CN114632078A - Heat shock protein inhibitor and preparation method and application thereof - Google Patents
Heat shock protein inhibitor and preparation method and application thereof Download PDFInfo
- Publication number
- CN114632078A CN114632078A CN202210142488.6A CN202210142488A CN114632078A CN 114632078 A CN114632078 A CN 114632078A CN 202210142488 A CN202210142488 A CN 202210142488A CN 114632078 A CN114632078 A CN 114632078A
- Authority
- CN
- China
- Prior art keywords
- heat shock
- shock protein
- drug
- nano
- egcg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010004889 Heat-Shock Proteins Proteins 0.000 title claims abstract description 20
- 102000002812 Heat-Shock Proteins Human genes 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940121649 protein inhibitor Drugs 0.000 title abstract description 8
- 239000012268 protein inhibitor Substances 0.000 title abstract description 8
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 claims abstract description 36
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229940030275 epigallocatechin gallate Drugs 0.000 claims abstract description 36
- 239000002105 nanoparticle Substances 0.000 claims abstract description 28
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 19
- 101710113864 Heat shock protein 90 Proteins 0.000 claims abstract description 10
- 239000003112 inhibitor Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 26
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 229930014626 natural product Natural products 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940044683 chemotherapy drug Drugs 0.000 claims description 5
- 239000008176 lyophilized powder Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 4
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims description 4
- 229910001424 calcium ion Inorganic materials 0.000 claims description 4
- 238000002512 chemotherapy Methods 0.000 claims description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 4
- 206010020843 Hyperthermia Diseases 0.000 claims description 3
- 230000036031 hyperthermia Effects 0.000 claims description 3
- 229910001437 manganese ion Inorganic materials 0.000 claims description 3
- 230000010412 perfusion Effects 0.000 claims description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 2
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims description 2
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims description 2
- 229940109262 curcumin Drugs 0.000 claims description 2
- 235000012754 curcumin Nutrition 0.000 claims description 2
- 239000004148 curcumin Substances 0.000 claims description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 2
- 229940074391 gallic acid Drugs 0.000 claims description 2
- 235000004515 gallic acid Nutrition 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- -1 iron ions Chemical class 0.000 claims description 2
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims description 2
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 2
- 229960001285 quercetin Drugs 0.000 claims description 2
- 235000005875 quercetin Nutrition 0.000 claims description 2
- 229910001427 strontium ion Inorganic materials 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 abstract description 9
- 102000004169 proteins and genes Human genes 0.000 abstract description 8
- 108090000623 proteins and genes Proteins 0.000 abstract description 8
- 238000000015 thermotherapy Methods 0.000 abstract description 7
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 abstract description 6
- 210000000683 abdominal cavity Anatomy 0.000 abstract description 4
- 230000002147 killing effect Effects 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 230000008827 biological function Effects 0.000 abstract description 2
- 238000001802 infusion Methods 0.000 abstract description 2
- 230000001681 protective effect Effects 0.000 abstract description 2
- 230000002829 reductive effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 24
- 230000000694 effects Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000011463 hyperthermic intraperitoneal chemotherapy Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 206010017758 gastric cancer Diseases 0.000 description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 description 5
- 201000011549 stomach cancer Diseases 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 150000002500 ions Chemical group 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 1
- 108010058432 Chaperonin 60 Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 101150051208 HSPH1 gene Proteins 0.000 description 1
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 1
- 102100021410 Heat shock 70 kDa protein 14 Human genes 0.000 description 1
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 1
- 102100031624 Heat shock protein 105 kDa Human genes 0.000 description 1
- 206010025538 Malignant ascites Diseases 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 101100071630 Mesocentrotus franciscanus HSP110 gene Proteins 0.000 description 1
- 101100451677 Mus musculus Hspa4 gene Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000025164 anoikis Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000008408 compound extracted from plant Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000005033 mesothelial cell Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 201000002513 peritoneal mesothelioma Diseases 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009991 scouring Methods 0.000 description 1
- 230000019491 signal transduction Effects 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
- 239000002356 single layer Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to the field of tumor treatment and biomedical materials, in particular to a heat shock protein inhibitor and a preparation method and application thereof. The invention firstly proposes that the heat shock protein inhibitor is infused during the abdominal cavity heat infusion, so that the protective effect of the heat shock protein on other target proteins can be reduced, and the killing effect of the heat therapy on tumors is improved. The natural inhibitor epigallocatechin gallate (EGCG) of HSP90 and metal ions are coordinated to form nanoparticles. Nanoparticles possess more stable chemistry and are more easily internalized by cells. After being internalized by cells, EGCG is dissociated from metal ions, so that HSP90 can be effectively inhibited, and the biological function of the metal ions can be exerted.
