Photosensitizer conjugate compound, pharmaceutical composition thereof, and use thereof

Abstract

A ligand photosensitizer conjugate, particularly a bi-ligand photosensitizer conjugate represented by formula I, a pharmaceutical composition based on the photosensitizer conjugate compound, and use thereof in the field of medicine. The photosensitizer conjugate compound of the present invention combines the advantages of the ligand-drug conjugate and photodynamic technology, and improves the targeting property of the photosensitizer by means of conjugating the photosensitizer to the ligand with the targeting effect while utilizing the inherent advantages of small side effects and low drug resistance of the photosensitizer drug.

Description

Photosensitizer conjugate compound and pharmaceutical composition and application thereof

[0001] Citation of Related Applications

[0002] This disclosure claims priority to an invention patent application filed with the Patent Office of China on October 30, 2023, with application number 202311425612.0 and title “Photosensitizer conjugate compounds, pharmaceutical compositions and applications thereof,” and the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of precision diagnosis and treatment, and relates to a photosensitizer conjugate compound, specifically a ligand-photosensitizer conjugate (especially a dual-ligand photosensitizer conjugate), a pharmaceutical composition based on the photosensitizer conjugate compound (or ligand-photosensitizer conjugate, dual-ligand photosensitizer conjugate), and its application in the medical field. Background Art

[0004] Photodynamic therapy (PDT) is a new technology that uses the photodynamic effect to diagnose and treat diseases. Photodynamic therapy consists of three major elements: light, oxygen, and photosensitizer (a compound with photosensitivity), which work together to achieve its effects (for example, inducing tumor cell death). The process of action is roughly as follows: first, the photosensitizer selectively accumulates in the tumor tissue, and then is exposed to light of an appropriate wavelength, allowing the photosensitizer to capture light energy. Finally, in the presence of molecular oxygen, the light energy is converted into a chemical reaction to produce singlet oxygen ( 1 O2) and other highly reactive oxygen species (ROS), and induce cell damage through direct or indirect cytotoxicity.

[0005] Compared to traditional tumor treatments, PDT is a non-invasive therapy with a range of significant advantages: minimal side effects, low drug resistance, and excellent selectivity; it can be used alone or in combination with other treatment modalities. PDT's selectivity for target tissue and degree of damage reduces damage to normal tissues, offering advantages such as minimal trauma, strong applicability, adjuvant therapy, repeatability, lack of drug resistance, the ability to eliminate tiny lesions, and preserve the function of vital organs. It offers a new treatment option, particularly for patients in the middle and late stages of cancer, particularly those unable to (or refusing) traditional treatments. Compared to traditional therapies, PDT can avoid the trauma of multiple surgeries while achieving excellent therapeutic results.

[0006] Currently, PDT has been widely used in the treatment of malignant tumors and precancerous lesions such as skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer, and bladder cancer. It is mainly used clinically for tumors in cavities, cavities, and body surfaces, as well as certain abnormal proliferations. However, there is only one APC (antibody photosensitizer conjugate) drug (i.e., cetuximab sarotalocan / ) has been approved for marketing, so there is an urgent need to develop more photosensitizer conjugates to meet the growing demand in the field of precision diagnosis and treatment.

[0007] Summary of the Invention

[0008] Problems to be solved by the invention

[0009] In response to the problems of current photosensitizer conjugates, such as a limited variety, lack of targeting, and difficulty in drug development, the present invention combines the advantages of ligand-drug conjugates (PDCs) and photodynamic therapy (PDT) to discover a series of new ligand-photosensitizer conjugates (LPCs), especially bi-ligand photosensitizer conjugates (BLPCs) constructed based on dual-targeting technology. By coupling a photosensitizer to a ligand with a targeting effect, while utilizing the advantages of photosensitizer drugs themselves, such as few side effects and low drug resistance, the targeting and drug development of the photosensitizer are improved, and the variety of photosensitizer conjugates is further enriched.

[0010] Solutions for solving problems

[0011] <First Aspect>

[0012] The present invention provides a conjugate compound, which may comprise a photosensitizer and a targeting ligand, preferably 1 to 6 targeting ligands, more preferably 2 or 4 targeting ligands.

[0013] In one embodiment of the present invention, the photosensitizer in the above-mentioned conjugate compound can be formed by porphyrins, phthalocyanines, cyanines or Bodipy compounds, preferably formed by phthalocyanine compounds, more preferably formed by silicon phthalocyanine or zinc phthalocyanine compounds.

[0014] In one embodiment of the present invention, each targeting ligand in the above-mentioned conjugate compound can independently bind to any one of the following cell surface proteins: PSMA, FOLR1 and TRPV6.

[0015] Furthermore, when the above-mentioned conjugate compound contains 2 or 4 targeting ligands, the above-mentioned conjugate compound can bind to any one of the following cell surface protein combinations: PSMA / FOLR1, FOLR1 / TRPV6 and PSMA / TRPV6, preferably PSMA / FOLR1 and FOLR1 / TRPV6, and more preferably PSMA / FOLR1.

