CN116462681A - Compound for treating tumors by photo-thermal-immune combination and application thereof - Google Patents
Compound for treating tumors by photo-thermal-immune combination and application thereof Download PDFInfo
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- CN116462681A CN116462681A CN202310143671.2A CN202310143671A CN116462681A CN 116462681 A CN116462681 A CN 116462681A CN 202310143671 A CN202310143671 A CN 202310143671A CN 116462681 A CN116462681 A CN 116462681A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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Abstract
The invention aims to solve the problems (mainly aiming at adverse reactions existing in the independent photothermal therapy and the independent immunotherapy) in the prior art, and provides an application of a compound and a pharmaceutical composition thereof for photothermal and immune combined therapy by constructing a supermolecule photothermal agent. The compound can self-assemble into a micro-nano structure in water, and enriches a photothermal agent in tumor tissues through 'passive targeting' of an EPR effect, emits heat while emitting light under 808nm laser irradiation, realizes diagnosis and treatment integration, has the advantages of high photothermal conversion efficiency, excellent photothermal stability and high degradation safety, and simultaneously can inhibit IDO-1 activity, reverse an immunosuppression microenvironment, activate an anti-tumor cascade immune effect, initiate cancer cell Immunogenic Cell Death (ICD), and effectively delay tryptophan degradation into an immunosuppressant kynurenin through NLG 919-mediated IDO1 inhibition, thereby promoting the reduction of the level of regulatory T cells, the rise of the level of effector T cells and the realization of the treatment effect of immune killing.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and relates to a supermolecule photothermal agent containing a 'passive' targeting effect and an immune check point inhibitor, wherein the supermolecule can be assembled into nano particles in water through disulfide bond bonding of stimulus response, and simultaneously can react to tumor microenvironment and release the immune check point inhibitor, so that photothermal and immune combined treatment is realized.
Background
Cancer, which is a medical problem commonly faced by all humans, has the characteristics of rapid growth, strong invasiveness and capability of spreading from a primary part to other parts of the body. In addition to the traditional cancer treatment means such as surgery, radiotherapy, chemotherapy and the like, researchers continue to develop innovation,
with the rising incidence of cancers year by year, the incidence of cancers has a great threat to the life health of people, researchers keep off innovative treatment means, and laser photothermal treatment gradually goes into the field of vision of people. Phototherapy (PTT) uses a beam of near infrared light to radiate tumor tissues, and fluorescent photothermal agents emit light and emit heat at the same time, so that cancer cells can be killed by heating to achieve a treatment effect; it has received extensive attention for its high specificity for tumors, minimal invasiveness for surrounding normal tissues, and time-space selectivity.
However, recent studies have found that photothermal therapy alone still has some problems, such as the generation of heat shock proteins, which are most typical, due to the sustained heat, the cancer cells produce heat shock proteins to counteract sudden environmental changes, and the sustained high temperature may adversely affect normal tissues. In addition, because of tumor-driven immunosuppression, the microenvironment in which the tumor is located integrally conveys signals of immunosuppression, so that the immune system is paralyzed, and the possibility of tumor recurrence and metastasis is high.
Immunotherapy is a revolutionary treatment of cancer that relies on activating the immune system to eliminate the cancer, and has received increasing attention in recent years due to its clinical efficacy. Immunotherapy is largely divided into Immune Checkpoint Blockade (ICB), adoptive T cell therapy, and cancer vaccines. ICB treatments typically utilize antagonists to block inhibition pathways such as the programmed death protein 1 pathway (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen 4. ICB has been greatly progressed in clinic and has been used for the treatment of various tumors, such as melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, classical hodgkin's lymphoma, etc. The most prominent checkpoint receptors are the apoptosis protein 1/apoptosis ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway Anti-PD-L1 atezolizumab and avelumab, which have been approved by the U.S. Food and Drug Administration (FDA). Over-expression of PD-L1 on cancer cells can provide an inhibitory signal to PD-1, which is expressed on activated T cells, and antagonizes activated T Cell Receptors (TCRs) and CD28 axis. Cancer cells utilize the immunosuppressive function of PD-L1 to avoid being killed.
Wherein indoleamine 2, 3-dioxygenase (IDO) is an important negative feedback regulator protein capable of producing an immunosuppressive microenvironment for tumor cell growth. IDO is over-expressed in some tumor cells, can catalyze the degradation of essential amino acid tryptophan (Trp), blocks the cell cycle and enables effector T cells to die, and researches show that the IDO synthesis can be restrained, tryptophan can be effectively delayed to be explained as an immunosuppressant kynurenine, so that the reduction of the level of regulatory T cells is promoted, the level of the effector T cells is increased, and the therapeutic effect of immune killing is achieved.
Immunotherapy has proven to be one of the most effective methods for treating different types of cancer clinically. However, in most cases, the immunotherapeutic target lacks specificity and may be expressed in normal tissues, and the non-targeted release of the immunotherapeutic agent into normal tissues sometimes causes serious side effects such as fever, hypotension, skin reactions, some hypersensitivity reactions and the like, so that the improvement of tumor specificity is of great significance.
Disclosure of Invention
The invention aims to solve the problems (mainly aiming at adverse reactions existing in independent photothermal therapy and independent immunotherapy) in the prior art, and provides application of a compound and a pharmaceutical composition thereof for photothermal and immune combined therapy by constructing a supermolecule photothermal agent.
