CN108078926B - 一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法 - Google Patents
一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法 Download PDFInfo
- Publication number
- CN108078926B CN108078926B CN201711379225.2A CN201711379225A CN108078926B CN 108078926 B CN108078926 B CN 108078926B CN 201711379225 A CN201711379225 A CN 201711379225A CN 108078926 B CN108078926 B CN 108078926B
- Authority
- CN
- China
- Prior art keywords
- star
- drug
- amphiphilic polymer
- peg
- pga
- 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.)
- Active
Links
- 229920000642 polymer Polymers 0.000 title claims abstract description 124
- 239000000693 micelle Substances 0.000 title claims abstract description 83
- 229940079593 drug Drugs 0.000 title claims abstract description 77
- 239000003814 drug Substances 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 41
- 230000008685 targeting Effects 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 22
- 239000004626 polylactic acid Substances 0.000 claims abstract description 13
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 claims abstract description 11
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 9
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 9
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 9
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 6
- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 240000004760 Pimpinella anisum Species 0.000 claims abstract description 3
- 125000000524 functional group Chemical group 0.000 claims abstract description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 67
- 229960001592 paclitaxel Drugs 0.000 claims description 67
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- 239000000178 monomer Substances 0.000 claims description 27
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 230000000977 initiatory effect Effects 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 14
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 230000004087 circulation Effects 0.000 claims description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 8
- 150000001879 copper Chemical class 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 230000001376 precipitating effect Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000009210 therapy by ultrasound Methods 0.000 claims description 8
- YOCIJWAHRAJQFT-UHFFFAOYSA-N 2-bromo-2-methylpropanoyl bromide Chemical compound CC(C)(Br)C(Br)=O YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 claims description 7
- 238000004321 preservation Methods 0.000 claims description 7
- 238000002390 rotary evaporation Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- -1 amino Chemical group 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- TXBCBTDQIULDIA-UHFFFAOYSA-N 2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)CO TXBCBTDQIULDIA-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- 125000003700 epoxy group Chemical group 0.000 claims description 4