[0016] In one embodiment of the present invention, each targeting ligand in the above-mentioned conjugate compound can be independently formed by a polypeptide, an antibody or a small molecule.

[0017] The present invention also provides a coupled compound, which may include a photosensitizer, a targeting ligand, and a connecting portion; the connecting portion may be used to connect the photosensitizer and the targeting ligand and / or connect multiple targeting ligands.

[0018] The present invention also provides a coupled compound, which may include a photosensitizer, a targeting ligand, a linker and a spacer; the linker may be used to connect the photosensitizer and the targeting ligand; the spacer may be used to connect multiple targeting ligands.

[0019] In one embodiment of the present invention, the above-mentioned coupled compound may have a structure as shown in Formula I,

[0020] in,

[0021] LG indicates targeting ligand;

[0022] S represents a spacer;

[0023] L represents a linker;

[0024] PS indicates photosensitizer;

[0025] n is 1 or 2;

[0026] and

[0027] The two LGs are identical to or different from each other;

[0028] When n is 2, two the same as or different from each other.

[0029] Furthermore, the compound of formula I may have a structure as shown in formula IA,

[0030] wherein LG, S, L and PS are as defined in Formula I.

[0031] Alternatively, further, the compound of formula I may have a structure as shown in formula IB,

[0032] wherein LG, S, L and PS are as defined in Formula I.

[0033] In one embodiment of the present invention, each LG in the compound of Formula I, Formula IA or Formula IB can independently bind to any one of the following cell surface proteins: PSMA, FOLR1 and TRPV6.

[0034] Furthermore, when containing 2 or 4 LGs, the above-mentioned compound of Formula I, Formula IA or Formula IB can bind to any one of the following cell surface protein combinations: PSMA / FOLR1, FOLR1 / TRPV6 and PSMA / TRPV6, preferably PSMA / FOLR1 and FOLR1 / TRPV6, and more preferably PSMA / FOLR1.

[0035] In one embodiment of the present invention, each LG in the compound of Formula I, Formula IA or Formula IB can be independently formed by a polypeptide, an antibody or a small molecule.

[0036] In one embodiment of the present invention, each LG in the compound of formula I, formula IA or formula IB can be independently formed by any one of the ligand compounds of formula LG-I, LG-II and LG-III.

[0037] In formula LG-I,

[0038] R LG1 For hydroxyl, Preferably, R LG1 For hydroxyl,

[0039] Formula LG-II is pteroic acid, folic acid or an analog thereof; preferably, the folic acid analog is selected from 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, methotrexate, aminopterin and raltitrexed;

[0040] Formula LG-III comprises all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; preferably, formula LG-III comprises 9 to 27 amino acids in the above polypeptide; more preferably, formula LG-III has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the polypeptide KEFLHPSKVDLPR; further preferably, formula LG-III is the polypeptide KEFLHPSKVDLPR.

[0041] In one embodiment of the present invention, each LG in the above-mentioned Formula I, Formula IA or Formula IB compound can be independently a targeting ligand formed by a ligand compound of Formula LG-I or an optical isomer thereof and binds to the cell surface protein PSMA; a targeting ligand formed by a ligand compound of Formula LG-II or an optical isomer thereof and binds to the cell surface protein FORL1; or, a targeting ligand formed by a ligand compound of Formula LG-III or an optical isomer thereof and binds to the cell surface protein TRPV6.

[0042] In one embodiment of the present invention, each LG in the compound of Formula I, Formula IA or Formula IB can be independently formed from any one of the following ligand compounds or optical isomers thereof.

[0043] In the present invention, the LG formed by the above-mentioned ligand compound can be various and is not specifically limited thereto. For example, it can be a monovalent group formed by the loss of a hydrogen atom from a primary amino group in the structure (preferably a primary amino group located at a main chain endpoint) (i.e., a secondary amino group, which can be linked to a carboxylic acid group of another fragment (e.g., S) in the conjugate to form an amide group); a monovalent group formed by the loss of a hydroxyl group from a carboxylic acid group in the structure (preferably a carboxylic acid group located at a main chain endpoint) (i.e., a carboxylic acid group, which can be linked to a secondary amino group in another fragment in the conjugate to form an amide group); or a monovalent group formed by the loss of a hydrogen atom from a hydroxyl group in the structure (preferably a hydroxyl group located at a main chain endpoint) (e.g., an alkoxy or aryloxy group, which can be linked to a carboxylic acid group in another fragment in the conjugate to form an ester group).

[0044] In the present invention, each ligand compound can independently form any one of the following fragments, wherein the end marked with * is connected to S in the conjugate.