The compound can self-assemble into a micro-nano structure in water, and enriches a photothermal agent in tumor tissues through 'passive targeting' of an EPR effect, emits heat while emitting light under the irradiation of laser, realizes diagnosis and treatment integration, has the advantages of high photothermal conversion efficiency, excellent photothermal stability and high degradation safety, and simultaneously can inhibit IDO-1 activity, reverse an immunosuppression microenvironment, activate an anti-tumor cascade immune effect, initiate cancer cell Immunogenic Cell Death (ICD), and effectively delay tryptophan degradation into an immunosuppressant kynurenin through the inhibition of the IDO1 mediated by the NLG919, thereby promoting the reduction of the level of regulatory T cells, the rise of the level of effector T cells and the realization of the treatment effect of immune killing.
The technical scheme of the invention is as follows:
a compound for use in photothermal-immunotherapy, said compound having a micro-nanostructure formed by self-assembly of a structure represented by formula (iii) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution:
or, a micro-nano structure formed by self-assembly of a structure shown in a formula (I) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution:
or, a micro-nano structure formed by self-assembly of a structure shown in a formula (II) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution:
in the above formula (I), formula (II) and formula (III): a is an immunoregulatory group, and can be divided into three major classes, namely cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibody, programmed death factor 1 (PD-1) monoclonal antibody and programmed death factor ligand 1 (PD-L1) monoclonal antibody according to different action targets, and other immune check points such as LAG-3, IDO inhibitor, CD137, CD134 and other inhibitory drugs.
In the formula (III):
X 2 selected from O, S or-CR 20 R 20 ’-;
Y 3 、Y 4 、Y 5 Each independently selected from the group consisting of H, hydroxyl, halogen atoms, substituted or unsubstituted amino groups, and hydrocarbyloxy groups;
t 1 、t 2 、t 3 each independently selected from integers from 0 to 5;
R 13 、R 13 ’、R 14 each independently selected from-CN, -CF 3 ,F,-SO 2 CF 3 ,-NO 2 ,-COOEt,-SO 2 ph,
R 15 Is- (CH) 2 ) m -、m is an integer of 0 to 5;
R 16 and R is 17 Together forming a linkage of one of:or R is 16 、R 17 And X 2 Together form the following connection->Wherein R is a 、R b 、R c 、R d 、R e 、R f 、R g Each independently selected from the group consisting of H, halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted carboxyl, substituted or unsubstituted hydroxyl, and substituted or unsubstituted amino;
R 18 、R 18 ’、R 19 、R 20 and R is 20 ' each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group, and a substituted or unsubstituted amino group;
in the formula (I):
b is a substituted or unsubstituted heterocycle that is uncharged and contains one or more heteroatoms in N, O and S;
l is a substituted or unsubstituted conjugated carbon chain, wherein the conjugated carbon chain comprises 2-5 double bonds;
X 1 is O, N or-CR 4 R 4 ’-;
n is 0 or 1;
R 1 、R 1 ’、R 2 each independently selected from atoms and groups having electron withdrawing capability;
R 3 and R is 3 ’、R 4 And R is 4 ' each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amido group, a substituted or unsubstituted ester group, and a substituted or unsubstituted amino group;
in the formula (II):
Y 2 is Cl, br,Wherein q, q' are each independently selected from integers from 0 to 12;
R 9 is-CN or
R 10 Is- (CH) 2 ) m -、m is an integer of 0 to 5,
R 11 is that
R 12 Is that
Q, q' are each independently selected from integers from 0 to 12;
in the above formula (I), formula (II) and formula (III), when the groups are substituted, the substituents are mono-substituted or poly-substituted.
Further, the A is selected from
Further, in formula (III), t is 1 And t 2 Are all 1, t 3 Is 0; m is 3;
the R is 13 、R 13 ' are both-CN, R 14 is-CN or
The R is 18 、R 18 ’、R 19 Each independently selected from H, - (CH) 2 ) q CH 3 、-(CH 2 ) q CF 3 、-(CH 2 ) q CHCH 2 、-(CH 2 ) q CCH、-(CH 2 ) q OH、-(CH 2 ) q COOH、-(CH 2 ) q NH 2 、-(CH 2 ) q CHO、-(CH 2 ) q CO(CH 2 ) q ’CH 3 、-(CH 2 ) q O(CH 2 ) r ’CH 3 、 Wherein q, q' are each independently selected from integers from 0 to 12; preferably, said R 19 is-CH 2 CH 3 ;
The Y is 3 And Y 5 All are H;
Y 4 is Cl, br or-NR 21 R 21 ' -, wherein R 21 、R 21 ' each independently selected from H, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alcohol, substituted or unsubstituted ether, substituted or unsubstituted aldehyde, substituted or unsubstituted carboxyl, substituted or unsubstitutedSubstituted amide groups, substituted or unsubstituted ester groups, and substituted or unsubstituted amino groups; l1 is an ester substituted or unsubstituted carbon chain.
Further, in the formula (I), the number of double bonds in the conjugated carbon chain is 2,3, 4 or 5; x is X 1 Is O; n is 0; the R is 1 、R 1 ’、R 2 Each independently selected from-CN, -CF 3 、-F、-SO 2 CF 3 、-NO 2 、-COOEt、-SO 2 ph、The R is 3 、R 3 ' each independently selected from H, - (CH) 2 ) q CH 3 、-(CH 2 ) q CF 3 、-(CH 2 ) q CH=CH 2 、-(CH 2 ) q C≡CH、-(CH 2 ) q OH、-(CH 2 ) q COOH、-(CH 2 ) q NH 2 、-(CH 2 ) q CHO、-(CH 2 ) q CO(CH 2 ) q ’CH 3 、-(CH 2 ) q O(CH 2 ) q ’CH 3 、/> Wherein q, q' are each independently selected from integers from 0 to 12.