Description
Technical Field
The invention relates to the field of tumor treatment and biomedical materials, in particular to a heat shock protein inhibitor and a preparation method and application thereof.
Background
Intraperitoneal chemohyperthermia (HIPEC) is a means of treating intraperitoneal tumors, and has been used in patients with digestive tract tumors developing peritoneal metastasis since first reported by Spratt et al in 1980 (J.S.Spratt, R.A.Adcock, W.Sherrill, S.Travehen, hyperthermia chemotherapy system in cans, Cancer research 40(2 (1980) 253-5)). At present, I-grade evidence proves that the HIPEC has good effects on treating and preventing malignant tumors such as gastric cancer, colorectal cancer, peritoneal pseudomyxoma, peritoneal mesothelioma and the like in the aspect of peritoneal plantation, and particularly has unique advantages on controlling the peritoneal pseudomyxoma and malignant ascites.
The peritoneum consists of a monolayer of mesothelial cells, basement membrane and 5 layers of fibrous connective tissue, approximately 90 μm thick. The peritoneal cavity is the main site of the late gynecological malignancy where the graft metastasis occurs. Possible mechanisms of HIPEC for prevention and treatment of tumor peritoneal cavity metastasis include: (1) irreversible lesions appeared in malignant tumors after 1h at 43 ℃ while normal tissues could tolerate 47 ℃ for 1 h. Thus, by appropriate temperature, HIPEC can kill tumor cells directly by thermal effects. In addition, HIPEC can directly inhibit DNA replication, transcription and repair, leading to tumor vascular thrombosis at the tissue level. (2) Shear force generated by liquid flow in the HIPEC treatment process can directly cause the death of tumor cells, and the anoikis of the tumor cells caused by the scouring of tissues. (3) The high temperature can cause the permeability of tumor cell membranes and tumor blood vessels to change, reduce the excretion rate of the tumor cells to the chemotherapeutic drugs and increase the concentration of the chemotherapeutic drugs in the tumor cells. (4) The HIPEC can increase the action concentration of local drugs of tumor focus in the abdominal cavity by intraperitoneal administration. (5) The maximum tissue penetration depth of HIPEC is 5mm, whereas the tissue penetration depth of common chemotherapeutic drugs is < 3mm, HIPEC increases the drug concentration of certain drugs in the deep part of the tumor, thus producing a synergistic effect with chemotherapy.
However, when cells are exposed to high temperatures, Heat Shock Proteins (HSPs) are synthesized by Heat activation to protect other proteins and enhance the resistance of the cells to Heat stimuli. So that the action of heating to kill tumor cells is greatly weakened or even the treatment is ineffective in the second and third heat treatments. The heat shock proteins can be classified into HSP110, HSP90 family, HSP70 family, HSP60, small molecule HSP and ubiquitin families according to the degree of homology and molecular weight. Among them, HSP90 is one of the families that are important to protect target proteins when stimulated. HSP90 inhibitors are mainly classified into two major classes, the first class being natural inhibitors, generally antibiotic compounds extracted from plants. The second class is the artificially synthesized inhibitors. Wherein, the natural inhibitor has small side effect and higher clinical transformation prospect. However, the existing Hsp90 inhibitors such as geldanamycin have poor water solubility and high toxicity, and are not suitable for synergistic tumor hyperthermia. Epigallocatechin gallate has poor stability in vivo and short half-life period, resulting in limited drug effect.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a heat shock protein inhibitor and a preparation method and application thereof.
Aiming at the defects of the prior art, the EGCG is coordinated with metal ions, so that hydroxyl on phenol is coordinated with the metal ions (such as manganese ions and calcium ions) in advance, and the stability of the EGCG is improved. After being internalized by cells, the coordination bonds are broken in a lysosome acidic environment, and the EGCG activity is released. And the metal ions can also exert the unique anti-tumor activity. For example, Mn2+Has the effect of activating immunity, Ca2+Has antitumor activity of inducing endoplasmic reticulum stress to further cause apoptosis. Heat perfusion in the abdominal cavityThe nano particles of the invention used in the tumor thermotherapy method can greatly increase the thermotherapy effect.