[0045] In the present invention, the above-mentioned compounds of Formula IA or Formula IB are relatively preferred because the structures of these conjugates contain at least two targeting ligands, which can act in multiple ways, improve therapeutic effects, and reduce toxic side effects; at the same time, the two targeting molecules enhance the affinity of the conjugate for target cells and reduce off-target toxicity.

[0046] Furthermore, when the conjugate compound of the present invention contains at least two targeting ligands, a linker (e.g., a spacer) can be used to connect the two targeting ligands. In the present invention, the spacer can be either cleavable (or degradable) or non-cleavable (or non-degradable), and the present invention has no particular requirements for the specific structure of the spacer.

[0047] In one embodiment of the present invention, each S in the compound of Formula I, Formula IA or Formula IB can be independently formed by any one of the following spacer compounds or optical isomers thereof.

[0048] In the present invention, each spacer compound can independently form any one of the following fragments, wherein the end marked by * is connected to one LG in the conjugate; the end marked by ** is connected to the other LG in the conjugate; the group marked by *** can react with the corresponding group in the linker compound (for example, a cycloaddition reaction of an alkynyl group and an azide group, or a double bond addition reaction of an alkenyl group in a maleimide ring and a thiol group), thereby completing the connection between S and L.

[0049] In one embodiment of the present invention, each S in the above-mentioned compound of Formula I, Formula IA or Formula IB can be independently formed by any one of the spacer compounds of S-1, S-2, S-3 and S-4 or its optical isomers and an additional amino acid or amino acid combination or its optical isomers, wherein the additional amino acid or amino acid combination can be selected from Lys, Cys, Glu, Lys-Cys, Cys-Cys, Lys-Cys-Lys, Arg-Arg, Ala-Ser-Asn, Ala-Ala-Ala, Ser-Ser-Arg, Pro-Arg, Asp-Asp-Lys-Cys and Pro-Leu-Gly, and the additional amino acid or amino acid combination can be optionally amidated (for example, Lys is amidated to L-2,6-diaminohexanamide).

[0050] Furthermore, a bi-ligand compound (BLG) can be formed by the spacer compound and the two ligand compounds, which also falls within the scope of protection of the present invention.

[0051] In the present invention, each BLG can independently be any one of the following compounds, wherein the alkynyl group or thiol group can react with the corresponding group in the linker compound (for example, the azide group or the alkenyl group in the maleimide ring) to complete the connection between the biligand fragment and the linker fragment.

[0052] In one embodiment of the present invention, each BLG can be independently any one of the following compounds or optical isomers thereof.

[0053] Furthermore, when the conjugate compound of the present invention contains at least two targeting ligands, a connecting moiety (e.g., a linker) can be used to connect the photosensitizer (PS) fragment and the biligand (BLG) fragment. In the present invention, the linker can be either cleavable (or degradable) or non-cleavable (or non-degradable), and the present invention has no particular requirements for the specific structure of the linker.

[0054] In one embodiment of the present invention, each L in the compound of formula I, formula IA or formula IB can be independently formed by any one of the linker compounds of formula LI and L-II.

[0055] In formula LI,

[0056] s is any integer from 1 to 8, preferably any integer from 3 to 5, more preferably 4 or 5;

[0057] R L1 Amino, carboxyl or Where W is and the two ends are connected to other fragments through amide bonds; t is 0 or 1; u is any integer from 1 to 4, preferably 2 or 3, more preferably 3; v is any integer from 1 to 4, preferably 1 or 2, more preferably 2; preferably, R L1 For amino, carboxyl,

[0058] In Formula L-II,

[0059] p is any integer from 1 to 4, preferably any integer from 1 to 3, more preferably 2 or 3;

[0060] q is any integer from 0 to 3, preferably any integer from 0 to 2, more preferably 0 or 1;

[0061] r is 0 or 1;

[0062] Preferably, when p is 2, q is 1, and r is 1; or

[0063] Preferably, when p is 3, q ​​is 0 or 1, and r is 0.

[0064] In one embodiment of the present invention, each L in the compound of Formula I, Formula IA or Formula IB can be independently formed by any one of the following linker compounds or optical isomers thereof.

[0065] In the present invention, each linker compound can independently form any one of the following fragments, wherein the end marked by * is connected to PS in the conjugate; the group marked by *** can react with the corresponding group in the spacer compound (for example, a cycloaddition reaction of an alkynyl group and an azide group, or a double bond addition reaction of an alkenyl group in a maleimide ring and a thiol group), thereby completing the connection between L and S.

[0066] In one embodiment of the present invention, in the above-mentioned compound of formula I, formula IA or formula IB, when S can be formed by any one of the spacer compounds S-1 and S-2, L can be formed by any one of the linker compounds L-2A, L-2B and L-2C, and the two are connected to each other through a cycloaddition reaction of an alkynyl group and an azide group (e.g., a [3+2] cycloaddition reaction).

