤3)中,所述引发剂为偶氮二异丁咪唑啉盐酸盐、偶氮二异丁腈、偶氮二异庚腈中的一种或几种,其用量为N-丙烯酰牛磺酸和硫辛酸-甲基丙烯酰氧基乙基酯重量之和的0.5~1%。
8.如权利要求1所述一种还原敏感性纳米胶束的制备方法,其特征在于,在步骤3)中,硫辛酸-甲基丙烯酰氧基乙基酯与二硫苏糖醇的重量比为17:1~6:1。
9.一种由权利要求1~8任一项所述还原敏感性纳米胶束的制备方法所制得的还原敏感性纳米胶束,其特征在于,作为抗癌药物载体的应用。
10.如权利要求9所述的还原敏感性纳米胶束作为抗癌药物载体的应用,其特征在于,称取10mg盐酸阿霉素溶于10mL二甲基亚砜,搅拌下加入0.1mL三乙胺,反应1h,再加入10mg还原敏感性纳米胶束,搅拌溶解,再滴加80mL超纯水,搅拌2h,将溶液转入截留分子量为3500的透析袋中透析8h,获得载药纳米胶束溶液,冷冻干燥后得到一种载药还原敏感性纳米胶束。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010835611.3A CN111840573A (zh) | 2020-08-19 | 2020-08-19 | 一种还原敏感性纳米胶束及其制备方法和应用 |
US17/139,566 US11510874B2 (en) | 2020-08-19 | 2020-12-31 | Method for making reduction sensitive nano micelles |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010835611.3A CN111840573A (zh) | 2020-08-19 | 2020-08-19 | 一种还原敏感性纳米胶束及其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111840573A true CN111840573A (zh) | 2020-10-30 |
Family
ID=72969307
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010835611.3A Pending CN111840573A (zh) | 2020-08-19 | 2020-08-19 | 一种还原敏感性纳米胶束及其制备方法和应用 |
Country Status (2)
Country | Link |
---|---|
US (1) | US11510874B2 (zh) |
CN (1) | CN111840573A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115337962A (zh) * | 2022-09-02 | 2022-11-15 | 四川大学华西医院 | 一种硫辛酸胶束仿酶催化剂及其制备方法 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115260617B (zh) * | 2022-09-02 | 2023-05-12 | 肇庆骏鸿实业有限公司 | 轻型载重子午线轮胎胎圈补强胶及其制备方法和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107312126A (zh) * | 2017-07-05 | 2017-11-03 | 江南大学 | 一种接枝改性黄原胶纳米微凝胶的制备方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011078457A2 (ko) * | 2009-12-22 | 2011-06-30 | 성균관대학교산학협력단 | 다이온성 복합체 마이셀을 형성하는 피에이치 민감성 블록공중합체 및 이를 이용한 약물 또는 단백질 전달체 |
CA2818075A1 (en) * | 2012-01-15 | 2013-07-15 | University Of Manitoba | Reducible self-assembled micelle drug delivery systems |
CN105524272B (zh) | 2014-10-24 | 2018-08-21 | 江苏师范大学 | 硫辛酸修饰的聚乙二醇-聚氨基酸嵌段共聚物的制备和应用 |
CN104788689B (zh) | 2015-03-31 | 2017-09-29 | 江南大学 | 一种可还原降解聚两性离子纳米胶束及其制备方法 |
CN106750376B (zh) * | 2016-12-26 | 2018-09-28 | 江南大学 | 一种电荷可翻转的还原敏感可逆交联纳米胶束的制备方法 |
-
2020
- 2020-08-19 CN CN202010835611.3A patent/CN111840573A/zh active Pending
- 2020-12-31 US US17/139,566 patent/US11510874B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107312126A (zh) * | 2017-07-05 | 2017-11-03 | 江南大学 | 一种接枝改性黄原胶纳米微凝胶的制备方法 |
Non-Patent Citations (3)
Title |
---|
LIPING ZHANG 等: "Synthesis of core-crosslinked zwitterionic polymer nano aggregates and pH/Redox responsiveness in drug controlled release", 《MATERIALS SCIENCE & ENGINEERING C》 * |
