CN114177137B - 一种基于免疫激活的胍基化纳米药物及其制备和应用 - Google Patents
一种基于免疫激活的胍基化纳米药物及其制备和应用 Download PDFInfo
- Publication number
- CN114177137B CN114177137B CN202111368696.XA CN202111368696A CN114177137B CN 114177137 B CN114177137 B CN 114177137B CN 202111368696 A CN202111368696 A CN 202111368696A CN 114177137 B CN114177137 B CN 114177137B
- Authority
- CN
- China
- Prior art keywords
- nano
- drug
- guanylated
- amphiphilic polymer
- btz
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 42
- 229940079593 drug Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 230000004913 activation Effects 0.000 title description 3
- 230000036039 immunity Effects 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 42
- 229920000642 polymer Polymers 0.000 claims abstract description 42
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 30
- 229940044683 chemotherapy drug Drugs 0.000 claims abstract description 30
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 19
- 239000002105 nanoparticle Substances 0.000 claims abstract description 14
- 230000005934 immune activation Effects 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 7
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 18
- NLFQKJIGJKCUHQ-UHFFFAOYSA-N n-(4-acetylphenyl)-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NC1=CC=C(C(C)=O)C=C1 NLFQKJIGJKCUHQ-UHFFFAOYSA-N 0.000 claims description 7
- 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 6
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 5
- 229960001467 bortezomib Drugs 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000012986 chain transfer agent Substances 0.000 claims description 4
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- 238000012712 reversible addition−fragmentation chain-transfer polymerization Methods 0.000 claims description 3
- 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 3
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 239000003999 initiator Substances 0.000 claims description 2
- 230000010355 oscillation Effects 0.000 claims description 2
- 230000000379 polymerizing effect Effects 0.000 claims description 2
- 238000001338 self-assembly Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 239000000427 antigen Substances 0.000 abstract description 13
- 102000036639 antigens Human genes 0.000 abstract description 13
- 108091007433 antigens Proteins 0.000 abstract description 13