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 claims description 3
- OGLYPTCFDGWITI-UHFFFAOYSA-N (4-methoxyphenyl)methylboronic acid Chemical compound COC1=CC=C(CB(O)O)C=C1 OGLYPTCFDGWITI-UHFFFAOYSA-N 0.000 claims description 2
- PTJWCLYPVFJWMP-UHFFFAOYSA-N 2-[[3-hydroxy-2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)COCC(CO)(CO)CO PTJWCLYPVFJWMP-UHFFFAOYSA-N 0.000 claims description 2
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical group CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 101710141544 Allatotropin-related peptide Proteins 0.000 claims 3
- 238000007664 blowing Methods 0.000 claims 1
- 229960004679 doxorubicin Drugs 0.000 claims 1
- 229920005862 polyol Polymers 0.000 claims 1
- 150000003077 polyols Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 229920000747 poly(lactic acid) Polymers 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000004593 Epoxy Substances 0.000 abstract 1
- 230000004913 activation Effects 0.000 abstract 1
- 238000006116 polymerization reaction Methods 0.000 abstract 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 18
- 230000000259 anti-tumor effect Effects 0.000 description 9
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000005760 tumorsuppression Effects 0.000 description 2
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical group CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
- ICNCZFQYZKPYMS-UHFFFAOYSA-N 2-methylpropanoyl bromide Chemical compound CC(C)C(Br)=O ICNCZFQYZKPYMS-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229920001553 poly(ethylene glycol)-block-polylactide methyl ether Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K47/34—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
-
- 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
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
- C08G81/025—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G containing polyether sequences
Abstract
本发明公开了一种星形两亲聚合物及其构筑胶束为载体的纳米药物及其制备方法。该星形两亲聚合物以多元醇为内核,通过活化引发甲基丙烯酸缩水甘油酯(GMA)聚合,再利用活性环氧功能基团分别与胺基封端的疏水链段(A‑NH2)和靶向基团(B)修饰的聚乙二醇(B‑PEG‑NH2)反应得到的。疏水链段优选聚乳酸(PLA‑NH2)或聚己内酯(PCL‑NH2),靶向基团优选茴香酰胺(Anis)或苯硼酸(PBA)。本发明制备的星形两亲聚合物原材料廉价易得,生物相容性好,制备工艺相对简单易行。同时,以其构筑胶束为载体的纳米药物能够在血液中长循环、且具有主动靶向功能,因而具有良好抑瘤效能。
Description
技术领域
本发明涉及功能高分子材料及抗肿瘤药物制备技术领域,具体是涉及一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法。
背景技术
近年来,随着纳米生物医药技术的飞速发展,纳米药物正好可以解决肿瘤化疗的不足,因此,纳米药物在肿瘤临床治疗方面极具发展潜力。纳米药物一般是由载体和抗肿瘤药物组成,药物起治疗作用,载体起包埋药物和输送作用。其中,以聚合物胶束为载体的纳米药物凭借良好的生物相容性、可降解、结构易修饰等特点成为当前的研究热点。截至目前己有多种聚合物胶束纳米药物进入临床试验阶段,例如包载紫杉醇的聚乙二醇-聚乳酸(PEG-b-PLA)聚合物胶束(Genexol-PM)、载SN-38的聚乙二醇-聚谷氨酸聚合物胶束(NK012)及载紫杉醇的聚乙二醇-聚天冬氨酸聚合物胶束(NK105)等已进入临床试验阶段。