In order to achieve the purpose, the invention adopts the technical scheme that: a nanoparticle is provided, wherein the nanoparticle is formed by coordinating a natural compound capable of inhibiting heat shock proteins with a metal ion.
The invention firstly proposes that the heat shock protein inhibitor is infused during the abdominal cavity heat infusion, so that the protective effect of the heat shock protein on other target proteins can be reduced, and the killing effect of the heat therapy on tumors is improved. The natural inhibitor epigallocatechin gallate (EGCG) of HSP90 and metal ions form nanoparticles through coordination. Nanoparticles possess more stable chemistry and are more easily internalized by cells. After being internalized by cells, EGCG is dissociated from metal ions, so that HSP90 can be effectively inhibited, and the biological function of the metal ions can be exerted. For example, Mn ions can kill tumor cells via fenton reaction, and can also activate immune response via cGAS-STING signaling pathway.
The invention provides a novel heat shock protein inhibitor, which is characterized in that epigallocatechin gallate (EGCG) and metal ions form nanoparticles through coordination, can be phagocytized by tumor cells, and can enhance the thermotherapy effect.
The invention aims to solve the problems of instability, large toxic and side effects and the like of an Hsp90 inhibitor, and provides a method for forming nanoparticles by the coordination of epigallocatechin gallate (EGCG) and metal ions, and a nano-drug prepared by the method for treating tumor: EGCG is prepared into water solution and added into metal ion water solution. Adjusting pH to neutral to alkaline condition, stirring at room temperature for a period of time, centrifuging to obtain nanometer medicinal preparation, washing with water solution and ethanol to remove free medicinal preparation, and making into lyophilized powder.
As a preferred embodiment of the nanoparticle of the present invention, the natural compound capable of inhibiting heat shock protein comprises epigallocatechin gallate, quercetin, gallic acid and curcumin.
As a preferred embodiment of the nanoparticle of the present invention, the metal ions include manganese ions, calcium ions, magnesium ions, strontium ions, and iron ions.
The invention also provides application of the nanoparticle in preparing an inhibitor capable of inhibiting heat shock protein 90.
The invention also provides a preparation method of the nano-particles, which is to coordinate the natural compound capable of inhibiting the heat shock protein and metal ions in a solution to assemble the nano-particles.
The invention also provides a nano-drug, which comprises the nano-particles.
As a preferred embodiment of the nano-drug of the present invention, the nano-drug further comprises other chemotherapeutic drugs or antibodies.
As the preferable embodiment of the nano-drug, the nano-drug is freeze-dried powder or suspension.
The invention also provides the application of the nano-drug in the preparation of drugs for abdominal cavity heat perfusion chemotherapy or tumor thermotherapy of tumor patients.
The invention has the beneficial effects that:
(1) compared with other inventions, the invention does not need a drug carrier, and EGCG and metal ions are self-assembled to form the nano-drug.
(2) The EGCG and the nanoparticles formed by the EGCG have the effect of inhibiting heat shock proteins, and can improve the effect of heat treatment in tumor treatment.
(3) The nano-particles of the invention have tumor killing effect when used alone.
(4) The nano-particles of the invention have simple preparation method, high stability, low cost and possibility of clinical application.
Drawings
FIG. 1: the transmission electron microscope picture of the sample 1 shows that the prepared sample 1 is nanoparticles with the size of about 200nm formed by agglomeration of 50nm small particles.
FIG. 2: the transmission electron microscope picture of the sample 2 shows that the prepared sample 2 is nanoparticles with the size of about 300nm formed by agglomeration of 50nm small particles.
FIG. 3: the expression of heat shock protein 90 of cells after EGCG and MnEGCG are used for treating human gastric cancer cells MGC803 at different temperatures.
FIG. 4: cell viability after treatment of human gastric carcinoma cells MGC803 with EGCG and MnEGCG at different temperatures.
Detailed Description
To more clearly illustrate the technical solutions of the present invention, the following embodiments are further described, but the present invention is not limited thereto, and these embodiments are only some examples of the present invention.