- 239000002086 nanomaterial Substances 0.000 abstract description 9
- 210000000612 antigen-presenting cell Anatomy 0.000 abstract description 8
- 239000000693 micelle Substances 0.000 abstract description 8
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 238000002512 chemotherapy Methods 0.000 abstract description 7
- 210000004443 dendritic cell Anatomy 0.000 abstract description 7
- 238000009169 immunotherapy Methods 0.000 abstract description 7
- 230000002378 acidificating effect Effects 0.000 abstract description 6
- 230000024932 T cell mediated immunity Effects 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 4
- 230000004044 response Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000002539 nanocarrier Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000011740 C57BL/6 mouse Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000005760 tumorsuppression Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 3
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 230000007969 cellular immunity Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000012202 endocytosis Effects 0.000 description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011549 displacement method Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 231100001083 no cytotoxicity Toxicity 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- 230000036326 tumor accumulation Effects 0.000 description 2
- 230000002100 tumorsuppressive effect Effects 0.000 description 2
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010050685 Cytokine storm Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000002699 waste material Substances 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
- A61K31/70—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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C08F120/00—Homopolymers 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
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/52—Amides or imides
- C08F120/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F120/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
-
- 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
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
-
- 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
- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Polymers & Plastics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种基于免疫激活的胍基化纳米药物及其制备和应用，属于医药技术领域。所述纳米药物为胍基化两亲性聚合物和疏水性化疗药物在水中自组装形成的胶束型纳米颗粒；所述胍基化两亲性聚合物的亲水段为聚乙二醇，疏水段为以pH响应型腙键连接氨基胍形成的聚合物。本发明提供的纳米材料可以在肿瘤酸性的环境下释放疏水性化疗药物，肿瘤细胞在化疗药的作用下产生大量抗原。随后，该胍基化纳米材料有效促进抗原被树突状细胞等抗原递呈细胞摄取与交叉呈递，进一步引起细胞免疫应答。该纳米材料实现了化疗和免疫治疗的联合治疗，大大增强了肿瘤的治疗效果。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种基于免疫激活的胍基化纳米药物及其制备和应用。
背景技术
癌症为全球第二大致死疾病。目前，癌症治疗在临床上主要通过手术切除、化疗和放疗为主。由于肿瘤细胞具有高侵袭性和转移性，手术一般无法完全切除肿瘤并且常常伴随着术后复发等问题，而化疗和放疗方法由于对正常细胞和肿瘤细胞缺乏选择性，副作用较强。因此，亟需开发更加安全可靠的非手术手段来治疗肿瘤。
近年来，肿瘤免疫疗法已经成为新的热点。免疫疗法可以通过靶向免疫系统本身，以抗原特异性的方式实现对肿瘤细胞的精准识别和杀伤。在过去的几十年里，嵌合抗原受体-T细胞(CAR-T)和免疫检查点抑制剂(ICI)均在临床上取得了很好的治疗效果，但仍旧存在一些问题：CAR-T会引起“细胞因子风暴”效应，接受ICI治疗的患者常常伴随严重的免疫相关不良反应。基于纳米粒子载体的递送系统为癌症的免疫疗法提供了新的思路。纳米粒子载体可以通过高渗透和滞留效应(enhanced permeability and retention effect,EPReffect)来增强药物的肿瘤蓄积，并且可以对肿瘤组织进行选择性靶向。因此，设计可以激活细胞免疫的纳米材料用于癌症治疗是极具潜力的。
抗原呈递是细胞免疫过程中最关键的步骤之一，主要是抗原呈递细胞摄取、加工抗原最终被免疫活性细胞识别的过程。树突状细胞(DCs)是目前发现的体内最强大的抗原呈递细胞，在调节肿瘤免疫反应中扮演了重要角色。然而，DC的功能通常会受到肿瘤微环境的免疫抑制作用的影响，抑制了抗原呈递和DC细胞成熟。申请号为CN201611119684.2的专利文献中公开利用表面胍基修饰的纳米佐剂材料聚乙二醇-b-聚己内酯-g-聚(胍基-乙基-甲基丙烯酸酯)mPEG-b-PCL-g-PGEM和抗原混合，来促进抗原被树突状细胞等抗原递呈细胞的摄取与交叉呈递。但相比化疗，治疗效果的提升并不显著。
因此，开发出一种结合化疗和免疫治疗的纳米药物，即利用纳米载体改善化疗药物的药代动力学特性输送化疗药至肿瘤组织，肿瘤细胞在化疗药的作用下产生大量抗原，可激活免疫的纳米载体促进了DC等抗原呈递细胞对肿瘤抗原的摄取和交叉呈递，进一步激发细胞免疫应答，是本领域技术人员需要解决的问题。
发明内容
本发明的目的在于提供一种能够激活细胞免疫应答的纳米药物，结合化疗和免疫治疗手段提升药物对肿瘤的治疗效果。
为实现上述目的，本发明采用如下技术方案：
本发明提供了一种基于免疫激活的胍基化纳米药物，所述纳米药物为胍基化两亲性聚合物和疏水性化疗药物在水中自组装形成的胶束型纳米颗粒；所述胍基化两亲性聚合物的亲水段为聚乙二醇，疏水段为以pH响应型腙键连接氨基胍形成的聚合物。
本发明构建了一种能够激活细胞免疫的胍基化纳米载体，该纳米载体可以高效输送化疗药至肿瘤组织，肿瘤细胞在化疗药的作用下产生大量抗原，随后，该纳米载体可以有效促进抗原被树突状细胞等抗原递呈细胞的摄取与交叉呈递，进一步引起细胞免疫应答。
所述胍基化两亲性聚合物在自组装成为胶束的过程中，其疏水端通过疏水相互作用和π键堆叠作用使得疏水化疗药物包裹在聚合物胶束内部，从而制得所述的纳米药物。
本发明在构建胍基化两亲性聚合物的疏水段时，首先以N-(4-乙酰苯基)甲基丙烯酰胺作为可聚合单体参与聚合，然后将氨基胍通过氨基和酮反应形成腙键接到聚合物上从而实现聚合物的胍基化。当纳米胶束进入肿瘤组织后，肿瘤组织酸性的pH环境引发腙键断裂，纳米胶束崩解，进而释放化疗药物，从而杀伤肿瘤产生抗原。
进一步的，所述胍基化两亲性聚合物的制备方法包括：首先在有机碱催化条件下，对氨基苯乙酮与甲基丙烯酰氯反应制得N-(4-乙酰苯基)甲基丙烯酰胺，再利用聚乙二醇大分子链转移剂通过可逆加成-断裂链转移聚合法或者利用聚乙二醇大分子链引发剂通过原子转移自由基聚合法对N-(4-乙酰苯基)甲基丙烯酰胺聚合制得聚合物，然后通过形成腙键将氨基胍连接到聚合物得到所述胍基化两亲性聚合物。
优选的，所述有机碱为三乙胺。
优选的，所述聚乙二醇大分子链转移剂为PETTC-PEG5k。
优选的，所述胍基化两亲性聚合物的结构式如式(Ⅰ)所示，
其中y＝1-50，m＝10-3000。
更为优选，y＝20-50，m＝200-500。
进一步的，胍基化两亲性聚合物包裹的化疗药物呈疏水性，疏水性化疗药在亲疏水的相互作用，高效装载在两亲性纳米粒子内部。在肿瘤的酸性pH下，纳米胶束崩解，化疗药迅速的释放和激活。所述疏水性化疗药物包括但不限于硼替佐米、阿霉素、紫杉醇。
具体的，硼替佐米的结构式如式(Ⅱ)所示，
阿霉素的结构式如式(Ⅲ)所示：
紫杉醇的结构式如式(Ⅳ)所示：
本发明构建的胍基化纳米载体具有长循环、高肿瘤积累等特性，可以增强化疗药物如硼替佐米的药代动力学特性并提高其对实体瘤的疗效。
本发明还提供了一种制备所述基于免疫激活的胍基化纳米药物的方法。具体来说，利用聚合物两亲性胶束制备方法如溶剂置换法、液膜法、透析法或超声法将两亲性聚合物与化疗药在水中自组装形成纳米颗粒。
其中，溶剂置换法包括：首先将胍基化两亲性聚合物和疏水性化疗药物溶解于良溶剂中，再在振荡条件下将混合液加入到水中，产物自组装形成所述纳米药物。
