CN117547600B - Preparation and application of liposome vaccine targeting HDAC - Google Patents
Preparation and application of liposome vaccine targeting HDAC Download PDFInfo
- Publication number
- CN117547600B CN117547600B CN202311535766.5A CN202311535766A CN117547600B CN 117547600 B CN117547600 B CN 117547600B CN 202311535766 A CN202311535766 A CN 202311535766A CN 117547600 B CN117547600 B CN 117547600B
- Authority
- CN
- China
- Prior art keywords
- tumor
- liposome
- liposome vaccine
- vaccine
- saha
- 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
- 239000002502 liposome Substances 0.000 title claims abstract description 75
- 229960005486 vaccine Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 102000003964 Histone deacetylase Human genes 0.000 title claims description 14
- 108090000353 Histone deacetylase Proteins 0.000 title claims description 14
- 230000008685 targeting Effects 0.000 title description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 48
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 46
- 230000000694 effects Effects 0.000 claims abstract description 29
- 239000000427 antigen Substances 0.000 claims abstract description 19
- 102000036639 antigens Human genes 0.000 claims abstract description 19
- 108091007433 antigens Proteins 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 17
- 238000009169 immunotherapy Methods 0.000 claims abstract description 17
- 230000002101 lytic effect Effects 0.000 claims abstract description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 16
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- VQFKFAKEUMHBLV-BYSUZVQFSA-N 1-O-(alpha-D-galactosyl)-N-hexacosanoylphytosphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)[C@H](O)CCCCCCCCCCCCCC)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQFKFAKEUMHBLV-BYSUZVQFSA-N 0.000 claims abstract description 11
- 239000002671 adjuvant Substances 0.000 claims abstract description 11
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims abstract description 9
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 8
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960001231 choline Drugs 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 229910021642 ultra pure water Inorganic materials 0.000 claims abstract description 4
- 239000012498 ultrapure water Substances 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract 3
- 238000010025 steaming Methods 0.000 claims abstract 2
- 210000004027 cell Anatomy 0.000 claims description 27
- 201000007270 liver cancer Diseases 0.000 claims description 25
- 208000014018 liver neoplasm Diseases 0.000 claims description 25
- 210000004881 tumor cell Anatomy 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 12
- 230000006907 apoptotic process Effects 0.000 claims description 10
- 230000001772 anti-angiogenic effect Effects 0.000 claims description 6
- 230000021736 acetylation Effects 0.000 claims description 5
- 238000006640 acetylation reaction Methods 0.000 claims description 5
- 230000025084 cell cycle arrest Effects 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 210000000987 immune system Anatomy 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 230000005917 in vivo anti-tumor Effects 0.000 claims description 3
- 230000002601 intratumoral effect Effects 0.000 claims description 3
- 108010033040 Histones Proteins 0.000 claims description 2
- 238000002604 ultrasonography Methods 0.000 claims description 2
- 230000003827 upregulation Effects 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims 2
- 238000006703 hydration reaction Methods 0.000 claims 2
- 239000004471 Glycine Substances 0.000 claims 1
- 102000006947 Histones Human genes 0.000 claims 1
- 230000003527 anti-angiogenesis Effects 0.000 abstract description 11
- 230000002829 reductive effect Effects 0.000 abstract description 5
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- 230000000887 hydrating effect Effects 0.000 abstract 2
- 230000006718 epigenetic regulation Effects 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 238000009210 therapy by ultrasound Methods 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 230000000259 anti-tumor effect Effects 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- 102000004196 processed proteins & peptides Human genes 0.000 description 11
- 229920001184 polypeptide Polymers 0.000 description 10
- 239000002245 particle Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000003213 activating effect Effects 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 230000002147 killing effect Effects 0.000 description 5
- 230000005975 antitumor immune response Effects 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 2
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 230000002934 lysing effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 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 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 230000005760 tumorsuppression Effects 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 1
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Pain & Pain Management (AREA)