[0067] In one embodiment of the present invention, in the above-mentioned compound of Formula I, Formula IA or Formula IB, when S can be formed by any one of the spacer compounds S-3 and S-4, L can be formed by any one of the linker compounds L-1A, L-1B, L-1C, L-1D, L-1E and L-1F, and the two are connected to each other through a double bond addition reaction between the alkenyl group in the maleimide ring and the thiol group (e.g., thiol-Michael reaction).

[0068] Furthermore, the photosensitizer (PS) contained in the coupled compound of the present invention can undergo a photochemical reaction after absorbing light, thereby generating reactive oxygen species that induce cancer cell death, thereby achieving a therapeutic effect.

[0069] In one embodiment of the present invention, the above-mentioned photosensitizer can be formed by porphyrins, phthalocyanines (for example, silicon phthalocyanine or zinc phthalocyanine), cyanines or Bodipy compounds, preferably formed by phthalocyanine compounds, more preferably formed by silicon phthalocyanine or zinc phthalocyanine compounds.

[0070] In one embodiment of the present invention, PS in the compound of formula I, formula IA or formula IB can be formed by any one of the following photosensitizer compounds or optical isomers thereof.

[0071] In the present invention, the photosensitizer compound can form any of the following fragments, wherein the end marked by * is connected to L in the conjugate.

[0072] In one embodiment of the present invention, in the compound of Formula I, Formula IA or Formula IB, when PS can be formed by any one of the photosensitizer compounds PS-1 and PS-3, L can be formed by any one of the linker compounds L-1A and L-2B, and the two are linked to each other through an amidation reaction between the carboxyl group and the primary amino group.

[0073] In one embodiment of the present invention, in the above-mentioned compound of Formula I, Formula IA or Formula IB, when PS can be formed by a PS-2 photosensitizer compound, L can be formed by an L-2A linker compound, and the two are connected to each other through an etherification reaction of two hydroxyl groups.

[0074] In one embodiment of the present invention, in the compound of Formula I, Formula IA or Formula IB, when PS can be formed by any one of the photosensitizer compounds PS-4, PS-7 and PS-8, L can be formed by any one of the linker compounds L-1B, L-1F and L-2C, and the two are connected to each other through an esterification reaction between the hydroxyl group and the carboxyl group.

[0075] In one embodiment of the present invention, in the compound of Formula I, Formula IA or Formula IB, when PS can be formed by any one of the photosensitizer compounds PS-5 and PS-6, L can be formed by any one of the linker compounds L-1C, L-1D and L-1E, and the two are interconnected through a nucleophilic substitution reaction between a silanol group and a silyl ether group.

[0076] Furthermore, the coupled compound intermediate (CM) formed by the linker compound and the photosensitizer compound also falls within the protection scope of the present invention.

[0077] In the present invention, each CM can independently be any one of the following compounds, wherein the alkenyl group in the azide group or maleimide ring can react with the corresponding group (e.g., alkynyl group or thiol group) in the spacer compound, thereby completing the connection between the coupled compound intermediate and the spacer fragment.

[0078] In one embodiment of the present invention, each CM can be independently any one of the following compounds or optical isomers thereof.

[0079] In the present invention, when different fragments used to construct a coupled compound are connected in series via an amide group, the amide group can be formed by a condensation reaction of a primary amino group (e.g., an amino group in a compound forming L, S, or LG) with a carboxyl group (e.g., a carboxyl group in a compound forming PS). Typically, the condensation reaction can be carried out in the presence of a coupling reagent to activate the carboxylic acid into a preferred electrophilic reagent, thereby promoting the forward reaction. Exemplary coupling reagents include, but are not limited to, EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), HOBt (1-hydroxybenzotriazole), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), etc. In addition, the formation of an amide bond can also be achieved by activating the carboxylic acid with N-hydroxysuccinimide (NHS) to form a succinimide ester, which can be further reacted with an amine in the absence of any other coupling reagents.

[0080] <Second Aspect>

[0081] The present invention provides the following specific presentation forms of the conjugate compound.

[0082] Preferably, the present invention provides the following specific forms of the conjugate compound or optical isomers thereof.

[0083] <Third Aspect>

[0084] The present invention provides a pharmaceutical composition comprising the conjugate compound described in <the first aspect> or <the second aspect>.

[0085] Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0086] <Fourth Aspect>

[0087] The present invention provides use of the conjugate compound described in <the first aspect> or <the second aspect> or the pharmaceutical composition described in <the third aspect> in the preparation of a medicament for diagnosing, preventing and / or treating a disease or condition.

[0088] <Fifth Aspect>

[0089] The present invention provides the conjugate compound described in <the first aspect> or <the second aspect> or the pharmaceutical composition described in <the third aspect>, which is used for diagnosing, preventing and / or treating a disease or condition.