进一步的，所述胍基化两亲性聚合物和疏水性化疗药物的质量比为1.5-5:1。胍基化两亲性聚合物的包药效率随着聚合物用量的提高而增加，但聚合物用量过多会造成浪费。在上述质量比范围内，能保证较高的包药率和聚合物利用率。
本发明还提供了所述的基于免疫激活的胍基化纳米药物在制备肿瘤治疗药物中的应用。本发明提供的胍基化纳米材料，可以促进DC等抗原呈递细胞对于化疗药产生的肿瘤抗原的摄取和交叉呈递，进而激活细胞免疫，同时增强了化疗药的治疗效果。
进一步的，所述肿瘤为实体瘤。更进一步，所述实体瘤包括但不限于乳腺癌。
本发明具备的有益效果：
(1)本发明提供的纳米材料可以在肿瘤酸性的环境下释放疏水性化疗药物，肿瘤细胞在化疗药的作用下产生大量抗原。随后，该胍基化纳米材料有效促进抗原被树突状细胞等抗原递呈细胞摄取与交叉呈递，进一步引起细胞免疫应答。该纳米材料实现了化疗和免疫治疗的联合治疗，大大增强了肿瘤的治疗效果。
(2)本发明构建的胍基化两亲性聚合物无细胞毒性，利用该材料包载化疗药物，可显著降低化疗药物对正常细胞的毒副作用。
附图说明
图1为实施例1中聚合物PAA的凝胶渗透色谱图。
图2为实施例1中纳米药物PAG/BTZ形成示意图。
图3为实施例1中纳米药物PAG/BTZ动态光散射图。
图4为实施例1中纳米药物PAG/BTZ透射电镜图。
图5为实施例1中纳米药物PAG/BTZ在不同的pH下以化疗药BTZ为示例的药物释放曲线。
图6为实施例1中纳米药物PAG/BTZ在不同细胞株上的细胞毒性，其中PAG是单独用载体处理细胞，Free AG+BTZ是用两种小分子药物处理细胞，PAA/BTZ是用未连接AG的载体PAA包裹BTZ形成的纳米药物处理细胞，Free BTZ是单独用BTZ处理细胞。
图7为实施例1中纳米药物PAG/BTZ在4T1细胞系上时间依赖和浓度依赖内吞的表征。
图8为实施例1中纳米药物PAG/BTZ在C57BL/6小鼠的4T1肿瘤模型中的抑瘤效果的评估，图示为抑瘤曲线。
图9为实施例1中纳米药物PAG/BTZ在C57BL/6小鼠的4T1肿瘤模型中的抑瘤效果的评估，图示为抑瘤周期终点时，肿瘤的照片。
图10为实施例1中纳米药物PAG/BTZ在C57BL/6小鼠的4T1肿瘤模型中的抑瘤效果的评估，图示为小鼠体重变化曲线。
具体实施方式
下面结合具体实施例对本发明做进一步说明。以下实施例仅用于说明本发明，不用来限制本发明的适用范围。在不背离本发明精神和本质的情况下，对本发明方法、步骤或条件所做的修改或替换，均属于本发明的范围。
下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例中涉及的化合物英文缩写说明如下：
DCM-二氯甲烷；AIBN-偶氮二异丁腈；DMF-N,N-二甲基甲酰胺。
实施例1
1、纳米药物的制备
(1)将对氨基苯乙酮(4.0g,29.6mmol)、甲基丙烯酰氯(3.6g,34.4mmol)和三乙胺(4.0g,39.6mmol)溶解在二氯甲烷(DCM,100mL)中并用冰浴冷却。将混合物搅拌12小时，然后依次用饱和碳酸氢钠溶液、盐酸、蒸馏水和饱和氯化钠溶液洗涤，通过旋转蒸发除去溶剂，分离出N-(4-乙酰苯基)甲基丙烯酰胺，并用硅胶色谱法(正己烷:乙酸乙酯＝4:1)纯化。真空干燥后的最终可聚合单体为2.8g(产率46.7％)。其反应过程为：
(2)聚合物PAA通过RAFT聚合得到。取上一步得到的可聚合单体N-(4-乙酰苯基)甲基丙烯酰胺(0.30g,1.5mmol)、大分子链转移剂PETTC-PEG5k(0.27g,0.05mmol)和AIBN(6.56mg,0.04mmol)溶解在二甲基甲酰胺(DMF，4mL)中，并在室温下用N2脱氧30分钟，将反应在70℃搅拌12小时。反应结束后，将溶液用200mL冰乙醚中沉淀3次真空干燥获得聚合物PAA。
如图1所示，通过凝胶渗透色谱表征聚合物，得到聚合物PAA的分子量为9.6kDa，多分散性指数为1.13。由此可知获得的聚合物具有良好的单分散性。
(3)将PAA(0.20g)与过量的盐酸氨基胍(0.11g,1.0mmol)在10mL DMF中混合。用盐酸将溶液的pH值调至2，并在70℃下搅拌6小时。用蒸馏水(Mw＝3000)透析三天得到两亲性纳米载体PAG(0.06g，25％)。
(4)共沉淀法制备PAG/BTZ：将PAG(15mg)和硼替佐米(BTZ,10mg)溶解在300μLDMSO中，并在剧烈搅拌下将溶液加入4mL去离子水中。然后通过透析(Mw＝3500)去除DMSO。过滤除去沉淀的BTZ。自组装过程如图2所示。
2、纳米药物的粒径分析
如图3所示，动态光散射(DLS)测得纳米材料PAG/BTZ的平均粒径是142nm(分布系数PDI＝0.15)。
如图4所示，透射电镜(TEM)观察到纳米材料PAG/BTZ的粒径为150.0nm左右，与DLS测得的粒径结果相符。
3、BTZ的体外释放
PAG/BTZ(2.0mL)密封在截留分子量为3500Da的透析袋中，并在pH分别为7.4和5.0的40mL含有2％Tween 80的PBS中孵育。每隔一定时间收集透析袋外的100μL溶液，用HPLC测定BTZ浓度。
药物的肿瘤酸性pH释放能力是评价PAG/BTZ在体内应用中非常重要的一部分，良好的响应释放能力，能保证药物在肿瘤区域的充分激活，并随后产生细胞毒性，同时对正常组织降低毒性。
如图5所示，在pH为7.4的PBS中，8h后BTZ释放不到20％，随着pH的降低，在pH为5.0的PBS中，8h后BTZ释放了约70％。
4、PAG/BTZ在不同细胞株上的毒性