- Dispersion Chemistry (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of biological medicine, and in particular relates to a preparation method and application of a liposome vaccine containing an HDAC inhibitor, pam2-MUC1 antigen peptide and alpha-GalCer, wherein the liposome is prepared by the following method: 1) The HDAC inhibitors SAHA, pam2-MUC1 antigen peptide, α -GalCer adjuvant, choline, cholesterol were dissolved in the organic solvent methanol/dichloromethane (volume ratio 1:1), respectively, and then these 5 ingredients were mixed in a molar ratio and ensured to be sufficiently dissolved (choline: cholesterol: pam2-MUC1 antigen peptide: alpha-GalCer adjuvant: saha=10:8: 2:1: 2) Spin-drying the dissolved mixture into a film by a spin-steaming instrument; 3) And (3) hydrating, namely adding a certain volume of ultrapure water or PBS into a round-bottomed flask for forming a film, and carrying out ultrasonic treatment for 30min for hydrating to finally obtain the target liposome vaccine. The liposome vaccine is combined with the anti-angiogenesis lytic peptide, so that the effects of tumor immunotherapy can be achieved in a synergistic manner from multiple aspects such as epigenetic regulation, tumor vaccine and anti-angiogenesis, and the use concentration of anti-tumor drugs is reduced, so that the toxic and side effects of the anti-tumor drugs are reduced. The invention provides a new treatment idea and direction for the limitation of the clinical tumor immunotherapy at present.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to preparation of a liposome vaccine targeting HDAC and application of the liposome vaccine in the field of liver cancer treatment in cooperation with an anti-angiogenesis split peptide.
Background
Liver cancer, represented by hepatocellular carcinoma (hepatocellular carcinoma, HCC), is the fifth most common cancer worldwide, and is also the second leading cause of cancer death. The immune system has been widely accepted in inhibiting the occurrence and development of liver cancer, and the tumor immunotherapy is currently combined with targeting drugs and chemotherapeutics to treat malignant tumors, so that a clinically significant therapeutic effect is obtained, and the treatment using anti-tumor immune response is a big support for cancer treatment. However, many patients with cancer including liver cancer have congenital or secondary immune tolerance after receiving tumor immunotherapy, resulting in poor therapeutic effects. Highly effective anti-tumor immune responses require very high levels of regulation, and there is a great clinical need to develop new methods to augment tumor immunotherapy, particularly malignant highly metastatic cancers. Research shows that histone deacetylase inhibitors (HDACi) can effectively inhibit proliferation of various malignant tumors (such as lymphoma, breast cancer, liver cancer, colon cancer and the like), 5 HDAC drugs are marketed in batches before the day of the expiration, namely vorinostat, romidepsin, belinostat, panobinostat and sitagliptin, and are mainly used for treating blood cancer or breast cancer. In recent years, more and more studies have found that HDAC inhibitors have significant effects in enhancing tumor immunotherapy, such as HDAC6 inhibitors improving patient response to immunotherapy and reducing invasiveness of breast cancer. Other preclinical studies have also demonstrated that many HDAC inhibitors, including broad-spectrum HDAC inhibitors and subtype-selective HDAC inhibitors, exhibit good in vitro and in vivo anti-tumor activity and tumor immunomodulation, not only significantly inhibit tumor growth in vivo, but also activate anti-tumor immunity by activating T cells, alleviating the inhibitory immune microenvironment and affecting macrophage polarization.
Clinical outcome of tumor immunotherapy depends on the presence of tumor-specific antigens, which is central to T lymphocyte-based tumor immunotherapy. Research shows that the fragments generated by killing tumors by the cytotoxic drugs can become tumor antigens for activating immune systems and promote the anti-tumor effect of the PD-1 monoclonal antibodies or the immunotherapeutic drugs such as tumor vaccines. The lytic peptide is a very potential anti-tumor drug which achieves an anti-tumor effect mainly by lysing tumor cell membranes, so that the peptide has a therapeutic effect on various tumors including chemotherapy-resistant tumor cells. The research shows that the intratumoral injection of the lytic peptide can enhance the therapeutic effect of the PD-1 monoclonal antibody on the far-end tumor, and the fact that the lytic peptide can enhance the immune curative effect of the PD-1 monoclonal antibody by lysing tumor cells or not is proved. The applicant has developed a VEGFR-targeted lytic peptide in the early stage, which can effectively target VEGFR protein on the cell surface, and can inhibit proliferation and anti-angiogenesis of tumor at the same time. Therefore, the cracking peptide is combined with tumor immunotherapy, and is expected to enhance the immunotherapy effect to a greater extent.