Example 1
45.8mg of EGCG was dissolved in 30mL of distilled water, and 197mg of MnCl was added2·4H2O was dissolved in 10mL of water. The manganese chloride solution was added to the EGCG solution, labeled as solution a. The solution A was adjusted to pH 7.5 with 0.05M NaOH solution and stirred at room temperature for 30 minutes. Centrifuging at 8000R for 10 min to obtain nanometer medicinal preparation, washing with water solution and ethanol to remove free medicinal materials, and making into lyophilized powder. This drug was named as the MnEGCG nano-drug and this sample was named sample 1.
Example 2
Dissolving 45.8mg EGCG in 30mL distilled water, and adding 111mg anhydrous CaCl2Dissolved in 10mL of water. The calcium chloride solution was added to the EGCG solution, labeled as solution a. The solution A was adjusted to pH 8.8 with 0.05M NaOH solution and stirred at room temperature for 30 minutes. Centrifuging at 8000R for 10 min to obtain nanometer medicinal preparation, washing with aqueous solution and ethanol to remove free medicinal components, and making into lyophilized powder. This drug was named CaEGCG nano-drug and this sample was named sample 2.
Example 3
45.8mg of EGCG was dissolved in 30mL of distilled water, and 106mg of MgCl was added2·6H2O was dissolved in 10mL of water. The magnesium chloride solution was added to the EGCG solution, labeled as solution a. The solution A was adjusted to pH 8.1 with 0.05M NaOH solution and stirred at room temperature for 30 minutes. Centrifuging at 8000R for 10 min to obtain nanometer medicinal preparation, washing with aqueous solution and ethanol to remove free medicinal components, and making into lyophilized powder. The medicine is prepared fromThe substance was named MgEGCG nano-drug, and this sample was named sample 3.
Example 4
The test uses 6-well plate, each well 100 ten thousand MGC803 human gastric cancer cells, each well 2ml culture medium is placed in 37 ℃ incubator for 24 hours and then administered, 37 ℃ PBS, 37 ℃ EGCG, 37 ℃ MnEGCG, 43 ℃ PBS, 43 ℃ EGCG, 43 ℃ MnEGCG six groups are set, each group has two multiple wells, 80mg/L medicament is administered to the medicament group, PBS with the same volume is administered to the control group, 43 ℃ EGCG, 43 ℃ MnEGCG groups are placed in 43 ℃ environment and heated for 30min, 37 ℃ EGCG, 37 ℃ MnEGCG groups are placed under the same condition at 37 ℃ for 30min, protein is extracted immediately after treatment, protein quantitative analysis is carried out, SDS-Sample loader Buffer5X and distilled water are added to make the total protein concentration reach 1ug/ul, each group has 20ul protein Sample, Beta-Actin Antibody is Beta-Monoclonal Antibody (HSP 661-009), produced by proteintech corporation, HSP 6628 is HSP 861-009, produced by HSP Antibody (HSP No. 861-8628 days), western Blot experiments were completed.
The results are shown in fig. 3, and it is shown from WB results that MnEGCG can significantly reduce the expression of heat shock protein 90 in tumor cells when heated to 43 ℃.
Example 5
The test uses four 96-well plates, 5000 MGC803 human gastric cancer cells per well and 90ul culture medium per well, the drug is administrated after being placed in an incubator at 37 ℃ for 24 hours, the killing effect of EGCG and MnEGCG on the MGC803 at 37 ℃ and 43 ℃ respectively is detected, and the drug gradient is set: 1.56, 3.12, 6.25, 12.5, 25, 50, 100, 200(mg/L), 10ul of PBS is administrated to each hole, PBS with the same volume is administrated to a control group, 6 multiple holes are administrated to each group, the 43 ℃ EGCG and 43 ℃ MnEGCG groups are placed in a 43 ℃ environment and heated for 30min, the 37 ℃ EGCG and 37 ℃ MnEGCG groups are placed in a 37 ℃ incubator under the same condition and at a temperature of 37 ℃ for 30min, the groups are placed in a 37 ℃ incubator after treatment, 10ul of CCK-8 solution (product number HY-K0301-12000T of the manufacturer MedChemExpress is added to each hole under a light-shielding condition after 24 hours, the groups are placed in a 37 ℃ incubator, the incubator is placed in the incubator for incubation for 1 hour, the absorbance at 450nm is measured by a multifunctional microplate reader, and a cell proliferation curve is drawn.