通过使用CCK8(Cell Counting Kit-8)测定，用于评估PAG/BTZ、PAG、Free AG+BTZ、PAA/BTZ和Free BTZ在4T1和B16F10细胞株上的细胞毒性。其中PAG是单独用载体处理细胞，Free AG+BTZ是用两种小分子药物处理细胞，PAA/BTZ是用未连接AG的载体PAA包裹BTZ形成的纳米药物处理细胞，Free BTZ是单独用BTZ处理细胞。
将细胞以每孔5000个细胞的密度接种在96孔板中并孵育过夜。将细胞暴露于连续稀释的药物中并再培养48小时，然后将培养基更换为含有180μL新鲜培养基和20μL CCK-8的混合溶液。在37℃下孵育1.5小时后，使用酶标仪在450nm处测定每个孔中的吸光度，细胞活力通过计算加药孔与空白对照组吸光值的比值即可获得。
如图6所示，通过细胞水平的毒性分析，我们可知，在4T1细胞株上，单独用PAG纳米颗粒处理的细胞中没有观察到明显的细胞生长抑制，与单独使用BTZ相比，装载BTZ的纳米颗粒的细胞毒性显着降低，这可以解释为BTZ可以自由扩散进入肿瘤细胞，而PAG/BTZ纳米颗粒通过细胞内吞作用进入细胞并在细胞内酸性pH下缓慢释放BTZ。与PAA/BTZ纳米颗粒相比，PAG/BTZ纳米颗粒在高浓度BTZ下表现出中等水平的细胞毒性，在B16F10细胞株上也观察到类似的趋势。以上结果表明PAG/BTZ纳米粒可以有效降低BTZ的细胞毒性，而药物载体PAG纳米粒几乎没有细胞毒性。
5、PAG/BTZ在4T1细胞株上的时间依赖和浓度依赖性内存实验
将收集的4T1细胞均匀铺于12孔板中，每孔细胞数大概为1.5×10 5，24h贴壁完全后，各孔分别加入PBS，Cy5.5PAG/BTZ(0.02μg/mL)，孵育一定时间后，胰酶消化细胞，并用PBS洗2次，最后重悬于0.4mL的PB溶液中，并用流式细胞仪检测其细胞内荧光值。
如图7所示，随着时间和浓度的增加，PAG/BTZ被4T1的内吞逐渐增加，说明PAG/BTZ可以很好地被4T1细胞内吞。
6、在C57BL/6小鼠的4T1肿瘤模型中的抑瘤效果评估
C57BL/6小鼠皮下注射5×105个4T1细胞。肿瘤体积达到80mm3左右时，小鼠被随机分配到6个治疗组(n＝5)：PBS、Free BTZ、Free AG+BTZ、PAG、PAA/BTZ和PAG/BTZ。AG等效剂量为5.0mg/kg，BTZ等效剂量为0.8mg/kg。药物通过尾静脉注射，每四天注射一次，共给药5次。使用公式计算肿瘤体积(mm3)：肿瘤体积＝(最短直径)2×(最长直径)×0.5。
通过在C57BL/6小鼠的4T1皮下瘤模型中的抑瘤评估。如图8-10所示，相比于BTZ组，PAG/BTZ表现出显著增强的抑瘤效果。同时，由于其体内循环过程中化疗前药的毒性较低，因此在PAG/BTZ组中，小鼠的体重降低也较BTZ组更小。
Claims (8)
1.一种基于免疫激活的胍基化纳米药物，其特征在于，所述纳米药物为胍基化两亲性聚合物和疏水性化疗药物在水中自组装形成的胶束型纳米颗粒；所述胍基化两亲性聚合物的结构式如式(Ⅰ)所示，
其中y＝1-50，m＝10-3000。
2.如权利要求1所述的基于免疫激活的胍基化纳米药物，其特征在于，所述胍基化两亲性聚合物的制备方法包括：首先在有机碱催化条件下，对氨基苯乙酮与甲基丙烯酰氯反应制得N-(4-乙酰苯基)甲基丙烯酰胺，再利用聚乙二醇大分子链转移剂通过可逆加成-断裂链转移聚合法或者利用聚乙二醇大分子链引发剂通过原子转移自由基聚合法对N-(4-乙酰苯基)甲基丙烯酰胺聚合制得聚合物，然后通过形成腙键将氨基胍连接到聚合物得到所述胍基化两亲性聚合物。
3.如权利要求1所述的基于免疫激活的胍基化纳米药物，其特征在于，y＝20-50，m＝200-500。
4.如权利要求1所述的基于免疫激活的胍基化纳米药物，其特征在于，所述疏水性化疗药物为硼替佐米、阿霉素或紫杉醇。
5.如权利要求1-4任一项所述的基于免疫激活的胍基化纳米药物的制备方法，其特征在于，包括：首先将胍基化两亲性聚合物和疏水性化疗药物溶解于良溶剂中，再在振荡条件下将混合液加入到水中，产物自组装形成所述纳米药物。
6.如权利要求5所述的制备方法，其特征在于，所述胍基化两亲性聚合物和疏水性化疗药物的质量比为1.5-5:1。
7.如权利要求1-4任一项所述的基于免疫激活的胍基化纳米药物在制备肿瘤治疗药物中的应用。
8.如权利要求7所述的应用，其特征在于，所述肿瘤为实体瘤。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111368696.XA CN114177137B (zh) | 2021-11-18 | 2021-11-18 | 一种基于免疫激活的胍基化纳米药物及其制备和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111368696.XA CN114177137B (zh) | 2021-11-18 | 2021-11-18 | 一种基于免疫激活的胍基化纳米药物及其制备和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114177137A CN114177137A (zh) | 2022-03-15 |
| CN114177137B true CN114177137B (zh) | 2023-04-14 |
Family