[0090] <Sixth Aspect>

[0091] The present invention provides a method for diagnosing, preventing and / or treating a disease or condition, comprising: administering a diagnostically, preventively and / or therapeutically effective amount of the conjugate compound described in <the first aspect> or <the second aspect> or the pharmaceutical composition described in <the third aspect> to an individual in need thereof.

[0092] Preferably, in the <Fourth Aspect>, <Fifth Aspect> and / or <Sixth Aspect>, the disease or condition is cancer or a precancerous lesion; preferably, the cancer or precancerous lesion occurs in a cavity, a lumen or a body surface; more preferably, the cancer is selected from skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer and bladder cancer.

[0093] Effects of the Invention

[0094] The conjugate compound of the present invention (or its pharmaceutically acceptable derivative form, such as an addition salt) combines the advantages of ligand-drug conjugates and photodynamic technology. By coupling a photosensitizer to a ligand with a targeting effect, while utilizing the advantages of the photosensitizer itself, such as low side effects and low drug resistance, it improves the targeting of the photosensitizer and provides a possible drug development of the photosensitizer. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] FIG1 is the MS spectrum of intermediate 1 in Example 3.

[0096] FIG2 is the MS spectrum of compound CM-5′ in Example 3.

[0097] FIG3 is the MS spectrum of compound 9′ in Example 3.

[0098] FIG4 is the MS spectrum of compound 10′ in Example 4.

[0099] FIG5 is the MS spectrum of compound CM-4′ in Example 5.

[0100] FIG6 is the MS spectrum of compound 7′ in Example 5.

[0101] FIG7 is the MS spectrum of compound 8′ in Example 6.

[0102] FIG8 is the MS spectrum of compound BLG-2′ (compound NC) in Example 7.

[0103] FIG9 is the MS spectrum of compound 11′ in Example 7.

[0104] FIG10 is a graph showing the effect of compound 8' on the body weight of mice in each group of the SKOV-3 model (mean ± standard error).

[0105] FIG11 is a graph showing the effect of compound 8' on the body weight changes of mice in each group of the SKOV-3 model (mean ± standard error).

[0106] FIG12 shows the effect of compound 8' on the tumor volume of mice in each group of the SKOV-3 model (mean ± standard error).

[0107] FIG13 shows the effect of compound 8' on the changes in tumor volume in each group of mice in the SKOV-3 model (mean ± standard error). DETAILED DESCRIPTION

[0108] General Terms and Definitions

[0109] Unless otherwise stated, the terms used in the present invention have the following meanings.

[0110] In this application, "target" or "drug target" refers to the binding site between a drug and a biological macromolecule, primarily involving receptors, enzymes, ion channels, transporters, the immune system, and genes. Among existing drugs, over 50% target receptors, making receptors the primary and most important target. Over 20% target enzymes, particularly enzyme inhibitors, which hold a special place in clinical practice. Approximately 6% target ion channels; 3% target nucleic acids; and the targets of 20% remain under further investigation.

[0111] In the present invention, "conjugate compound", "conjugate", "drug conjugate" or "drug conjugate" refers to a pharmaceutically acceptable compound that is formed by linking fragments of different functions through optional linking fragments and can exert corresponding activities, such as antibody-drug conjugates (ADCs), polypeptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), radionuclide-drug conjugates (RDCs), ligand-photosensitizer conjugates (LPCs), etc.

[0112] In the present invention, "photosensitizer" refers to a drug that can trigger a photodynamic reaction to destroy cell structures.

[0113] In the present invention, "ligand-photosensitizer conjugate" or "ligand-coupled photosensitizer" refers to a pharmaceutically acceptable conjugate formed by interconnecting a photosensitizer and a targeting ligand (Ligand) for at least one target through a linker and a spacer, wherein the photosensitizer portion is capable of exerting a photodynamic effect, the targeting ligand portion is used to target and position one or more specific targets (e.g., receptors), and the linker portion and the spacer portion are used to interconnect the photosensitizer portion and the targeting ligand portion to form the complete structure of the ligand-photosensitizer conjugate.

[0114] In the present invention, "targeting ligand" refers to any molecule or part that can be targeted to a target site, target tissue, target organ, target cell or target cell intracellular region. In some embodiments, the targeting ligand causes the portion connected to the targeting ligand to be distributed more at the target site, target tissue, target organ, target cell or target cell intracellular region compared to non-target sites, non-target tissues, non-target organs, non-target cells or non-target cell intracellular regions, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more. In some embodiments, the conjugate compound or agent with a targeting ligand is distributed more at the target site, target tissue, target organ, target cell or target cell intracellular region compared to the conjugate compound without a targeting ligand, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more. In some embodiments, the targeting ligand is capable of triggering or promoting the specific binding of a conjugate compound containing such a targeting ligand to a target molecule, triggering or promoting the endocytosis of the conjugate compound by target cells, and triggering or promoting the enrichment of the conjugate compound around target cells and / or entry into target cells.