然而,对于许多聚合物胶束纳米药物来说,虽然在一定程度上可减轻毒副作用,但疗效较原药并没有明显提高。究其原因,这是因为纳米药物需要面对人体循环系统长距离运输过程中各种因素的干扰如血液的冲洗与稀释、器官的清除及各种酶解等,进而导致纳米药物在体内循环过程过早发生分解,导致药物很难被输送进入病灶细胞,进而表现出疗效降低、甚至没有疗效。相较于传统的线形两亲嵌段共聚物而言,星形两亲聚合物具有更多的支化结构和结合位点,且具有相对精确可控的结构以及简单的制备工艺条件,当作为药物载体时显示出更低的临界胶束浓度(CMC)、更小的流体力学半径、更低的黏度以及较高的载药量和包封率。因此,以星形两亲聚合物及其构筑胶束为载体的纳米药物的研究近年来备受关注。
与人体正常细胞相比,多数肿瘤细胞表面呈现出一些特定受体的高表达,比如叶酸、半乳糖基及核酸等受体等。因此,针对肿瘤细胞表面的特殊受体,在药物载体上通过化学键链接一些相应配体,通过这种受体-配体的特异性结合可以实现纳米药物的主动靶向功能,再结合肿瘤高通透性和滞留效应(EPR效应),可以大幅提高纳米药物在肿瘤细胞的富集。
本发明设计制备了一种生物相容性优异的星形两亲聚合物,利用星形两亲聚合物的星核和支化主链为稳定“类交联”结构组装构筑了一种具有较低临界胶束浓度稳定的聚合物胶束,然后以其为载体制备了一种既能够在血液中长循环,又能够对肿瘤细胞主动靶向的聚合物胶束纳米药物。
发明内容
为了解决现有技术的缺点和不足之处,本发明的目的在于提供一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物。
本发明的另一目的在于提供一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法。
本发明采用以下技术方案:
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,它包括如下步骤:
(1)以多元醇为核ATRP引发单体S-Brx的制备:将多元醇和进一步除水的三乙胺以及二氯甲烷加到圆底烧瓶中,冷却到0℃,接着滴加含溴单体,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可;反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得以多元醇为核ATRP引发单体S-Brx,其中x=3,4,5,6…;
(2)星形聚合物S(PGA)x的制备:将步骤(1)制备的ATRP引发单体S-Brx和甲基丙烯酸缩水甘油酯溶于溶剂中,控制体系的含固量为40%,接着加入催化剂溴化亚铜和配体N,N,N',N,'N”-五甲基二亚乙基三胺,经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.25-1h,过中性氧化铝柱子除铜盐,接着用正己烷沉淀,干燥,即得星型聚合物S(PGA)x,其中x=3,4,5,6…;
(3)星形两亲聚合物S(PGA-g-(A-r-PEG-B)x的制备:将步骤(2)制备的星形聚合物[S(PGA)x]溶于四氢呋喃中,首先加入胺基封端的疏水链段A-NH2,40℃反应12h,接着再加入靶向功能基团修饰的聚乙二醇B-PEG-NH2,40℃反应12h,该反应利用星形聚合物S(PGA)x中的活性环氧基团(EG)分别与A-NH2和B-PEG-NH2反应得到产物,结束反应用正己烷沉淀、干燥,即得星形两亲聚合物[S(PGA-g-(A-r-PEG-B)x],其中x=3,4,5,6…;
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:将步骤(3)所制备的星形两亲聚合物[S(PGA-g-(A-r-PEG-B)x]和小分子抗肿瘤药物D按照9:1~4:1的质量比溶于有机溶剂,超声使其充分溶解,然后逐滴匀速滴加到去离子水中,继续搅拌1h,然后过滤、旋除有机溶剂,即得目标产物肿瘤主动靶向星形两亲聚合物胶束纳米药物。
优选的,步骤(1)中所述多元醇为三羟基丙烷、丙三醇、季戊四醇、甘露醇、双季戊四醇或三季戊四醇,所述含溴单体为2-溴丙酸或2-溴异丁酰溴。
优选的,步骤(2)中所用反应物的摩尔配比为M(S-Brx):M(GMA):M(催化剂):M(配体)为1:30~200:1:2,所述的溶剂为苯甲醚或二苯醚。
优选的,所述步骤(3)中所用反应物的摩尔配比M(EG):M(A-NH2):M(B-PEG-NH2)为1:0.5~0.9:0.1~0.5。
优选的,步骤(4)中所述有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺或二甲亚砜。
优选的,所述胺基封端的疏水链段A-NH2中的A为聚乳酸PLA或聚己内酯PCL,所述PLA和PCL的分子量为1000、2000、3000或4000。
优选的,所述靶向功能基团B修饰的聚乙二醇B-PEG-NH2中的B为茴香酰胺Anis、苯硼酸PBA,所述PEG的分子量为2000、3000、4000和5000。
优选的,所述小分子抗肿瘤药物D为紫杉醇、多烯紫杉醇、喜树碱、阿霉素。
本发明还提供了采用上述的方法制备得到的一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物。
由本发明所设计制备的一种肿瘤主动靶向聚合物胶束纳米药物具有如下优点及有益效果:
(1)本发明星型两亲聚合物及其构筑的聚合物胶束纳米药物所涉及原材料廉价易得,制备工艺简单易行,应用前景广阔。
(2)本发明制备的星形两亲聚合物生物相容性好且具有良好的生物降解性。
(3)本发明涉及的星形两亲聚合物组装构筑的胶束以星核和支化主链为稳定“类交联”结构。因此,胶束稳定性能优异、且具有较低的临界胶束浓度。以其为载体时聚合物胶束纳米药物也具有良好的稳定性,进而能够保证纳米药物在体内长循环而避免早释或突释。
(4)本发明制备的聚合物胶束纳米药物粒径分布均一,同时也引入了主动靶向基团。因此,该纳米药物可快速靶向到肿瘤细胞,具有优异抗肿瘤效能。
附图说明
图1星形两亲聚合物[S(PGA-g-(PLA-r-PEG)x]的合成路线。
图2线形两亲聚合物(mPEG5000-PLA3000)和实施例1、3和4制备的星形两亲聚合物[S(PGA-g-(PLA-r-PEG)x]的临界胶束浓度(CMC)图。
图3实施例1、3和5制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX的粒径分布图。
图4实施例1和3制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX与紫杉醇(PTX,Taxol)进行血浆清除试验的血药浓度-时间曲线图。