Preferably, said R 1 、R 1 ' are both-CN; r is R 2 is-CN or
In the formula (I), in particular, L may beWherein Y is 1 Is a halogen atom, a substituted or unsubstituted amino group or a hydrocarbyloxy group; m is an integer from 0 to 5, preferably m is 3; r7 is each independently selected from H, halogen atom, substituted or unsubstituted hydrocarbon group,Substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alcohol, substituted or unsubstituted ether, substituted or unsubstituted aldehyde, substituted or unsubstituted carboxyl, substituted or unsubstituted amido, substituted or unsubstituted ester, and substituted or unsubstituted amino. Particularly preferably, m is 3, Y 1 Is Cl, br, -NR 8 R 8 ' OR-OR 8 The method comprises the steps of carrying out a first treatment on the surface of the And R is 7 Is H, -CH 3 、R 8 And R is 8 ' each independently selected from the group consisting of H, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alcohol, substituted or unsubstituted ether, substituted or unsubstituted aldehyde, substituted or unsubstituted carboxyl, substituted or unsubstituted amido, substituted or unsubstituted ester, and substituted or unsubstituted amino.
The micro-nano structure formed by self-assembling the compound of the formula (I) in the aqueous solution has the combined treatment effect of photo-thermal and immune, and simultaneously has the advantages of high photo-thermal conversion efficiency, excellent photo-thermal stability and high degradation safety.
Preferably, B is selected from the group consisting of a substituted or unsubstituted pyrrole or hydrogenated pyrrole ring, a substituted or unsubstituted furan or hydrogenated furan ring, a substituted or unsubstituted thiophene or hydrogenated thiophene ring, a substituted or unsubstituted pyrazole or hydrogenated pyrazole ring, a substituted or unsubstituted imidazole or hydrogenated imidazole ring, a substituted or unsubstituted oxazole or hydrogenated oxazole ring, a substituted or unsubstituted isoxazole or hydrogenated isoxazole ring, a substituted or unsubstituted thiazole or hydrogenated thiazole ring, a substituted or unsubstituted indole or hydrogenated indole ring, a substituted or unsubstituted benzofuran or hydrogenated benzofuran ring, a substituted or unsubstituted benzimidazole or hydrogenated benzimidazole ring, a substituted or unsubstituted carbazole or hydrogenated carbazole ring, a substituted or unsubstituted pyridine or hydrogenated pyridine ring, a substituted or unsubstituted pyran or hydrogenated pyran ring, a substituted or unsubstituted thiopyran ring, a substituted or unsubstituted benzopyrazole or hydrogenated benzopyrazole ring, a substituted or unsubstituted pyridazine or hydrogenated pyridazine ring, a substituted or unsubstituted pyrimidine or hydrogenated pyrimidine ring, a substituted or unsubstituted pyrazine or hydrogenated pyrazine ring, a substituted or piperidine or substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine or unsubstituted piperidine ring, and a substituted or unsubstituted morpholine or unsubstituted ring;
more preferably, the B is Wherein R is 5 、R 6 、R 6 ' each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amido group, a substituted or unsubstituted ester group, and a substituted or unsubstituted amino group.
Further, in formula (II), R 10 is-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or- (CH) 2 ) 4 -, preferably, R 10 Is- (CH) 2 ) 3 -。
The micro-nano structure of the compound II is formed by self-assembling the compound II (including the compounds II-1 to II-50 in the table 1) in an aqueous solution. The particle size of the micro-nano structure is 1nm to 500nm, preferably 10nm to 200nm, more preferably 30nm to 150nm.
Because of the abundance of blood vessels in tumor (especially solid tumor) tissues and the lack of lymphatic return systems, the micro-nano structure of the invention has passive high permeability and retention at tumor sites, and the high permeability and retention effect of the micro-nano structure in solid tumor tissues is called EPR effect. The ability of the passive targeting tumor enables the micromolecule compound which can be assembled into a micro-nano structure by supermolecules to have obvious advantages compared with other reported micromolecule photo-thermal conversion reagents.
Further, the compound is a compound II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, II-24, II-25, II-26, II-27, II-28, II-29, II-30, II-31, II-32, II-33, II-34, II-35, II-36, II-37, II-38, II-39, II-40, II-41, II-42, II-43, II-44, II-45, II-46, II-47, II-48, II-49 or II-50.
The invention also provides a pharmaceutical composition comprising:
1) A therapeutically effective dose of a compound having a structure represented by formula (I), formula (II) or formula (III) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof
2) A pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier comprises a diluent, a disintegrant, an excipient, a binder, a stabilizer, or a combination thereof.
The application of the compound provided by the invention in preparing a medicament for photo-thermal-immune combined treatment and preparing a medicament for diagnosing and/or treating cancers. The combined therapeutic drug is a photothermal therapeutic drug or a photoacoustic therapeutic drug.
The cancer includes esophageal cancer, non-small cell lung cancer, biliary tract cancer, head and neck cancer, barrett's esophagitis, bladder cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain tumor, breast cancer, or skin cancer, including melanoma.