Although existing immunotherapy has achieved significant results in the field of tumor treatment, the unique advantages of tumor vaccines have attracted attention from the scientific and medical industries. Tumor vaccines can target intracellular antigens other than tumor-specific surface antigens and even potentially elicit new tumor-specific T cell responses. However, the number of clinical trials of cancer vaccines currently being developed is limited, and their therapeutic efficacy and detailed and well-defined principles require further exploration by researchers. Research shows that the liposome as vaccine adjuvant can raise cell mediated immune response and strengthen body fluid, and is favorable to raising vaccine effect. Further research shows that the encapsulation of Pam 2 -MUC1 polypeptide and alpha-GalCer liposome can significantly improve the IgG antibody titer in mice, suggesting that the liposome is expected to be a very effective liposome vaccine for resisting Pam 2 -MUC1, however the anti-tumor treatment effect of the liposome has not been reported so far.
Tumor immunotherapy is a very complex procedure, and how to effectively use the sharps to exert the greatest effect thereof has been a focus and difficulty of attention of scientists. The adoption of multifactor synergistic activation of the immune system in vivo and the exertion of the anti-tumor effect are expected to become effective tools for solving clinical immune escape or immune tolerance.
Disclosure of Invention
Although tumor immunotherapy has shown great promise in cancer treatment, only a small percentage of people can get obvious therapeutic effects in specific clinical applications. How to improve the immune response of tumor immunotherapy, and thus the therapeutic effect, has been the direction of scientists. The technical problem to be solved by the invention is to provide a preparation method of an anti-tumor liposome vaccine containing Pam 2 -MUC1 antigen peptide, HDAC inhibitor SAHA and alpha-GalCer adjuvant and an application of the anti-tumor liposome vaccine in combination with anti-angiogenesis cleavage peptide, wherein a specific structure diagram is shown in figure 1. The technical scheme for solving the technical problems is as follows:
1. Preparing antitumor liposome vaccine with uniform size. The nano liposome structure formed by mixing an HDAC inhibitor SAHA, pam 2 -MUC1 antigen peptide, alpha-GalCer adjuvant, cholesterol and choline according to a certain proportion is specifically prepared as follows: choline, cholesterol, pam 2 -MUC1 antigen peptide, SAHA, α -GalCer were dissolved in dichloromethane/methanol (volume ratio 1:1), respectively, and then in a molar ratio of 10:8:2:2:1, and then placing the mixture in a round bottom flask, and performing reduced pressure spin drying to form a film. The proportion of the liposome is obtained through earlier literature investigation and cytotoxicity screening after SAHA introduction. Then, a certain volume of PBS or ultrapure water H2O is added, ultrasonic (53 Hz,90% power) is carried out for 30 hours in an ultrasonic instrument at 25 ℃, every 10 minutes of ultrasonic is carried out in the ultrasonic process, 1 minute is carried out in a cyclone instrument, and 3 times are carried out alternately until a uniformly dispersed suspension which can be seen by naked eyes is formed. Centrifugation was performed using an ultracentrifuge at 10000rpm for 30min to allow the liposomes to precipitate sufficiently, the supernatant was discarded, the precipitated liposomes were resuspended in PBS again, the size of the liposomes was measured using a particle sizer, the average particle size of the liposomes was about 177nm (pdi=0.462) as measured by the particle sizer, and the potential detection revealed that the liposomes were positively charged, more conducive to penetration of negatively charged cell membranes, as shown in fig. 2.