图5基于星形两亲聚合物[S(PGA-g-(PLA-r-PEG)x]构筑具有稳定类交联结构胶束及其为载体的纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX的机理图。
图6实施例1、3和4制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX、PBS对照组以及紫杉醇(PTX,Taxol)对荷4T1乳腺癌细胞瘤小鼠抑瘤试验的肿瘤生长-时间曲线图。
图7实施例1、3和4制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX、PBS对照组以及紫杉醇(PTX,Taxol)对荷4T1乳腺癌细胞瘤小鼠抑瘤试验的小鼠体重-时间曲线图。
具体实施方式
下面结合实施例对本发明作进一步详细描述,但本发明的实施方式不限于此。
实施例1
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法:
(1)ATRP引发单体制备:将1.35g三羟甲基丙烷和3g除水三乙胺和100mL二氯甲烷中加到圆底烧瓶中,冷却到0℃,滴加含14g 2-溴异丁酰溴,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可。反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得ATRP引发单体(S-Br3)。
(2)星形聚合物[S(PGA)3]的制备:0.058g ATRP引发单体(S-Br3)和0.43g甲基丙烯酸缩水甘油酯(GMA)溶于20mL苯甲醚中,接着加入0.042g溴化亚铜(CuBr)和0.1gN,N,N',N,'N”-五甲基二亚乙基三胺(PMDETA),经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.25-1h,过中性氧化铝柱子除铜盐,接着用5℃的正己烷沉淀,冷冻干燥,即得星形聚合物。
(3)星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)3]的制备:将0.05g S(PGA)3溶于40mL四氢呋喃中,加入0.36g PLA2000-NH2,40℃反应12h,接着再加入0.6g Anis-PEG5000-NH2,40℃反应12h,结束反应。用正己烷沉淀、干燥,即得星形两亲聚合物。
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:称取10mg星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)3]和2mg紫杉醇(PTX)溶于四氢呋喃中,超声10min使其充分溶解,然后逐滴匀速滴加到10mL去离子水中,继续搅拌1h,然后过滤、旋除四氢呋喃,即得聚合物胶束纳米药物。测定聚合物胶束的理化参数和抗肿瘤效能。
实施例2
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法:
(1)ATRP引发单体制备:将1.35g三羟甲基丙烷和3g除水三乙胺和100mL二氯甲烷中加到圆底烧瓶中,冷却到0℃,滴加含14g 2-溴异丁酰溴,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可。反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得ATRP引发单体(S-Br3)。
(2)星形聚合物[S(PGA)3]的制备:0.058g ATRP引发单体(S-Br3)和0.85g甲基丙烯酸缩水甘油酯(GMA)溶于20mL苯甲醚中,接着加入0.042g溴化亚铜(CuBr)和0.1gN,N,N',N,'N”-五甲基二亚乙基三胺(PMDETA),经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.25-1h,过中性氧化铝柱子除铜盐,接着用5℃的正己烷沉淀,冷冻干燥,即得星形聚合物。
(3)星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)3]的制备:将0.1g S(PGA)3溶于40mL四氢呋喃中,加入0.72g PLA2000-NH2,40℃反应12h,接着再加入1.2g Anis-PEG5000-NH2,40℃反应12h,结束反应。用正己烷沉淀、干燥,即得星形两亲聚合物。
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:称取10mg星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)3]和2mg紫杉醇(PTX)溶于四氢呋喃中,超声10min使其充分溶解,然后逐滴匀速滴加到10mL去离子水中,继续搅拌1h,然后过滤、旋除四氢呋喃,即得聚合物胶束纳米药物。测定聚合物胶束的理化参数和抗肿瘤效能。
实施例3
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法:
(1)ATRP(S-Br4)引发单体制备:将1.36g季戊四醇和4g除水的三乙胺和100mL二氯甲烷中加到圆底烧瓶中,冷却到0℃,滴加含18.4g 2-溴异丁酰溴,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可。反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得ATRP引发单体。
(2)星形聚合物[S(PGA)4]的制备:0.073g ATRP引发单体(S-Br4)和0.56g甲基丙烯酸缩水甘油酯(GMA)溶于20mL苯甲醚中,接着加入0.056g溴化亚铜(CuBr)和0.144gN,N,N',N,'N”-五甲基二亚乙基三胺(PMDETA),经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.5h,过中性氧化铝柱子除铜盐,接着用5℃的正己烷沉淀,冷冻干燥,即得星形聚合物。
(3)星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)4]的制备:将0.06g S(PGA)4溶于40mL四氢呋喃中,加入0.48g PLA2000-NH2,40℃反应12h,接着再加入0.8g Anis-PEG5000-NH2,40℃反应12h,结束反应。用正己烷沉淀、干燥,即得星形两亲聚合物。