[0115] In the present invention, "ligand" may include a variety of chemical molecules or polypeptides that have specific binding affinity for a selected target, and the selected target may be a cell surface protein (such as a cell surface receptor or a cell surface antigen), a specific protein, a cell, a tissue, an organ, etc. In some embodiments, the ligand may specifically bind to a cell surface receptor. In some embodiments, the ligand may specifically bind to a cell surface antigen. In some embodiments, the ligand may specifically bind to a specific protein, and the specific protein may be a disease-causing protein. In some embodiments, the overexpression of the specific protein may cause a disease or the specific protein may be a mutant protein that causes a disease. In some embodiments, the ligand of the present application may be expressed in 10 -6 ~10 -11 M(K d In some embodiments, the ligand of the present application binds to the target with an affinity of at least 10-6 , at least 10 -7 , at least 10 -8 or at least 10 -9 M(K d In some embodiments, the ligand of the present application binds to the target with an affinity of at least two times, three times, four times, five times, six times, eight times, ten times, twenty times, fifty times, one hundred times or more compared to the affinity of the non-target (e.g., other cell surface receptors, cell surface antigens or specific proteins, etc.). In some embodiments, the expression of the cell surface receptors, cell surface antigens, and specific proteins of the present application on the surface of target cells (e.g., cancer cells or cells with abnormal physiological functions) or in target cells is significantly higher than that in normal cells. The term "significant" as used in this application refers to a statistically significant difference, or a significant difference that can be recognized by those skilled in the art.

[0116] In this paper, "FOLR1," or folate receptor 1, is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that binds folate with nanomolar affinity, thereby promoting receptor-mediated endocytosis. Fast-growing solid malignancies, including ovarian and lung cancers, rely on folate for metabolism and nucleic acid synthesis.

[0117] In the present invention, "TRPV6" is transient receptor potential cation channel subfamily V member 6, which is a highly selective calcium ion transmembrane transport channel that mediates the active transport of calcium ions from the extracellular to the intracellular. TRPV6 is expressed in normal human kidneys, gastrointestinal tract, pancreas, mammary glands, salivary glands, etc., but is mainly expressed in intestinal epithelial cells, where it participates in the transport of calcium ions into the cells. Therefore, when the number or function of TRPV6 channels changes, changes in calcium ion regulation may be caused, further leading to structural or functional abnormalities in related tissues and organs. Compared with normal tissues, TRPV6 expression is significantly increased in malignant tumors such as breast cancer, bile duct cancer, ovarian cancer, squamous cell lung cancer, and prostate cancer, and its abnormal expression may be related to the formation and progression of tumors.

[0118] In the present invention, "PSMA" refers to prostate-specific membrane antigen, which refers to a type II transmembrane glycoprotein present in the membrane of prostate epithelial cells. It is composed of 750 amino acids, which have 19 intracellular amino acids, 24 transmembrane amino acids and 707 extracellular amino acids. Prostate-specific membrane antigen is expressed in normal prostate epithelial cells, but its expression level in prostate cancer cells is much higher. Compared with the prostate-specific antigen traditionally used for clinical detection, prostate-specific membrane antigen is a more sensitive and specific prostate cancer tumor marker, especially in hormone-refractory prostate cancer and prostate cancer metastases, which are highly expressed. It has high sensitivity and specificity in distinguishing prostate cancer from other types of malignant tumors. At the same time, in a variety of solid tumors of non-prostate origin (such as lung cancer, bladder cancer, gastric cancer, pancreatic cancer, kidney cancer and colorectal cancer, etc.), prostate-specific membrane antigen is also highly specifically expressed on tumor vascular endothelial cells.

[0119] In the present invention, a "pharmaceutical composition" refers to a pharmaceutical composition comprising a small molecule drug, a polypeptide, an antibody (or an antibody-like ligand) or a conjugate thereof as an active pharmaceutical ingredient (API), and other components (e.g., pharmaceutically acceptable excipients). The pharmaceutical composition can be prepared using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding, and / or lyophilizing processes.

[0120] In the present invention, "pharmaceutically acceptable excipients" refer to auxiliary materials widely used in the field of drug production. The main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and / or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be dissolved at a desired rate, or to promote the effective absorption of the active ingredient in the body of the subject receiving the drug. Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function to the pharmaceutical composition (such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient in the composition). Examples of "pharmaceutically acceptable excipients" include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, photosensitizers, preservatives, colorants, flavoring agents, sweeteners, etc.

[0121] The technical solutions of the present invention will be described below in conjunction with specific embodiments. The following embodiments are provided to further illustrate the present invention and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0122] The starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means. The separation and purification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC) and the like. The structural identification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS) and the like.