2. Application of liposome vaccine in anti-liver cancer treatment
Firstly, we verify that the HDAC inhibitor SAHA and the anti-angiolytic peptide have anti-liver cancer effect, and as shown in figures 3A-D, the two medicaments have anti-tumor effect in different liver cancer cells and have inhibition effect on normal cells at higher concentration. Then, in order to improve the curative effect and reduce the toxicity, the liposome is taken as a carrier to wrap Pam 2 -MUC1 antigen peptide capable of activating tumor immune response and an adjuvant alpha-GalCer for enhancing the immune effect, so that the liposome has stronger immune response effect, and meanwhile, the liposome wraps SAHA, so that the liposome has the effect of killing tumor cells and reduces the toxicity. As shown in FIG. 3E, the liposome has strong anti-tumor effect at low concentration after wrapping SAHA, but has no toxicity to normal cells. Therefore, the liposome vaccine obtained by the invention has the double effects of killing tumors and activating immune response. The anti-angiogenesis lytic peptide reported by the inventor in the prior period can resist tumor microvessels and lyse tumor cells so as to achieve the dual anti-tumor effect. By utilizing the characteristics, the lytic peptide is combined with the liposome vaccine of the invention, and firstly, apoptosis and cell cycle experiments prove that the lytic peptide combined with the liposome vaccine wrapped with SAHA can obviously cause apoptosis and cell cycle arrest of liver cancer cells in the G2 phase, as shown in figures 4 and 5. We also demonstrated that the liposomes have an effect of inhibiting intracellular HDAC activity by WB, as shown in fig. 6. Then, constructing a subcutaneous tumor animal model of liver cancer, firstly injecting a lytic peptide into tumor in an animal body to enable the tumor cells to be lysed to release new antigens, then injecting a liposome vaccine into the abdominal cavity of the animal, and activating tumor immune response in the body by cooperating with the new antigens to enhance the anti-tumor immune response effect. As shown in fig. 7-8, the liposome can effectively inhibit tumor proliferation, prolong the life cycle of mice, and the medicine has no remarkable toxicity and does not cause the change of the body weight of mice. Further immunohistochemical experiments and loss analysis show that the liposome vaccine prepared by the invention can remarkably improve immune response in mice, cause proliferation of anti-tumor immune related cells CD4 +、CD8+、CD11b+ and CD11c +, and simultaneously can cause expression of immune related cytokines such as TNF-alpha and IFN-gamma. Further proving our hypothesis as shown in fig. 9-10.
Compared with the prior art, the invention has obvious technical progress. The invention combines the liposome vaccine without tumor killing effect with the SAHA of the HDAC inhibitor to form a novel multifunctional nano liposome vaccine, so that the novel multifunctional nano liposome vaccine has dual effects of anti-tumor activity and immune response activation. The cytotoxicity experiment proves that the liposome vaccine containing SAHA has specific and obvious capability of killing liver cancer cells, and the liposome vaccine without SAHA can not effectively kill liver cancer cells. The western blot experiment proves that the liposome vaccine can effectively inhibit the activity of HDAC in cells, further influence the related signal paths, and induce apoptosis and cell cycle retardation of tumor cells. Animal tumor suppression experiments prove that the liposome vaccine wrapping SAHA has more remarkable tumor suppression effect than liposome vaccine without SAHA, and the synergistic intra-tumor administration of the anti-angiogenesis lytic peptide can remarkably suppress the proliferation of tumors in mice, but does not influence the change of the weight of the mice. Further HE staining experiments prove that the SAHA-containing liposome vaccine cooperates with the anti-angiogenesis lytic peptide, so that the weight of the mice is not reduced, the internal organs of the mice are not damaged, and the effectiveness and safety of the medicine in treating liver cancer are proved. The research result provides a new reference for developing novel anti-tumor vaccine in future and providing curative effect of clinical tumor immunotherapy.