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:称取10mg星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)4]和2mg紫杉醇(PTX)溶于四氢呋喃中,超声10min使其充分溶解,然后逐滴匀速滴加到10mL去离子水中,继续搅拌1h,然后过滤、旋除四氢呋喃,即得聚合物胶束纳米药物。测定聚合物胶束的理化参数和抗肿瘤效能。
实施例4
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法:
(1)ATRP(S-Br4)引发单体制备:将1.36g季戊四醇和4g除水的三乙胺和100mL二氯甲烷中加到圆底烧瓶中,冷却到0℃,滴加含18.4g 2-溴异丁酰溴,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可。反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得ATRP引发单体。
(2)星形聚合物[S(PGA)4]的制备:0.073g ATRP引发单体(S-Br4)和1.12g甲基丙烯酸缩水甘油酯(GMA)溶于20mL苯甲醚中,接着加入0.056g溴化亚铜(CuBr)和0.144gN,N,N',N,'N”-五甲基二亚乙基三胺(PMDETA),经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.5h,过中性氧化铝柱子除铜盐,接着用5℃的正己烷沉淀,冷冻干燥,即得星形聚合物。
(3)星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)4]的制备:将0.12g S(PGA)4溶于40mL四氢呋喃中,加入0.96g PLA2000-NH2,40℃反应12h,接着再加入1.6g Anis-PEG5000-NH2,40℃反应12h,结束反应。用正己烷沉淀、干燥,即得星形两亲聚合物。
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:称取10mg星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)4]和2mg紫杉醇(PTX)溶于四氢呋喃中,超声10min使其充分溶解,然后逐滴匀速滴加到10mL去离子水中,继续搅拌1h,然后过滤、旋除四氢呋喃,即得聚合物胶束纳米药物。测定聚合物胶束的理化参数和抗肿瘤效能。
实施例5
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法:
(1)ATRP(S-Br6)引发单体制备:将2.54g双季戊四醇和6.0g除水的三乙胺和200mL二氯甲烷中加到圆底烧瓶中,冷却到0℃,滴加含27.6g 2-溴异丁酰溴,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可。反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得ATRP引发单体。
(2)星形聚合物[S(PGA)6]的制备:0.12g ATRP引发单体(S-Br6)和0.85g甲基丙烯酸缩水甘油酯(GMA)溶于20mL苯甲醚中,接着加入0.084g溴化亚铜(CuBr)和0.22gN,N,N',N,'N”-五甲基二亚乙基三胺(PMDETA),经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.5h,过中性氧化铝柱子除铜盐,接着用5℃的正己烷沉淀,冷冻干燥,即得星形聚合物。
(3)星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)6]的制备:将0.09g S(PGA)6溶于40mL四氢呋喃中,加入0.72g PLA2000-NH2,40℃反应12h,接着再加入1.2g Anis-PEG5000-NH2,40℃反应12h,结束反应。用正己烷沉淀、干燥,即得星形两亲聚合物。
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:称取10mg星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)6]和2mg紫杉醇(PTX)溶于四氢呋喃中,超声10min使其充分溶解,然后逐滴匀速滴加到10mL去离子水中,继续搅拌1h,然后过滤、旋除四氢呋喃,即得聚合物胶束纳米药物。测定聚合物胶束的理化参数和抗肿瘤效能。
实施例6
一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法:
(1)ATRP(S-Br6)引发单体制备:将2.54g双季戊四醇和6.0g除水的三乙胺和200mL二氯甲烷中加到圆底烧瓶中,冷却到0℃,滴加含27.6g 2-溴异丁酰溴,滴加时间控制为2h,滴加完毕后继续在0℃下保温反应2h,接着缓慢升温至30℃反应48h即可。反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得ATRP引发单体。
(2)星形聚合物[S(PGA)6]的制备:0.12g ATRP引发单体(S-Br6)和1.7g甲基丙烯酸缩水甘油酯(GMA)溶于20mL苯甲醚中,接着加入0.084g溴化亚铜(CuBr)和0.22gN,N,N',N,'N”-五甲基二亚乙基三胺(PMDETA),经三次冷冻-抽真空-融化-鼓氩气循环后,20-30℃下反应0.5h,过中性氧化铝柱子除铜盐,接着用5℃的正己烷沉淀,冷冻干燥,即得星形聚合物。
(3)星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)6]的制备:将0.18g S(PGA)6溶于40mL四氢呋喃中,加入1.44g PLA2000-NH2,40℃反应12h,接着再加入2.4g Anis-PEG5000-NH2,40℃反应12h,结束反应。用正己烷沉淀、干燥,即得星形两亲聚合物。
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:称取10mg星形两亲聚合物[S(PGA-g-(PLA-r-PEG-Anis)6]和2mg紫杉醇(PTX)溶于四氢呋喃中,超声10min使其充分溶解,然后逐滴匀速滴加到10mL去离子水中,继续搅拌1h,然后过滤、旋除四氢呋喃,即得聚合物胶束纳米药物。测定聚合物胶束的理化参数和抗肿瘤效能。
实施例7
本例是将实施例1中的聚乳酸(PLA2000-NH2)疏水链段换成聚己内酯(PCL2000-NH2)疏水链段,其他方法同实施例1。