The result is shown in figure 4, according to the cell proliferation test result, the drug has the gastric cancer cell killing effect of 43 ℃ MnEGCG which is more than 43 ℃ EGCG which is more than 37 ℃ MnEGCG which is more than 37 ℃, and the nano-drug and the thermotherapy have synergistic effect to kill the gastrointestinal tumor cells.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A nanoparticle, wherein the nanoparticle is formed by coordinating a natural compound capable of inhibiting a heat shock protein with a metal ion.
2. The nanoparticle according to claim 1, wherein the natural compound capable of inhibiting heat shock proteins comprises epigallocatechin gallate, quercetin, gallic acid and curcumin.
3. The nanoparticle of claim 1, wherein the metal ions comprise manganese ions, calcium ions, magnesium ions, strontium ions, and iron ions.
4. Use of the nanoparticle of any one of claims 1 to 3 for preparing an inhibitor capable of inhibiting heat shock protein 90.
5. The method of preparing nanoparticles according to any one of claims 1 to 3, wherein the nanoparticles are prepared by coordinating the natural compound capable of inhibiting heat shock protein with metal ions in a solution.
6. A nano-drug comprising the nanoparticle according to any one of claims 1 to 3.
7. The nano-drug of claim 6, further comprising other chemotherapeutic drugs or antibodies.
8. The nano-drug of claim 6, wherein the nano-drug is a lyophilized powder or a suspension.
9. The use of the nano-drug of any one of claims 6 to 8 in the preparation of a medicament for use in peritoneal thermal perfusion chemotherapy or tumor hyperthermia of a tumor patient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210142488.6A CN114632078B (en) | 2022-02-16 | 2022-02-16 | Heat shock protein inhibitor and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210142488.6A CN114632078B (en) | 2022-02-16 | 2022-02-16 | Heat shock protein inhibitor and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114632078A true CN114632078A (en) | 2022-06-17 |
| CN114632078B CN114632078B (en) | 2023-12-19 |
Family
ID=81946673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210142488.6A Active CN114632078B (en) | 2022-02-16 | 2022-02-16 | Heat shock protein inhibitor and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114632078B (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108057120A (en) * | 2016-11-08 | 2018-05-22 | 首都师范大学 | Phenol iron complex is as the application in optical-thermal conversion material |
| CN109847062A (en) * | 2019-04-09 | 2019-06-07 | 中山大学 | A kind of Quercetin metal nano drug and its preparation method and application |
| CN112168963A (en) * | 2020-09-18 | 2021-01-05 | 暨南大学 | Nano photothermal medicine and its preparing method |
| CN112791185A (en) * | 2021-01-20 | 2021-05-14 | 广州医科大学 | Nano medicine for treating tumor by combining photothermal treatment with iron agent and preparation method thereof |
| CN112826939A (en) * | 2021-02-03 | 2021-05-25 | 中山大学附属第七医院(深圳) | Abdominal perfusion nano-medicine and preparation method and application thereof |
| CN113304264A (en) * | 2021-06-13 | 2021-08-27 | 重庆医科大学 | Quercetin tellurium nanoparticles and preparation method thereof |
| CN113577101A (en) * | 2020-04-30 | 2021-11-02 | 四川大学 | Tea polyphenol-metal nanoparticles, drug-loaded nanoparticles, preparation method and application thereof |
| CN113599525A (en) * | 2021-07-28 | 2021-11-05 | 中山大学附属第七医院(深圳) | Anti-tumor nano-drug and preparation method and application thereof |
-
2022
- 2022-02-16 CN CN202210142488.6A patent/CN114632078B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108057120A (en) * | 2016-11-08 | 2018-05-22 | 首都师范大学 | Phenol iron complex is as the application in optical-thermal conversion material |
| CN109847062A (en) * | 2019-04-09 | 2019-06-07 | 中山大学 | A kind of Quercetin metal nano drug and its preparation method and application |
| CN113577101A (en) * | 2020-04-30 | 2021-11-02 | 四川大学 | Tea polyphenol-metal nanoparticles, drug-loaded nanoparticles, preparation method and application thereof |
| CN112168963A (en) * | 2020-09-18 | 2021-01-05 | 暨南大学 | Nano photothermal medicine and its preparing method |