Drawings
Fig. 1 is: the nano liposome structure and the anti-angiogenesis cleavage peptide structure diagram of the invention;
fig. 2 is: the structure characterization diagram of the nano liposome is shown in the specification;
fig. 3 is: toxicity patterns of the nano liposome drug in liver cancer cells and normal cells;
Fig. 4 is: the nano liposome induces apoptosis patterns of liver cancer cells;
Fig. 5 is: the nano liposome of the invention causes a liver cancer cell cycle arrest diagram;
fig. 6 is: the nanoliposome of the invention has an influence diagram on the acetylation level of HDAC protein substrates in liver cancer cells;
Fig. 7 is: the nano liposome has the effect of inhibiting tumor growth in a mouse liver cancer model;
Fig. 8 is: graph of the influence of nanoliposomes of the invention on mouse body weight during dosing;
Fig. 9 is: the nano-lipid of the invention can cause the expression of anti-tumor immune cells in tumor tissues
Fig. 10 is: the nano-lipid can enhance the expression of anti-tumor immune factors in mice.
Detailed Description
The principles and features of the present invention are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention.
Example 1: preparation of nanoliposome comprising SAHA, pam 2 -MUC1 polypeptide, alpha-GalCer adjuvant.
The synthetic route of Pam 2 -MUC1 polypeptide has been reported in the literature, and the synthetic route of the polypeptide used in the present invention is strictly carried out in accordance with the literature. The nano liposome structure is prepared by mixing SAHA, pam2-MUC1 antigen peptide, alpha-GalCer adjuvant, cholesterol and choline according to a certain proportion, and is specifically prepared as follows: choline, cholesterol, pam 2 -MUC1 antigen, SAHA, α -GalCer were dissolved in dichloromethane/methanol (volume ratio 1:1), respectively, and then in a molar ratio of 10:8:2:2:1, and then placing the mixture in a round bottom flask, and performing reduced pressure spin drying to form a film. Then, a volume of PBS or ddH2O was added and ultrasound (53 Hz,90% power) was performed in an sonicator at 25℃for 30 hours, every 10 minutes during the sonication, and 1 minute was vortexed in the vortexing instrument, alternating 3 times until a macroscopically homogeneously dispersed suspension was formed. Centrifuging with an ultracentrifuge at 10000rpm for 30min to precipitate liposome, discarding supernatant, re-suspending the precipitated liposome with PBS, measuring the particle size of the liposome with a particle size analyzer, and detecting the average particle size of the liposome with a particle size of 177nm (PDI=0.462), wherein the liposome is positively charged as detected by electric potential detection, and is more helpful for penetrating negatively charged cell membrane.
Example 2: synthesis preparation of antiangiogenic lytic peptides
The synthetic route of the anti-angiogenic cleavage peptide has been reported in patent and literature, and the synthetic route of the polypeptide used in the invention is strictly carried out according to literature, and polypeptide molecules with accurate structure and single component are obtained. Therefore, the synthetic route of the polypeptide is not described in detail.
Example 3: detection of killing action of nanoliposomes of the invention on different cells
Cytotoxicity experiments were determined by CCK8 cytotoxicity experiments. Cells were seeded at 8×10 3 in 96-well plates, after 24 hours, nanoliposomes containing SAHA, pam2-MUC1 polypeptide and α -GalCer adjuvant, nanoliposomes containing Pam 2 -MUC1 polypeptide and α -GalCer adjuvant, and anti-angiogenic polypeptides were incubated with hepatoma Huh7 cells, hepG2 cells, hep3B cells and normal LO2 cells, respectively, at different concentration gradients for 48 hours, CCK8 was added to each well of cells and incubation was continued for 1 hour. Absorbance was measured at 450nm using an enzyme-labeled instrument. Wherein the untreated cell viability was 100%. The results show that the nanoliposome of the present invention comprising HDAC has a remarkable antitumor effect, but has no remarkable toxicity to normal cells, as shown in fig. 3. Meanwhile, the anti-angiogenesis lytic peptide has very obvious inhibition effect on liver cancer cells. But liposome vaccines without SAHA have no significant toxicity to tumor cells. The results indicate that nanoliposome vaccines comprising SAHA have more pronounced anti-tumor selective toxicity.