实施例8
本例是将实施例1中的茴香酰胺靶向修饰的聚乙二醇(Anis-PEG-NH2)换成苯硼酸靶向修饰的聚乙二醇(PBA-PEG-NH2),其他方法同实施例1。
实施例9
本例是将实施例1中的抗肿瘤小分子模型药物紫杉醇(PTX)换成多烯紫杉醇(DTX),其他方法同实施例1。
实施例10
本例是将实施例1中的抗肿瘤小分子模型药物紫杉醇(PTX)换成喜树碱(CPT),其他方法同实施例1。
本发明聚合物的临界胶束浓度(CMC)采用尼罗红荧光探针法进行测定,其中实施例1、3和4制备的聚合物[S(PGA-g-(PLA-r-PEG)x]的CMC结果如图2所示。由图2可知,与线形两亲聚合物mPEG5000-PLA3000相比,本发明实施例1、3和4的CMC有明显降低的趋势,且随着支化臂数的增加和疏/亲水链段比例的增加,CMC则会进一步降低。说明本发明设计制备的星形聚合物在构筑胶束时其星核和支化主链起到了稳定“类交联”的作用,因而得到的聚合物胶束具有更好的稳定性。
本发明制备的聚合物胶束纳米药物的粒径分布采用马尔文激光粒度仪测定,其中实施例1、3和5制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX的粒径分布如图3所示。由图3可知,本发明制备的纳米药物的平均粒径为20-60nm,且粒径分布均一,因而非常有利于纳米药物通过EPR效应和主动靶向效应在肿瘤病灶蓄积。为了进一步验证本发明制备的聚合物胶束纳米药物的性能特点,分别将实施例1和3制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX与市售紫杉醇(PTX,Taxol)进行血浆清除试验;以及将实施例1、3和4制备的聚合物胶束纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX与市售紫杉醇(PTX,Taxol)对荷4T1乳腺癌细胞瘤小鼠进行抑瘤试验,具体结果如图4、图5和图6、图7所示。
由图4血浆清除试验结果可知,与Taxol相比,本发明制备的基于星形两亲聚合物构筑胶束为载体的紫杉醇纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX具有长循环的特征,这是因为星形聚合物的星核和支化主链在构筑胶束的过程中起到稳定“类交联”的作用,使其构筑的胶束具有更小的临界胶束浓度,因而当作纳米药物载体面对体内血液循环冲刷和稀释时能够表现出较好的稳定性,机理如图5所示。
图6和图7抑瘤试验也进一步印证了本发明设计制备的基于星形两亲聚合物构筑胶束为载体的紫杉醇纳米药物[S(PGA-g-(PLA-r-PEG)x]/PTX具有良好的抑瘤效能。同时,在抑瘤试验过程中小鼠体重基本保持必变、且小鼠生长状态良好,说明该纳米药物能够降低紫杉醇的毒性,避免Taxol所涉及有机溶剂的毒副作用。因此,本发明设计制备的基于星形两亲聚合物构筑胶束为载体的紫杉醇纳米药物具有良好的抑瘤效能。
Claims (7)
1.一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,其特征在于,它包括如下步骤:
(1)以多元醇为核ATRP引发单体S-Brx的制备:将多元醇和进一步除水的三乙胺以及二氯甲烷加到圆底烧瓶中,冷却到0 ℃,接着滴加含溴单体,滴加时间控制为2 h,滴加完毕后继续在0 ℃下保温反应2 h,接着缓慢升温至30 ℃反应48 h即可;反应结束后产物用分别用饱和碳酸氢钠溶液、饱和食盐水和去离子水洗涤三次,有机相用无水硫酸镁干燥,旋蒸、干燥即得以多元醇为核ATRP引发单体S-Brx,其中x=3, 4,6;
(2)星形聚合物S(PGA)x的制备:将步骤(1)制备的ATRP引发单体S-Brx和甲基丙烯酸缩水甘油酯溶于溶剂中,控制体系的含固量为40%,接着加入催化剂溴化亚铜和配体N,N,N',N,'N''-五甲基二亚乙基三胺,经三次冷冻-抽真空-融化-鼓氩气循环后,20-30 ℃下反应0.25-1 h,过中性氧化铝柱子除铜盐,接着用正己烷沉淀,干燥,即得星型聚合物S(PGA)x,其中x=3, 4,6;
(3)星形两亲聚合物S(PGA-g-(A-r-PEG-B)x的制备:将步骤(2)制备的星形聚合物[S(PGA)x]溶于四氢呋喃中,首先加入胺基封端的疏水链段A-NH2,40 ℃反应12h,接着再加入靶向功能基团修饰的聚乙二醇B-PEG-NH2,40 ℃反应12 h,该反应利用星形聚合物S(PGA)x中的活性环氧基团EG分别与A-NH2和B-PEG-NH2反应得到产物,结束反应用正己烷沉淀、干燥,即得星形两亲聚合物[S(PGA-g-(A-r-PEG-B)x],其中x=3, 4,6;
所述胺基封端的疏水链段A-NH2中的A为聚乳酸PLA或聚己内酯PCL,所述PLA和PCL的分子量为1000、2000、3000或4000;
所述靶向功能基团B修饰的聚乙二醇B-PEG-NH2中的B为茴香酰胺Anis、苯硼酸PBA,所述PEG的分子量为2000、3000、4000和5000;
(4)具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备:将步骤(3)所制备的星形两亲聚合物[S(PGA-g-(A-r-PEG-B)x]和小分子抗肿瘤药物D按照9:1~4:1的质量比溶于有机溶剂,超声使其充分溶解,然后逐滴匀速滴加到去离子水中,继续搅拌1 h,然后过滤、旋除有机溶剂,即得目标产物肿瘤主动靶向星形两亲聚合物胶束纳米药物。
2.根据权利要求1所述的具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,其特征在于,步骤(1)中所述多元醇为三羟基丙烷、丙三醇、季戊四醇、甘露醇、双季戊四醇或三季戊四醇,所述含溴单体为2-溴丙酸或2-溴异丁酰溴。
3.根据权利要求1所述的具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,其特征在于,步骤(2)中所用反应物的摩尔配比为M(S-Brx):M(GMA):M(催化剂):M(配体)为1:30~200:1:2,所述的溶剂为苯甲醚或二苯醚。
4.根据权利要求1所述的具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,其特征在于,所述步骤(3)中所用反应物的摩尔配比M(EG):M(A-NH2):M(B-PEG-NH2)为1:0.5~0.9:0.1~0.5。