| CN112791185A (en) * | 2021-01-20 | 2021-05-14 | 广州医科大学 | Nano medicine for treating tumor by combining photothermal treatment with iron agent and preparation method thereof |
| CN112826939A (en) * | 2021-02-03 | 2021-05-25 | 中山大学附属第七医院(深圳) | Abdominal perfusion nano-medicine and preparation method and application thereof |
| CN113304264A (en) * | 2021-06-13 | 2021-08-27 | 重庆医科大学 | Quercetin tellurium nanoparticles and preparation method thereof |
| CN113599525A (en) * | 2021-07-28 | 2021-11-05 | 中山大学附属第七医院(深圳) | Anti-tumor nano-drug and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 林小玲;朱尤庆;汤小燕;谢兆兰;: "儿茶素单体对胃癌细胞热休克蛋白70和多药耐药蛋白1的影响", 中华消化杂志, no. 10, pages 694 - 695 * |
| 罗浩铭;孙薇;尹建元;杨晓虹;: "热休克蛋白90抑制剂的研究进展", 药学学报, no. 07, pages 813 - 820 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114632078B (en) | 2023-12-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5685243B2 (en) | Pharmaceutical carrier, its preparation method and use | |
| CN105288622B (en) | The preparation method of chemotherapeutics and the cell membrane vesicles of optical dynamic therapy medicine is loaded simultaneously | |
| CN113577101A (en) | Tea polyphenol-metal nanoparticles, drug-loaded nanoparticles, preparation method and application thereof | |
| CN108785275A (en) | A kind of preparation method of the targeting being embedded with anticancer drug-optothermal polymerization object particle | |
| CN105056244B (en) | A kind of Fe of mesoporous door-control type2+Donor and Fe2+Dependence antineoplastic cotransports system and preparation method and application | |
| CN105001426B (en) | A kind of polyaminoacid graft copolymer with tumor-targeting and preparation method thereof | |
| JP2020536914A (en) | Autophagy inhibitors and their preparation methods and applications | |
| Pang et al. | NIR-absorbing Prussian blue nanoparticles for transarterial infusion photothermal therapy of VX2 tumors implanted in rabbits | |
| Zhang et al. | Effect of alginate‐chitosan sustained release microcapsules for transhepatic arterial embolization in VX2 rabbit liver cancer model | |
| CN103169968A (en) | Hydrophobic dihydroporphin photosensitizer nanometer pharmaceutic preparation based on albumin as well as preparation method and application of nanometer pharmaceutic preparation | |
| US20170216436A1 (en) | A method for treating cancer based on metallofullerene monocrystalline nanoparticles that specifically disrupt tumor blood vessels | |
| CN113209292B (en) | Quercetin nano self-assembly material, preparation method and application | |
| Zhan et al. | Polydopamine-guarded metal-organic frameworks as co-delivery systems for starvation-assisted chemo-photothermal therapy | |
| CN114632078A (en) | Heat shock protein inhibitor and preparation method and application thereof | |
| CN109364253B (en) | Nano particles for improving tumor tissue permeability and preparation method and application thereof | |
| CN106606783B (en) | A kind of targeting is passed altogether to be released the drug of photosensitizer and chemotherapeutics and passs release system | |
| CN109953974B (en) | Preparation method of enzyme-reduction dual-responsiveness hyaluronic acid-polypropylene sulfide copolymer nanocapsule | |
| CN115475250B (en) | Drug-loaded exosome targeting hepatic stellate cells and inhibiting activation thereof, and preparation and application thereof | |
| CN110575546A (en) | preparation method and application of high nuclear targeting anti-tumor nano-drug | |
| CN110420335B (en) | Preparation and application of nano immune preparation based on porous calcium carbonate | |
| JP2021501777A (en) | Mycobacterium paragordone anti-cancer immunotherapeutic application | |
| CN110951072B (en) | Compound with cell calcification inducing capability, preparation method and application thereof | |
| Mehvari et al. | A panoramic perspective of recent progress in 2D and 3D covalent organic frameworks for drug delivery | |
| CN114306340A (en) | Preparation method and application of cholic acid-quaternized chitosan oligosaccharide-ES 2 peptide/camptothecin conjugate | |
| CN105664174A (en) | Lf-HA-DOX macromolecule prodrug compound, constructing method thereof and application of Lf-HA-DOX macromolecule prodrug compound to treating glioma |
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 |