Example 4: the nano liposome vaccine of the invention has the effects on apoptosis and cell cycle arrest of liver cancer cells.
In order to evaluate whether the nanoliposome vaccine causes apoptosis of tumor cells, an Annexin V-FITC apoptosis detection kit is adopted, and the apoptosis condition caused by medicines is detected by a flow cytometer. As shown in fig. 5, the drug did significantly induce apoptosis of tumor cells, as shown in fig. 4.
For cell cycle experiments, cells treated with drug for 24 hours were collected, first incubated with 70% glacial ethanol overnight at-20 ℃, PI stained, and then analyzed by flow cytometry. The results show that nanoliposomes can significantly induce cell cycle arrest in G1 phase of tumor cells, as shown in FIG. 5.
Example 5: nanolipids can significantly increase the substrate acetylation level of HDAC
Immunoblotting experiments (WB) were used to study the effect of SAHA-containing liposome vaccines on the level of HDAC substrate acetylation after treatment of tumor cells at different dosing concentrations. Repeated WB experiments show that the designed liposome can obviously cause up-regulation of the acetylation level of the HDAC histone substrate, and as shown in fig. 6, it is revealed that our drugs can obviously inhibit the activity of tumor cell HDAC.
Example 6: mouse subcutaneous liver cancer model, nano liposome in vivo tumor inhibition and safety evaluation
To further verify the in vivo anti-tumor effect of the nanoliposome, we constructed a mouse subcutaneous liver cancer model, and after the mouse subcutaneous tumor size was about 150mm 3, the intervention experiment was started, i.e., mice were divided into 5 groups, PBS group, SAHA group (2, 6,10,14 days of administration, intraperitoneal injection, 1 mg/kg) anti-angiogenic lytic peptide group (every 1 day of administration, 2 weeks, 2 mg/kg), SAHA-containing nanoliposome group (2, 6,10,14 days of intraperitoneal injection, liposome containing about SAHA1 mg/kg), nanoliposome+anti-angiogenic lytic peptide group (2 mg/kg of intratumoral injection on days 1,3,5,7,9,11,13, and nanoliposome administration on days 2,6,10, 14). Tumor size was assessed after 2 weeks. As shown in fig. 7, the nano-liposome combined anti-angiogenesis lytic peptide has the strongest anti-tumor activity, and can remarkably prolong the life cycle of mice. Moreover, the drug does not affect the weight of mice during the administration period, thus proving the relative safety of the drug. Further immunohistochemistry and cell flow type ELISA experiments prove that the liposome vaccine can effectively cause proliferation of anti-tumor immune cells in tumor tissues, as shown in figure 8, enhance expression of the anti-tumor immune cells in mice, as shown in figure 9, and expression of anti-tumor cytokines, as shown in figure 10.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (3)
1. The application of the liposome vaccine in preparing an anti-tumor drug is characterized in that the liposome vaccine comprises an HDAC inhibitor, pam 2 -MUC1 antigen peptide and alpha-GalCer, and the preparation method of the liposome vaccine is as follows: preparing liposome by adopting a film hydration method, respectively dissolving an HDAC inhibitor SAHA, pam 2 -MUC1 antigen peptide, alpha-GalCer adjuvant, cholesterol and choline in an organic solvent methanol/dichloromethane, wherein the volume ratio of the two organic solvents is 1:1, and taking choline: cholesterol: pam 2 -MUC1 antigen peptide: alpha-GalCer adjuvant: SAHA=10:8:2:1:2, and then spin-drying the mixture in a spin-steaming instrument to form a film, preparing liposome vaccine by adopting PBS or ultrapure water hydration ultrasound, centrifuging at a high speed at 10000rpm for 30 minutes, removing non-encapsulated free molecules, and re-suspending and centrifuging again by using ultrapure water to precipitate to obtain the required liposome vaccine, wherein the sequence of Pam 2 -MUC1 antigen peptide is Pam 2 -lysine-glycine-alanine-proline-aspartic acid-valine-arginine-proline-alanine-proline-glycine, and the antitumor drug is a drug for treating liver cancer.