5.根据权利要求1所述的具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,其特征在于,步骤(4)中所述有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺或二甲亚砜。
6.根据权利要求1所述的具有肿瘤主动靶向星形两亲聚合物胶束纳米药物的制备方法,其特征在于,所述小分子抗肿瘤药物D为紫杉醇、多烯紫杉醇、喜树碱、阿霉素。
7.一种具有肿瘤主动靶向星形两亲聚合物胶束纳米药物,其特征在于,采用权利要求1~6中任一项所述的方法制备得到的。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711379225.2A CN108078926B (zh) | 2017-12-20 | 2017-12-20 | 一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711379225.2A CN108078926B (zh) | 2017-12-20 | 2017-12-20 | 一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108078926A CN108078926A (zh) | 2018-05-29 |
CN108078926B true CN108078926B (zh) | 2020-07-07 |
Family
ID=62177563
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711379225.2A Active CN108078926B (zh) | 2017-12-20 | 2017-12-20 | 一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108078926B (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110393700A (zh) * | 2019-04-02 | 2019-11-01 | 武汉理工大学 | F3多肽导向的pamam为核心的肿瘤药物纳米载体的制备与应用 |
CN110790911A (zh) * | 2019-11-05 | 2020-02-14 | 临沂大学 | 一种两亲性聚三亚甲基碳酸酯及其制备方法和应用 |
CN110859825B (zh) * | 2019-11-26 | 2021-12-07 | 武汉理工大学 | 一种靶向给药纳米传递系统的制备方法 |
EP4169960A4 (en) * | 2020-06-23 | 2023-07-05 | TMD Lab Co. Ltd | TEMPERATURE DEPENDENT SHAPE MEMORY POLYMER |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006038110A2 (en) * | 2004-10-08 | 2006-04-13 | Firmenich Sa | Amphiphilic star block copolymers |
CN101961494A (zh) * | 2010-09-26 | 2011-02-02 | 苏州同科生物材料有限公司 | 用于细胞内药物传递的星形聚合物纳米药物载体制剂及其制备方法 |
CN106963733A (zh) * | 2017-05-15 | 2017-07-21 | 西南大学 | 一类两亲性星形阿霉素聚合物前药的制备方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7018655B2 (en) * | 2002-03-18 | 2006-03-28 | Labopharm, Inc. | Amphiphilic diblock, triblock and star-block copolymers and their pharmaceutical compositions |
-
2017
- 2017-12-20 CN CN201711379225.2A patent/CN108078926B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006038110A2 (en) * | 2004-10-08 | 2006-04-13 | Firmenich Sa | Amphiphilic star block copolymers |
CN101961494A (zh) * | 2010-09-26 | 2011-02-02 | 苏州同科生物材料有限公司 | 用于细胞内药物传递的星形聚合物纳米药物载体制剂及其制备方法 |
CN106963733A (zh) * | 2017-05-15 | 2017-07-21 | 西南大学 | 一类两亲性星形阿霉素聚合物前药的制备方法 |
Non-Patent Citations (2)
Title |
---|
Synthesis and Evaluation of a Star Amphiphilic Block Copolymer from Poly(E-caprolactone) and Poly(ethylene glycol) as a Potential Drug Delivery Carrier;Fei Wang等;《Bioconjugate Chem》;20050223;第16卷(第2期);第397-405页 * |
Synthesis of an Amphiphilic Multiarm Star Polymer as Encapsulation and Release Carrier for Guest Molecules;Guohua Jiang等;《Designed Monomers and Polymers》;20120402;第13卷(第3期);第277-286页 * |
Also Published As
Publication number | Publication date |
---|---|
CN108078926A (zh) | 2018-05-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108078926B (zh) | 一种肿瘤主动靶向星形两亲聚合物胶束纳米药物及其制备方法 | |