The micro-nano structure is a nano-disc structure formed by self-assembling a compound with a structure shown in a formula (I), a formula (II) or a formula (III), an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution.
The invention also provides a preparation method of the micro-nano structure, which comprises the following steps:
1) Dissolving a compound having a structure represented by formula (I), formula (ii) or formula (iii), an isomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, with an organic solvent;
the organic solvent is one or more of alkane, alkene, aromatic hydrocarbon, alcohol, ketone, aldehyde, carboxylic acid, ester or ether; specifically, the organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, methanol, ethanol, ethylene glycol, N-propanol, isopropanol, propylene glycol, glycerol, N-butanol, isobutanol, butanediol or polyethylene glycol, acetone, dichloromethane or acetonitrile; ethanol is preferred.
2) Adding the solution obtained by dissolution into water to obtain a compound solution with the final concentration of 1 nM-1M;
the final concentration is preferably 100nM to 500. Mu.M; most preferably 0.46. Mu.M to 300. Mu.M.
3) The compound self-assembles in aqueous solution to form a micro-nano structure.
The preparation method is simple, convenient and suitable for large-scale production.
The invention also provides a micro-nano structured pharmaceutical composition comprising: a therapeutically effective dose of the micro-nano structure, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier comprises a diluent, a disintegrant, an excipient, a binder, a stabilizer, or a combination thereof.
The pharmaceutical composition provided by the invention can be prepared into injection, and the injection comprises a micro-nano structure with a therapeutically effective dose and an injection solvent or additive or a combination thereof; wherein the injection solvent is one or more of water for injection, ethanol, propylene glycol, glycerol and polyethylene glycol. Preferably, the pharmaceutical composition can be prepared as an injection.
The micro-nano structure is a nano-disc structure, the pharmaceutical composition further comprises an active agent encapsulated in the micro-nano structure, the active agent is a therapeutic agent or a diagnostic agent, preferably a chemotherapeutic agent or a radiotherapeutic agent, and the active agent comprises a small molecule chemotherapeutic drug, a targeted therapeutic drug, a chemotherapeutic drug, an antibody drug and the like. Further, the micro-nanostructure further comprises a targeting molecule, preferably an antibody, a peptide, an aptamer, folic acid or the like.
In another aspect, the invention also provides the use of the micro-nanostructure or pharmaceutical composition thereof in the manufacture of a medicament for phototherapy, and as a photosensitizer. The photosensitizer is used for preparing a phototherapy medicine. The photo-therapeutic drug is photo-thermal therapeutic drug or photo-acoustic therapeutic drug.
The invention also provides application of the micro-nano structure or the pharmaceutical composition thereof in preparing medicines for diagnosing and/or treating cancers. The cancer includes esophageal cancer, non-small cell lung cancer, biliary tract cancer, head and neck cancer, barrett's esophagitis, bladder cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain tumor, breast cancer, or skin cancer, including melanoma.
The invention also provides a method of light treatment at a target region of a subject, comprising:
1) Providing the micro-nano structure;
2) Administering the micro-nanostructure to a subject;
3) Waiting for enrichment of the micro-nano structure in a target region;
3) The target region of the subject is irradiated with light in the micro-nanostructure excitation band, preferably with light waves of 808 nm.
The invention has the beneficial effects that:
(1) The compound provided by the invention can self-assemble in aqueous solution to form a micro-nano structure, and can simultaneously realize the passive targeting of EPR effect, so that the photothermal agent is more enriched in tumors, the targeting tumor effect is excellent, and the compound further has the advantages of high photothermal conversion efficiency, good photothermal stability, good photothermal effect, easy degradation and high safety, and has wide prospects in the aspects of cancer diagnosis and treatment.
(2) The compound shown in the formula (I), the formula (II) or the formula (III) has the application of preparing a combined light therapeutic drug and preparing a drug for diagnosing and treating cancers, has good targeting effect, good treatment effect and small wound, and has great market value and wide economic prospect.
(3) After NLG919 groups are introduced, the whole organic micromolecules can still be assembled through supermolecules to construct a micro-nano structure, the micro-nano structure can be used for passively targeting tumors through an EPR effect, meanwhile, the accurate release of immune checkpoint inhibitors is realized under the stimulation of high glutathione in tumor tissues, the immune adverse reaction is avoided, and the safety of immune treatment is further improved. The Cy7-TCF after bond breaking can realize fluorescence enhancement, further improve fluorescence imaging intensity and photothermal treatment effect, and further improve immunogenicity after photothermal treatment and improve immune curative effect, thereby realizing the treatment process of 1+1> 2'.