[0123] List of abbreviations

[0124] Preparation method of double ligand compound (BLG)

[0125] The resin was loaded onto a solid-phase reaction column, and DMF was added. Nitrogen was bubbled into the solvent to allow the resin to swell for 30 minutes. Fmoc-Arg-OH, DCC, and DMAP were added and reacted at 25°C for 3 hours. Acetic anhydride and pyridine were then capped for 1 hour, followed by washing three times with DMF. The Fmoc protecting group on the resin was removed with DBLK, and then washed five times with DMF. Fmoc-Pro-OH and HOBt were weighed and dissolved in DMF. DIC was added to the solution in a 0°C ice-water bath and mixed to activate it for 5 minutes. This solution was added to the reaction column and reacted for 3 hours. The solvent was then drained, and the resin in the reaction column was washed three times. The Fmoc protecting group was then removed with DBLK. Repeat the above steps and sequentially couple Fmoc-Leu-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Boc)OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-His(Trt)-OH, Fmoc-Leu-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Glu-OtBu, and pteroic acid according to the structure to obtain a peptide resin. After the peptide resin is cleaved with a cleavage solution, it is filtered, the cleavage solution is collected and poured into MTBE, the precipitated solid is washed with MTBE, and a crude product is obtained. The crude product is purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain BLG-4'.

[0126] BLG-1', BLG-2' and BLG-3' were obtained by similar steps to the above method.

[0127] Example 1: Synthesis of Compound 5'

[0128] Step 1: Synthesis of CM-3

[0129] Under nitrogen protection, PS-3 (0.60 g, 0.799 mmol) was added to DMF (9 ml), and then EDC·HCl (0.32 g), HOSU (0.19 g) and DIPEA (0.4 ml) were added, and the reaction was carried out at room temperature for 17 h. After the reaction was completed, the reaction solution was poured into MTBE (30 ml), a solid precipitated, stirred for 10 min, filtered, and the filter cake was washed with MTBE and dried to obtain an intermediate. The intermediate was dissolved in DMF (9 ml), DIPEA (0.3 ml) was added, and then raw material 1 (0.17 g) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was purified by preparative chromatography (acetonitrile / water = 5%-80%, v / v) to obtain CM-3 (0.50 g, yield: 65.8%).

[0130] Step 2: Synthesis of compound 5'

[0131] Under a nitrogen atmosphere, CM-3 (9.8 mg, 6.09 mmol) was added to DMF (0.8 ml), and purified water (0.17 ml) was added, and the mixture was stirred at 25°C. BLG-1' (19.2 mg) was weighed and added to the reaction solution. The pH of the reaction system was adjusted to about 8 with DIPEA, and cuprous bromide (2.7 mg) was added. The reaction was allowed to react for 1 h. After completion of the reaction, the mixture was purified by preparative chromatography (acetonitrile / water = 5%-80%, v / v) to give compound 5' (16.2 mg, yield: 55.2%).

[0132] Example 2: Synthesis of Compound 6'

[0133] Compound 6' was synthesized by referring to the method of compound 5'.

[0134] Example 3: Synthesis of Compound 9'

[0135] Step 1: Synthesis of Intermediate 1

[0136] PS-5 (3.0 g, 5.2 mmol) was dispersed in pyridine (30 ml), and (3-aminopropyl)dimethylethoxysilane (6.7 g, 41.6 mmol) was added dropwise. The mixture was refluxed under argon for 4 h and concentrated under reduced pressure to remove most of the pyridine. The residue was filtered, washed with a water-ethanol solution (v:v = 2:1), and then dried in vacuo to obtain Intermediate 1 (2.8 g, 4.06 mmol, yield: 78%); MS (ESI-): m / z 803.9 [MH] - (As shown in Figure 1).

[0137] Step 2: Synthesis of CM-5'

[0138] Under nitrogen, Intermediate 1 (2.7 g, 3.357 mmol) and 6-maleimidocaproic acid (1.4 g, 6.71 mmol) were dissolved in DMF (50 ml). HATU (3.8 g, 10.07 mmol) was added, followed by dropwise addition of DIPEA (2.6 g, 20.14 mmol). The mixture was allowed to react at room temperature for 1.5 h. The reaction was quenched with water (150 ml) and extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with water and saturated brine, dried, and concentrated under reduced pressure. Purification by preparative chromatography (acetonitrile / water = 5%-80%, v / v) afforded CM-5' (1.9 g, 2.15 mmol, yield: 64.2%); MS (ESI+): m / z 885.6 [M+H] + (As shown in Figure 2).

[0139] Step 3: Synthesis of compound 9'

[0140] Under nitrogen atmosphere, CM-5' (50 mg, 0.0566 mmol) was dissolved in DMF (7.5 mL), and a solution of BLG-4' (165.6 mg, 0.079 mmol) in water (3.0 mL) was added dropwise. The mixture was reacted at room temperature for 1 h. After dissolution with PBS solution, the product was purified by preparative chromatography (acetonitrile / water = 5%-80%, v / v) to give compound 9' (83.0 mg, yield: 49.5%); MS (ESI+): m / z 991.6 [M-3H] 3- (As shown in Figure 3).