2. The use according to claim 1, wherein said liposome vaccine promotes apoptosis and cell cycle arrest in liver cancer cells by inhibiting HDAC activity in liver cancer cells, resulting in up-regulation of the level of acetylation of HDAC specific substrate histone H3, as compared to a liposome vaccine without SAHA.
3. The use according to claim 1, wherein the liposome vaccine is combined with an anti-angiogenic lytic peptide QR-KLU, which kills tumor cells and releases tumor neoantigens by intratumoral administration, activates the in vivo anti-tumor immune system, and cooperates with the liposome vaccine in a mouse tumor model, enhancing the in vivo tumor immunotherapy effect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311535766.5A CN117547600B (en) | 2023-11-15 | 2023-11-15 | Preparation and application of liposome vaccine targeting HDAC |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311535766.5A CN117547600B (en) | 2023-11-15 | 2023-11-15 | Preparation and application of liposome vaccine targeting HDAC |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117547600A CN117547600A (en) | 2024-02-13 |
| CN117547600B true CN117547600B (en) | 2024-04-30 |
Family
ID=89814256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311535766.5A Active CN117547600B (en) | 2023-11-15 | 2023-11-15 | Preparation and application of liposome vaccine targeting HDAC |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117547600B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017071380A1 (en) * | 2015-10-28 | 2017-05-04 | 李淑兰 | Tumor vaccine for use in treating liver cancer and preparation method for vaccine |
| WO2018174544A2 (en) * | 2017-03-21 | 2018-09-27 | 주식회사 펩트론 | Antibody binding specifically to muc1 and use thereof |
| CN113499433A (en) * | 2021-06-21 | 2021-10-15 | 复旦大学 | GalNAc/CpG liposome vaccine with anti-tumor activity, preparation method and application |
| CN114146186A (en) * | 2021-11-04 | 2022-03-08 | 华中科技大学同济医学院附属协和医院 | Sulfonium salt stabilization based HDAC (HDAC) -targeted polypeptide drug conjugate and application thereof |
| CN114213546A (en) * | 2021-12-03 | 2022-03-22 | 华中科技大学同济医学院附属协和医院 | Cleavage peptide conjugate of targeting VEGFR and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103619350A (en) * | 2011-03-11 | 2014-03-05 | 麦克马斯特大学 | A method of vaccination comprising a histone deacetylase inhibitor |
-
2023
- 2023-11-15 CN CN202311535766.5A patent/CN117547600B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017071380A1 (en) * | 2015-10-28 | 2017-05-04 | 李淑兰 | Tumor vaccine for use in treating liver cancer and preparation method for vaccine |
| WO2018174544A2 (en) * | 2017-03-21 | 2018-09-27 | 주식회사 펩트론 | Antibody binding specifically to muc1 and use thereof |
| CN113499433A (en) * | 2021-06-21 | 2021-10-15 | 复旦大学 | GalNAc/CpG liposome vaccine with anti-tumor activity, preparation method and application |
| CN114146186A (en) * | 2021-11-04 | 2022-03-08 | 华中科技大学同济医学院附属协和医院 | Sulfonium salt stabilization based HDAC (HDAC) -targeted polypeptide drug conjugate and application thereof |
| CN114213546A (en) * | 2021-12-03 | 2022-03-22 | 华中科技大学同济医学院附属协和医院 | Cleavage peptide conjugate of targeting VEGFR and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| Effects of SAHA on proliferation and apoptosis of hepatocellular carcinoma cells and hepatitis B virus replication;Ying-Chun Wang等;World J Gastroenterol .;20130821;第19卷(第31期);5159-5164 * |
| HDAC inhibitors enhance the anti-tumor effect of immunotherapies in hepatocellular carcinoma;Chen Shen等;Front Immunol.;20230526;第14卷;1-20 * |
| Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid-Dependent Immunodominant Response;Jing-Jing Du等;Chem. Asian J.;20190521;第14卷;2116 – 2121 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117547600A (en) | 2024-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lai et al. | The enhanced antitumor-specific immune response with mannose-and CpG-ODN-coated liposomes delivering TRP2 peptide | |
| Gao et al. | Engineering nanoparticles for targeted remodeling of the tumor microenvironment to improve cancer immunotherapy | |
| Li et al. | Dual-blockade immune checkpoint for breast cancer treatment based on a tumor-penetrating peptide assembling nanoparticle | |
| Zhou et al. | FAP‐targeted photodynamic therapy mediated by ferritin nanoparticles elicits an immune response against cancer cells and cancer associated fibroblasts | |
| Liu et al. | BSA‐AIE nanoparticles with boosted ROS generation for immunogenic cell death immunotherapy of multiple myeloma | |
| Zhang et al. | Application of mesenchymal stem cell exosomes and their drug‐loading systems in acute liver failure | |
| Pi et al. | Exosomes: powerful weapon for cancer nano-immunoengineering | |
| Yao et al. | Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy | |
| Fathi et al. | Simultaneous blockade of TIGIT and HIF-1α induces synergistic anti-tumor effect and decreases the growth and development of cancer cells | |
| Vangala et al. | Combating glioblastoma by codelivering the small-molecule inhibitor of STAT3 and STAT3siRNA with α5β1 integrin receptor-selective liposomes | |
| Hallaj et al. | Inhibition of CD73 using folate targeted nanoparticles carrying anti-CD73 siRNA potentiates anticancer efficacy of Dinaciclib | |
| Kiani et al. | Simultaneous silencing of the A2aR and PD-1 immune checkpoints by siRNA-loaded nanoparticles enhances the immunotherapeutic potential of dendritic cell vaccine in tumor experimental models | |
| Li et al. | A platinum@ polymer-catechol nanobraker enables radio-immunotherapy for crippling melanoma tumorigenesis, angiogenesis, and radioresistance | |
| Li et al. | Anti-tumor immunity and ferroptosis of hepatocellular carcinoma are enhanced by combined therapy of sorafenib and delivering modified GO-based PD-L1 siRNAs | |
| Yang et al. | Toll-like receptor-targeted anti-tumor therapies: Advances and challenges | |
| Li et al. | Liposomal Co-delivery of PD-L1 siRNA/Anemoside B4 for enhanced combinational immunotherapeutic effect | |
| Li et al. | Targeting the innate immune system with nanoparticles for cancer immunotherapy | |
| Gerritsen et al. | A dose-escalation trial of GM-CSF-gene transduced allogeneic prostate cancer cellular immunotherapy in combination with a fully human anti-CTLA antibody (MDX-010, ipilimumab) in patients with metastatic hormone-refractory prostate cancer (mHRPC) | |
| Du et al. | Preparation of C6 cell membrane-coated doxorubicin conjugated manganese dioxide nanoparticles and its targeted therapy application in glioma | |
| CN117547600B (en) | Preparation and application of liposome vaccine targeting HDAC | |
| Lai et al. | Study on the mechanism of diosgenin targeting STAT3 to inhibit colon cancer proliferation and migration | |
| Deng et al. | Biogenic platinum nanoparticles on bacterial fragments for enhanced radiotherapy to boost antitumor immunity | |
| Bai et al. | Methionine enkephalin activates autophagy and stimulates tumour cell immunogenicity in human cutaneous squamous cell carcinoma | |
| Wang et al. | Advance of nano anticancer therapies targeted on tumor-associated macrophages | |
| Guo et al. | Gemini nanoparticles-based quadruple therapy (GNQT) achieved effective tumor immunotherapy by comprehensive regulation of tumor microenvironment |
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 |