Drawings
FIG. 1 is a synthetic scheme for compound II-1 provided by the present invention;
FIG. 2 shows the binding pocket of Compound II-1 in a protein and the interaction with the protein. The method comprises the steps of carrying out a first treatment on the surface of the
FIG. 3 is a projection electron microscope image and a particle size test result of the compound provided by the invention in an aqueous solution for self-assembly to form a nano disk, which shows that the whole molecule can self-assemble into a micro-nano structure after the compound is chemically bonded with an immunostimulating group;
FIG. 4 is a graph showing the temperature change of 10umol of Compound II-1 under 808nm laser irradiation;
FIG. 5 is a microscopic image of the assembled nano-discs of compound II-1 phagocytosed by cells;
FIG. 6 is a fluorescence imaging of a nano-disc assembled from compound II-1 by "passive" targeting HeLa cells;
FIG. 7 is a photograph showing the whole body of a tumor mouse after the nano-disc assembled by the compound II-1 is injected into the mouse intravenously;
FIG. 8 is a graph showing tumor fluorescence imaging at various time points and fluorescence intensity of main organs of dissected mice after intravenous injection of nano-discs assembled from Compound II-1 into tumor mice
FIG. 9 is a photothermal image in photothermal therapy in vivo in compound II-1 mice;
FIG. 10 shows the change in tumor volume of tumor-bearing mice after intravenous injection of compound II-1 assembled nanodiscs and photothermal treatment;
FIG. 11 is a H & E stained photograph of sections of heart, liver, spleen, lung, kidney of a tumor-bearing mouse after intravenous injection of a nano-dish assembled from Compound II-1 and administration of photothermal therapy for 22 days;
FIG. 12 is a graph showing lung and section of treated and untreated mice;
FIG. 13 shows the change in body weight and tumor volume of mice in the treatment group and control group;
FIG. 14 shows liver function and blood normals of mice 24h after intravenous injection of compound II-1 into the assembled nano-disc;
FIG. 15 shows the levels of cytokine expression associated with the vicinity of metastases in mice from the experimental and control groups.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
For a further understanding of the present invention, reference will now be made to the drawings and examples.
The present invention provides certain specific examples of compounds, including compounds II-1 to II-50 shown in Table 1 below:
TABLE 1 structural formulas of Compounds II-1 to II-50
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The above compounds can be synthesized by the following reaction scheme:
the main synthesis steps include:
(1) Compound a, b, c, d was provided separately;
synthesis of compound a:
compound 1 'and compound 2' and magnesium ethoxide were dissolved in ethanol and reacted at 60 ℃ for 24 hours. The solvent was distilled off in vacuo, and the resulting solid was purified by column chromatography to give the objective compound a.
Synthesis of compound b:
adding dichloromethane and a compound 4' into a bottle under ice bath, stirring, adding the compound 5' under constant pressure, stirring, adding the compound 3', and reacting at 80 ℃ for 3 hours; after completion of the reaction, the product was poured into crushed ice to quench the reaction, and left in the refrigerator overnight. The solvent was distilled off under vacuum to give the crude product compound b, which was used directly in the next reaction without purification.
Synthesis of Compound c:
compound 6 'and compound 7' were added to acetonitrile. Heated to 110 ℃ and reacted under reflux for 24 hours. The solvent was evaporated under vacuum and the resulting solid was washed 3 times with diethyl ether to give compound c.
Compound d was purchased directly.
(2) Dissolving a compound a and a compound b in ethanol, heating and refluxing, then adding a compound c, heating and refluxing, evaporating a solvent under vacuum, purifying the obtained solid by column chromatography, dissolving the obtained product and a compound d in dichloromethane, adding EDCHCl and DMAP, reacting at room temperature overnight, washing for 3 times by using a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution, and purifying the obtained solid by column chromatography after water removal to obtain a product compound II.
EXAMPLE 1 Synthesis of Compound II-1 and its fluorescence Properties
As shown in FIG. 1, the synthesis of the compound II-1 comprises the following steps:
1) Synthesis of Compound 1: 3g of Compound 6 and 3.89g of iodoethanol were weighed into 15mL of ethanol, heated to 110℃and reacted under reflux for 18 hours, and washed 3 times with diethyl ether to obtain Compound 1.
2) Synthesis of Compound 2: 0.97g of malononitrile and 0.62g of magnesium ethoxide are weighed and added into 10mL of ethanol, 0.5mL of 3-hydroxy-3-methylbutan-2-one is added, the mixture is heated to 60 ℃ to react for 12 hours, the solvent is distilled off under vacuum, and the obtained solid is purified by column chromatography to obtain the target compound 2.
1 H NMR(400MHz,CDCl 3 ):δ(ppm):2.36(s,3H),1.63(s,6H)。
3) Synthesis of Compound 3: 20mL of dichloromethane and 20mL of DMF are added into a bottle under ice bath for stirring, 17.5mL of phosphorus oxychloride is added under constant pressure for stirring, 5.3mL of cyclohexanone is added, the mixture is heated to 80 ℃ for reaction for 3 hours, after the reaction is completed, the product is poured into crushed ice for quenching reaction, the mixture is placed in a refrigerator overnight, and the solvent is distilled off under vacuum to obtain a crude product compound 3, and the crude product compound 3 is directly used for the next reaction without purification.
4) Synthesis of Compound 4: 1.00g of Compound 2 and 1.27g of Compound 3 were added to 50mL of ethanol, heated to 90℃and refluxed for 12 hours, cooled to room temperature, and then suction-filtered to give crude product Compound 4, which was used in the next reaction without purification.
5) Synthesis of Cy 7-TCF-OH: 2.04g of Compound 1 and 2.00g of Compound 4 were weighed out in 100mL of ethanol, heated to 100℃and refluxed for 10 hours, the solvent was distilled off under vacuum, and the obtained solid was purified by column chromatography to give the objective compound Cy7-TCF-OH.
6) Synthesis of Compound 5: 1g of Cy7-TCF-OH and 0.53g of Compound 12 are weighed and dissolved in 50mL of dichloromethane, 1.35g of EDC. HCl and 0.25g of DMAP are added dropwise under ice bath, and the mixture is reacted overnight at room temperature; 50mL of methylene chloride were then added, each with 100mL of saturated NH 4 Washing with Cl aqueous solution and saturated saline 3 times, and washing with anhydrous Na 2 SO 4 After water removal, the solvent was distilled off in vacuo, and the resulting solid was purified by column chromatography to give the objective compound 5.