Chan et al. | Dual location disulfide degradable interlayer-crosslinked micelles with extended sheddable coronas exhibiting enhanced colloidal stability and rapid release | |
Li et al. | Ternary polyplex micelles with PEG shells and intermediate barrier to complexed DNA cores for efficient systemic gene delivery | |
Yoon et al. | Amphiphilic poly (ethylene glycol)-poly (ε-caprolactone) AB 2 miktoarm copolymers for self-assembled nanocarrier systems: Synthesis, characterization, and effects of morphology on antitumor activity | |
JP6768069B2 (ja) | 生分解性両親媒性ポリマー、それにより製造されるポリマーベシクル、及び肺がん標的治療薬の製造における使用 | |
CN107952079B (zh) | 一种联合给药的热致凝胶缓释注射剂及其制备方法 | |
Najafi et al. | Biodegradable micelles/polymersomes from fumaric/sebacic acids and poly (ethylene glycol) | |
CN104758247B (zh) | 一种pH响应聚合物混合胶束及其应用 | |
CN106177979B (zh) | 一种具有多药协同作用的抗肿瘤高分子键合药及其制备方法 | |
Du et al. | Poly (d, l-lactic acid)-block-poly (N-(2-hydroxypropyl) methacrylamide) nanoparticles for overcoming accelerated blood clearance and achieving efficient anti-tumor therapy | |
CN103159959B (zh) | 一种m-plga-tpgs星型两亲性共聚物及其制备方法与应用 | |
CN102432783B (zh) | 一种pH响应/疏水基团无规共聚聚合物及其制法和应用 | |
Lin et al. | Micelle formation and drug release behavior of polypeptide graft copolymer and its mixture with polypeptide block copolymer | |
Li et al. | Synthesis and characterization of amphiphilic block polymer poly (ethylene glycol)-poly (propylene carbonate)-poly (ethylene glycol) for drug delivery | |
Akram et al. | Sustained release of hydrophilic drug from polyphosphazenes/poly (methyl methacrylate) based microspheres and their degradation study | |
CN103705460A (zh) | 一种酶促交联载药纳米胶束的制备方法 | |
US20140086995A1 (en) | Polymer microsphere compositions for localized delivery of therapeutic agents | |
CN103720675A (zh) | 一种具有氧化还原敏感的姜黄素前药胶束、胶束单体及其制备方法 | |
Zhang et al. | Preparation of core cross-linked PCL-PEG-PCL micelles for doxorubicin delivery in vitro | |
CN109134870B (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 | |
CN105327362B (zh) | 一种两亲性聚合物刷修饰的石墨烯靶向性药物载体的制备方法 | |
WO2017075760A1 (zh) | 桥联的聚乙二醇-脂肪族聚酯嵌段共聚物、其制备方法、中间体和用途 | |
Yang et al. | Folate-modified poly (malic acid) graft polymeric nanoparticles for targeted delivery of doxorubicin: synthesis, characterization and folate receptor expressed cell specificity | |
CN108774301A (zh) | 一类基于葡聚糖的酸响应聚合物药物的制备方法及其应用 | |
CN104974353A (zh) | 基于聚β胺基酯的pH响应三嵌段线性聚合物及胶束系统 |
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 | ||
TR01 | Transfer of patent right |
Effective date of registration: 20240307 Address after: Room 701, Unit 1, Building 3, No. 169 Zhufeng Street, Yuhua District, Shijiazhuang City, Hebei Province, 050000 Patentee after: Liu Qingfeng Country or region after: China Address before: 276000 west side of north section of Industrial Road, Lanshan District, Linyi, Shandong Patentee before: LINYI University Country or region before: China |
|
TR01 | Transfer of patent right |