ID=80540946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111368696.XA Active CN114177137B (zh) | 2021-11-18 | 2021-11-18 | 一种基于免疫激活的胍基化纳米药物及其制备和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114177137B (zh) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11166464B2 (en) * | 2017-03-06 | 2021-11-09 | The United States Of America, As Represented By The Secretary Of Agriculture | Self-assembled active agents |
| CN109172521B (zh) * | 2018-10-25 | 2021-12-10 | 广州医科大学附属第二医院 | 一种用于载药的酸性响应纳米胶束及其制备方法和应用 |
| CN110615891B (zh) * | 2019-08-16 | 2020-06-23 | 河南大学 | 一类茄呢基硫代水杨酸化合物、其制备方法及应用 |
-
2021
- 2021-11-18 CN CN202111368696.XA patent/CN114177137B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114177137A (zh) | 2022-03-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Recent advances in engineered chitosan-based nanogels for biomedical applications | |
| CN107095859B (zh) | 一种具有肿瘤细胞生物还原性微环境敏感的载药纳米胶囊及其制备方法 | |
| US10874609B2 (en) | ß-cyclodextrin-based star-shaped polymer, a preparation method therefor and an integrated unimolecular micelle system for diagnosis and treatment thereof | |
| CN102120036B (zh) | 生物降解的高分子键合Pt(IV)类抗癌药物纳米胶束及其制备方法 | |
| CN110229323B (zh) | 还原敏感可逆交联的具有不对称膜结构的聚合物囊泡及其在制备治疗肝癌药物中的应用 | |
| JP4991563B2 (ja) | 胆汁酸−キトサン複合体内部に疎水性抗癌剤が封入された剤形及びその製造方法 | |
| CN103251596A (zh) | 7-乙基-10-羟基喜树碱的两亲性聚合物药物前体及其制备方法和纳米颗粒 | |
| CN101474411B (zh) | 一种两亲性超支化聚酯为载体的抗肿瘤前药及制备方法 | |
| CN111632153B (zh) | 一种化学基因药物共载的靶向纳米递药系统及其制备方法 | |
| CN107998082B (zh) | 囊泡纳米药物在制备脑肿瘤治疗药物中的应用 | |
| CN104530256A (zh) | 透明质酸维生素e琥珀酸酯聚合物及其制备和用途 | |
| CN108409756A (zh) | 一种基于喜树碱类的异二聚体多功能前药及其制备方法和应用 | |
| Blanchette et al. | Oral chemotherapeutic delivery: design and cellular response | |
| CN108126210B (zh) | 一种单靶向还原响应囊泡纳米药物在制备脑肿瘤治疗药物中的应用 | |
| CN104027813B (zh) | 一种pH/还原双重敏感的亲水性共聚物药物载体及其合成方法和应用 | |
| WO2014155145A1 (en) | Stable nanocomposition comprising epirubicin, process for the preparation thereof, its use and pharmaceutical compositions containing it | |
| CN115120738A (zh) | 一种咪喹莫特前药纳米粒及其制备方法和应用 | |
| CN114099705B (zh) | 一种基于肼屈嗪改善肿瘤微环境的纳米药物及其制备和应用 | |
| CN114177137B (zh) | 一种基于免疫激活的胍基化纳米药物及其制备和应用 | |
| CN109953974B (zh) | 一种酶-还原双响应性透明质酸-聚硫化丙烯共聚物纳米胶囊的制备方法 | |
| CN109954144B (zh) | 基于改性聚β-氨基酯材料的双级pH响应纳米粒及其制备方法 | |
| NL2013317B1 (en) | Amphiphilic block copolymers for delivery of active agents. | |
| CN112546236B (zh) | 一种pH敏感的双药物骨架聚合物前药及其制备方法和应用 | |
| CN112608487B (zh) | 一种Aptamer和上转换纳米粒修饰共聚物及合成与应用 | |
| Huang et al. | Two important polysaccharides as carriers for drug delivery |
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 |