7) Synthesis of Compound II-1: 0.8g of Compound 5 and 0.25g of Compound 11 were dissolved in 50mL of dichloromethane, 0.39g of EDC. HCl and 0.09g of DMAP were added dropwise under ice bath and reacted overnight at room temperature, followed by 50mL of dichloromethane with 100mL of saturated NH respectively 4 Washing with Cl aqueous solution and saturated saline 3 times, and washing with anhydrous Na 2 SO 4 After water removal, the solvent is distilled off in vacuo, and the solid obtained is purified by column chromatography to give the target compound II-1。
1 H NMR(400MHz,CDCl 3 ):δ(ppm):2.36(s,3H),1.63(s,6H)。
1H NMR(400MHz,CDCl3):δ(ppm)8.06(d,1H),7.84(d,1H),7.75(s,1H),7.51–7.42(m,2H),7.32–7.27(m,1H),7.19–7.15(m,2H),6.97(td,J=7.5,1H),6.79(d,1H),6.32(d,1H),5.69(d,1H),5.23(s,2H),5.13–5.04(m,1H),4.90(ddd,1H),4.34(t,2H),4.00(d,2H),2.60–2.47(m,9H),2.34(ddd,2H),2.25(dd,3H),2.17–2.09(m,2H),1.84(dq,7H),1.69(s,6H),1.57(s,7H),1.43–1.35(m,2H),1.33–1.16(m,6H),1.13–0.99(m,3H),0.96–0.75(m,4H).
Experimental example 2 cell imaging experiments
The cell nuclear dye Hoechst33342 (100 nM), lysosome dye Lyso-Green (75 nM) and II-1 (8. Mu.M) were added to the cell culture medium for 30 min staining, and after staining was washed twice with PBS, photographs were observed under confocal fluorescence microscopy, as shown in FIG. 5, and the three channel photographs were combined to find that II-1 was almost completely coincident with the lysosome moiety, indicating that compound II-1 was a lysosome-targetable dye.
Test example 3 intracellular photothermal Effect detection experiment
HeLa cells were cultured in 96-well plates, 104 cells per well, after 24 hours, different concentrations (0.1. Mu.M-100. Mu.M) of II-1 were added, and after the cell well plates for detection of dark toxicity were placed in an incubator for 24 hours, the live cell dye Calcein-AM and the dead cell dye EthD-I were added for 20 minutes. Following observation under a fluorescence microscope, almost all cells were found to survive, demonstrating minimal toxicity of compound II-1 itself.
As shown in the bar graph of FIG. 6, cells in the cell well plate for detecting phototoxicity are irradiated under a 808nm laser for 6 minutes, and are observed and photographed under a fluorescence microscope, and the result shows that when the concentration of II-1 is more than 12.5 mu M, the cells are 100% dead, and the compound II-1 has stronger photo-thermal killing power on cancer cells under the irradiation of laser and has excellent photo-thermal effect.
The combination of the laser irradiation group and the dark toxicity group shows that the compound has extremely low toxicity, but has extremely high photo-thermal effect on cancer cells, and has bright prospect in clinical application of photo-thermal treatment of cancers in the future. Other compounds of the invention also have similar photothermal therapeutic effects.
Test example 4 photoacoustic imaging test of mice
First, a model of a tumor mouse in front of the chest was constructed. A6-week-old female nude mouse was injected with 107HeLa cells at the chest to grow the tumor volume to 60mm3, and 200. Mu.L of II-1 (200. Mu.g) was injected into the mouse via the tail vein. Monitored at different times with a three-dimensional photoacoustic tomography system. As shown in fig. 7, the difference in photoacoustic signal at the tumor site was found most clearly around 4 hours after injection, and the tumor site had a photoacoustic signal up to 24 hours with an increase in time, which demonstrates that compound ii-1 has excellent tumor targeting and has excellent photoacoustic signal. Moreover, the body of the nude mice does not generate abnormal symptoms such as spasm, convulsion and the like within 24 hours, and the compound II-1 is proved to have almost no toxicity and extremely high safety.
Test example 5 fluorescence imaging experiment in vivo photothermal treatment of mice
A model of a tumor mouse before the chest was also constructed.
200. Mu.L of II-1 (200. Mu.g) was injected intravenously into mice from the tail of a 6-week-old female nude mouse, 107HeLa cells were injected into the chest of the mouse, the tumor volume was grown to 60mm3, and 200. Mu.L of II-1 (200. Mu.g) was injected into the body of the mouse through the tail vein. The fluorescence imaging system was used to detect at various time points, as shown in fig. 8, and the tumor of the experimental group showed an increasing trend of fluorescence after 84 hours, indicating that cleavage of SS bond occurred, fluorescence of the nanodisk was increased after cleavage of bond, this example demonstrates that compound ii-1 was able to respond to high concentration of glutathione in tumor tissue and recombinant the nanodisk while releasing NLG919 to achieve fluorescence enhancement.
Experimental example 5 photoacoustic imaging experiment in vivo photothermal treatment of mice
200 μL II-1 (200 μg) was injected intravenously at the tail of the mice in the experimental group, and the tumor sites of the mice were irradiated with a 808nm laser for 10 minutes while continuously photographing with a thermal imager. Under the irradiation of laser, the tumor part can be heated to 57 ℃, and as can be seen from fig. 15, the temperature of the tissue around the tumor is not increased, which shows that II-1 has the advantage of low damage to the tissue near the tumor when used for photothermal treatment.