MANUEL SCHMIDT 等: "Chiral discrimination of amines byanisotropic NMR parameters using chiralpolyacrylamide-based gels", 《MAGN. RESON. CHEM.》 * |
WEIFENG LIN 等: "Highly hemocompatible zwitterionic micelles stabilized by reversible cross-linkage for anti-cancer drug delivery", 《COLLOIDS AND SURFACES B: BIOINTERFACES》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115337962A (zh) * | 2022-09-02 | 2022-11-15 | 四川大学华西医院 | 一种硫辛酸胶束仿酶催化剂及其制备方法 |
CN115337962B (zh) * | 2022-09-02 | 2023-09-15 | 四川大学华西医院 | 一种硫辛酸胶束仿酶催化剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
US20220054415A1 (en) | 2022-02-24 |
US11510874B2 (en) | 2022-11-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106750376B (zh) | 一种电荷可翻转的还原敏感可逆交联纳米胶束的制备方法 | |
Chen et al. | pH-responsive polymeric carrier encapsulated magnetic nanoparticles for cancer targeted imaging and delivery | |
CN108752594B (zh) | 基于偶氮还原酶响应的两亲性嵌段聚合物及其制备方法与应用 | |
CN111840573A (zh) | 一种还原敏感性纳米胶束及其制备方法和应用 | |
Zhang et al. | Near infrared light triggered reactive oxygen species responsive nanoparticles for chemo-photodynamic combined therapy | |
WO2017107486A1 (zh) | 可还原降解超支化聚合物纳米胶束及其制备方法和应用 | |
Wu et al. | Porphyrin and galactosyl conjugated micelles for targeting photodynamic therapy | |
CN111053911A (zh) | 还原响应型交联剂及其交联羟基药物分子的制备及应用 | |
CN106432647B (zh) | 基于叔氨基的pH响应嵌段聚合物及其混合胶束与应用 | |
Feng et al. | Poly (amino acid) s-based star AIEgens for cell uptake with pH-response and chiral difference | |
Liu et al. | Synthesis of folic acid functionalized gold nanoclusters for targeting folate receptor-positive cells | |
CN111592634B (zh) | 一种光还原自降解高分子及其制备方法和应用 | |
CN113633785A (zh) | 一种智能响应性壳-核式聚电解质纳米凝胶的制备方法与应用 | |
CN109134870A (zh) | 一种pH响应聚合物载体及其制备的胶束、制备方法和应用 | |
CN111789964A (zh) | 具有还原响应性的硒类聚合物前药胶束、制备方法和应用 | |
CN111944140A (zh) | 具有还原响应性的聚合物前药胶束及其制备方法和应用 | |
CN104758244B (zh) | 一种纳米凝胶、其制备方法和抗肿瘤纳米凝胶载药体系及其制备方法 | |
CN114409607B (zh) | 一种含有硫醚基团的n-羧基环内酸酐及其制备方法和应用 | |
CN114146188B (zh) | 一种修饰型LMSNs纳米药物载体的制备方法 | |
CN107412159B (zh) | 一种三嵌段聚合物胶束的制备方法及其应用 | |
CN106279678B (zh) | 一种可共价载药的还原敏感性纳米胶束的制备 | |
CN115212185B (zh) | pH敏感型阿霉素-脂肪酸前药的白蛋白纳米粒 | |
Zhao et al. | Self-assembled thermosensitive nanoparticles based on oligoethylene glycol dendron conjugated doxorubicin: preparation, and efficient delivery of free doxorubicin | |
CN103301470A (zh) | 一种植物甾醇乙二醇壳聚糖靶向载体、制备方法及其应用 | |
CN113975244A (zh) | 一种仿生磁靶向阳离子脂质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 | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201030 |