200. Mu.L II-1 (200. Mu.g) was injected intravenously at the tail of the mice in the experimental group,
test example 6 in vivo photothermal treatment experiment in mice
Nude mice were divided into 6 groups. The method comprises the steps of carrying out a first treatment on the surface of the Group 1 was injected with 200. Mu.L II-1 (200. Mu.g) without laser irradiation; group 2 200. Mu.L II-1 (200. Mu.g) was injected into mice via the tail vein and the tumor sites of the mice were irradiated with 808nm laser for 10 minutes. Group 3 was injected with 200. Mu.L II-2 (200. Mu.g) without laser irradiation; group 2 200. Mu.L II-2 (200. Mu.g) was injected into mice via the tail vein and the tumor sites of the mice were irradiated with 808nm laser for 10 minutes; group 5, injecting normal saline without laser irradiation; group 6 was injected with physiological saline and irradiated with laser light for 10 minutes, and tumor volumes of each group of mice were measured with vernier calipers daily for 22 days.
As shown in fig. 10, the tumor is broken the next day after photothermal treatment, no obvious tumor growth is seen at the primary tumor with time, the tumor broken part starts to heal, the broken part heals completely at the 18 th day, and a small scar is formed. The tumor size of the far-end tumor is obviously inhibited only by injecting the II-1, and other groups are increased to different degrees. Tumor volume change as shown in fig. 13, tumor elimination was performed in the mice of the experimental group (group 2) after laser irradiation, while tumor volume was continuously increased in the mice of the control group (groups 1, 3, 4, 5, 6). The change in body weight of mice is shown in FIG. 13, and the body weight of the mice in the experimental group and the control group is not abnormally changed, and no obvious side effect of II-1 is seen. As shown in fig. 11, the mice of the experimental group after 22 days of the experiment were dissected, and the heart, liver, spleen, and kidney were observed by section H & E staining. The tumor cells are found to undergo apoptosis, and the liver is not obviously damaged. The II-1 has excellent photo-thermal treatment capability, does not damage viscera, has small side effect, and is relatively safe and reliable.
Test example 7 evaluation of the effects of mouse immunotherapy
The conclusion that immunotherapy significantly inhibited the distal tumor was evident by measuring the size of the distal tumor, and by observing the lungs and sections of 6 groups of different mice, as can be seen in fig. 12, only the lungs of the experimental group injected with ii-1 and irradiated with laser had no apparent nodules, while the lungs of the other groups had different degrees of tumor metastasis, which can also be significantly observed in the section of the lung tissue of fig. 12. The simultaneous detection of relevant cytokine levels at distant tumors in different groups is shown in FIG. 13. It can be seen that the CD3, CD8, treg-T levels in the treated group are significantly higher compared to the other control groups, while the INF-gamma levels are significantly lower. This shows that II-1 can effectively play an immunotherapeutic role in inhibiting tumor metastasis.
The experiment shows that the compound II-1 has excellent photo-thermal tumor killing effect and outstanding immune treatment effect under 808nm laser irradiation, has high safety and has wide application prospect in clinical photo-thermal treatment of cancers. Other compounds of the invention are also shown to have similar therapeutic effects.
Test example 8 safety test of Compound II-1 in mice
And 6 Balb/c mice after injection are selected, and blood of the mice is taken for blood routine and liver function detection. As shown in FIG. 14, the blood normals of lymphocytes, average erythrocyte volume and distribution width of erythrocyte volume of 6 mice were within the normal range, and the liver function indexes of albumin, cholesterol, alkaline phosphatase and blood glucose were within the normal range. The result shows that the compound II-1 has higher safety, does not damage the liver in a short period, and is relatively safe and reliable.
The foregoing description is only a preferred embodiment of the present invention and is not intended to limit the present invention, but although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or that equivalents may be substituted for part of the technical features thereof. Any modification, equivalent replacement, variation, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A compound with a combined therapeutic effect of 'photo-thermal' — 'immunization', which is characterized in that the compound has a micro-nano structure formed by self-assembly of a structure shown in a formula (iii) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution:
or, a micro-nano structure formed by self-assembly of a structure shown in a formula (I) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution:
or, a micro-nano structure formed by self-assembly of a structure shown in a formula (II) or an isomer, pharmaceutically acceptable salt, hydrate or solvate thereof in an aqueous solution:
in the above formula (I), formula (II) and formula (III): a is an immunoregulatory group, and can be divided into three major classes, namely cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibody, programmed death factor 1 (PD-1) monoclonal antibody and programmed death factor ligand 1 (PD-L1) monoclonal antibody according to different action targets, and other immune check points such as LAG-3, IDO inhibitor, CD137, CD134 and other inhibitory drugs.
In the formula (III):
X 2 selected from O, S or-CR 20 R 20 ’-;
Y 3 、Y 4 、Y 5 Each independently selected from the group consisting of H, hydroxyl, halogen atoms, substituted or unsubstituted amino groups, and hydrocarbyloxy groups;
t 1 、t 2 、t 3 each independently selected from integers from 0 to 5;
R 13 、R 13 ’、R 14 each independently ofAt the site selected from-CN, -CF 3 ,F,-SO 2 CF 3 ,-NO 2 ,-COOEt,-SO 2 ph,
R 15 Is- (CH) 2 ) m -、m is an integer of 0 to 5;
R 16 and R is 17 Together forming a linkage of one of:or R is 16 、R 17 And X 2 Together form the following connection->Wherein R is a 、R b 、R c 、R d 、R e 、R f 、R g Each independently selected from the group consisting of H, halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted carboxyl, substituted or unsubstituted hydroxyl, and substituted or unsubstituted amino;
R 18 、R 18 ’、R 19 、R 20 and R is 20 ' each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group, and a substituted or unsubstituted amino group;
in the formula (I):
b is a substituted or unsubstituted heterocycle that is uncharged and contains one or more heteroatoms in N, O and S;
l is a substituted or unsubstituted conjugated carbon chain, wherein the conjugated carbon chain comprises 2-5 double bonds;
X 1 is O, N or-CR 4 R 4 ’-;
n is 0 or 1;
R 1 、R 1 ’、R 2 each independently selected from atoms and groups having electron withdrawing capability;
R 3 and R is 3 ’、R 4 And R is 4 ' each independently selected from the group consisting of H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amido group, a substituted or unsubstituted ester group, and a substituted or unsubstituted amino group;
in the formula (II):
Y 2 is Cl, br,Wherein q, q' are each independently selected from integers from 0 to 12;
R 9 is-CN or
R 10 Is- (CH) 2 ) m -、m is an integer of 0 to 5,
R 11 is that
R 12 Is that
Q, q' are each independently selected from integers from 0 to 12;
in the above formula (I), formula (II) and formula (III), when the groups are substituted, the substituents are mono-substituted or poly-substituted.
2. The compound of claim 1, wherein a is selected from the group consisting of
3. The compound according to claim 1, wherein in formula (iii), said t 1 And t 2 Are all 1, t 3 Is 0; m is 3;
the R is 13 、R 13 ' are both-CN, R 14 is-CN or
The R is 18 、R 18 ’、R 19 Each independently selected from H, - (CH) 2 ) q CH 3 、-(CH 2 ) q CF 3 、-(CH 2 ) q CHCH 2 、-(CH 2 ) q CCH、-(CH 2 ) q OH、-(CH 2 ) q COOH、-(CH 2 ) q NH 2 、-(CH 2 ) q CHO、-(CH 2 ) q CO(CH 2 ) q ’CH 3 、-(CH 2 ) q O(CH 2 ) r ’CH 3 、 Wherein q, q' are each independently selected from integers from 0 to 12; preferably, said R 19 is-CH 2 CH 3 ;
The Y is 3 And Y 5 All are H;
Y 4 is Cl, br or-NR 21 R 21 ' -, wherein R 21 、R 21 ' each independently selected from the group consisting of H, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alcohol, substituted or unsubstituted ether, substituted or unsubstituted aldehyde, substituted or unsubstituted carboxyl, substituted or unsubstituted amido, substituted or unsubstituted ester, and substituted or unsubstituted amino; l1 is an ester substituted or unsubstituted carbon chain.
4. The compound of claim 1, wherein in formula (i), the number of double bonds in the conjugated carbon chain is 2,3, 4 or 5; x is X 1 Is O; n is 0; the R is 1 、R 1 ’、R 2 Each independently selected from-CN, -CF 3 、-F、-SO 2 CF 3 、-NO 2 、-COOEt、-SO 2 ph、 The R is 3 、R 3 ' each independently selected from H, - (CH) 2 ) q CH 3 、-(CH 2 ) q CF 3 、-(CH 2 ) q CH=CH 2 、-(CH 2 ) q C≡CH、-(CH 2 ) q OH、-(CH 2 ) q COOH、-(CH 2 ) q NH 2 、-(CH 2 ) q CHO、-(CH 2 ) q CO(CH 2 ) q ’CH 3 、-(CH 2 ) q O(CH 2 ) q ’CH 3 、 Wherein q, q' are each independently selected from integers from 0 to 12.
5. The compound of claim 4, wherein R 1 、R 1 ' are both-CN; r is R 2 is-CN or
6. The compound of claim 1, wherein in formula (II), R 10 is-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -or- (CH) 2 ) 4 -, preferably, R 10 Is- (CH) 2 ) 3 -。
7. The compound of claim 1, wherein the compound is compound ii-1, ii-2, ii-3, ii-4, ii-5, ii-6, ii-7, ii-8, ii-9, ii-10, ii-11, ii-12, ii-13, ii-14, ii-15, ii-16, ii-17, ii-18, ii-19, ii-20, ii-21, ii-22, ii-23, ii-24, ii-25, ii-26, ii-27, ii-28, ii-29, ii-30, ii-31, ii-32, ii-33, ii-34, ii-35, ii-36, ii-37, ii-38, ii-39, ii-40, ii-41, ii-42, ii-43, ii-44, ii-45, ii-46, ii-47, ii-48, ii-49, or ii-50.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for dual targeting phototherapy, for the manufacture of a medicament for the diagnosis and/or treatment of cancer.
10. The use according to claim 9, wherein the cancer comprises esophageal cancer, non-small cell lung cancer, biliary tract cancer, head and neck cancer, barrett's esophagitis, bladder cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain tumor, breast cancer or skin cancer; the double-targeting photo-therapeutic drug is a photo-thermal therapeutic drug or a photo-acoustic therapeutic drug.
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CN202310143671.2A CN116462681A (en) | 2023-02-21 | 2023-02-21 | Compound for treating tumors by photo-thermal-immune combination and application thereof |
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