[0141] Example 4: Synthesis of Compound 10'

[0142] Compound 10' was synthesized by referring to the method of compound 9' (yield: 14.5%); MS (ESI-): m / z 801.2 [M-3H] 3- (As shown in Figure 4).

[0143] Example 5: Synthesis of Compound 7'

[0144] Step 1: Synthesis of Intermediate 1

[0145] PS-5 (3.0 g, 5.2 mmol) was dispersed in pyridine (30 ml), and (3-aminopropyl)dimethylethoxysilane (6.7 g, 41.6 mmol) was added dropwise. The mixture was refluxed under an argon atmosphere for 4 h and concentrated under reduced pressure to remove most of the pyridine. The residue was filtered, washed with a water-ethanol solution (v:v = 2:1), and then dried in vacuo to obtain intermediate 1 (2.8 g, 4.06 mmol, yield: 78%).

[0146] Step 2: Synthesis of CM-4'

[0147] Under nitrogen, Intermediate 1 (4.90 g, 6.09 mmol) and 6-maleimidocaproic acid (3.08 g, 14.61 mmol) were dissolved in DMF (100 mL). HATU (6.94 g, 18.28 mmol) was added, followed by the dropwise addition of DIPEA (4.73 g, 36.56 mmol). The reaction was allowed to react at room temperature for 1.5 h. The reaction was quenched by the addition of water (300 mL). The precipitated solid was stirred and filtered, the filter cake washed with water, dried, and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1-10 / 1, v / v) to afford CM-4' (1.9 g, 1.60 mmol, yield: 26%); MS (ESI+): m / z 1192.7 [M+H] + (As shown in Figure 5).

[0148] Step 3: Synthesis of compound 7'

[0149] Under nitrogen atmosphere, CM-4' (20 mg, 0.0168 mmol) was dissolved in DMF (3 mL), and a solution of BLG-4' (84.31 mg, 0.0403 mmol) in water (1.2 mL) was added dropwise. The pH was adjusted to 6-7 with PBS solution. The mixture was reacted at room temperature for 1 h. After dissolution with PBS solution, it was purified to obtain compound 7' (33.6 mg, 0.0063 mmol, yield: 37.5%); MS (ESI-): m / z 1342.3 [M-4H] 4- (As shown in Figure 6).

[0150] Example 6: Synthesis of Compound 8'

[0151] Compound 8' was synthesized by referring to the method of compound 7' (yield: 54.4%); MS (ESI-): m / z 1411.8 [M-3H] 3- (As shown in Figure 7).

[0152] Example 7: Synthesis of Compound 11'

[0153] Step 1: Synthesis of Intermediate 1

[0154] PS-5 (3.0 g, 5.2 mmol) was dispersed in pyridine (30 ml), and (3-aminopropyl)dimethylethoxysilane (6.7 g, 41.6 mmol) was added dropwise. The mixture was refluxed under an argon atmosphere for 4 h and concentrated under reduced pressure to remove most of the pyridine. The residue was filtered, washed with a water-ethanol solution (v:v = 2:1), and then dried in vacuo to obtain intermediate 1 (2.8 g, 4.06 mmol, yield: 78%).

[0155] Step 2: Synthesis of CM-6'

[0156] Under nitrogen protection, intermediate 1 (200 mg) and raw material 2 (161 mg) were dissolved in DMAc (5 ml). After adding HOBt (33 mg), DIPEA (64 mg) was added dropwise. The reaction was carried out at room temperature for 0.5 h. Sampling was performed and after completion of the reaction, the reaction solution was poured into water (40 ml). The precipitated solid was filtered, and the filter cake was washed with water (10 ml*4) and dried in vacuo to obtain a dark green solid CM-6' (144 mg, yield: 31.6%).

[0157] Step 3: Synthesis of compound 11'

[0158] Under nitrogen, CM-6' (140 mg) was dissolved in DMF (5 mL), and a solution of BLG-2' (i.e., compound NC, as shown in Figure 8) (300 mg) in water (5 mL) was added dropwise. The pH value was adjusted to approximately 7 with PBS solution, and the reaction was allowed to proceed at room temperature. After the intermediate control reaction was completed, the reaction solution was purified by preparative chromatography (acetonitrile / water = 5%-80%, v / v) and lyophilized to obtain compound 11' (110 mg, yield: 29.6%); MS (ESI-): m / z 1217.3 [M-4H] 4- (As shown in Figure 9).

[0159] Comparative Example: Synthesis of Compound PC

[0160] Step 1: Synthesis of raw material 3

[0161] Fmoc-Cys(Trt)-OH was immobilized on an amino resin through Fmoc chemical solid-phase synthesis, and then the Fmoc protecting group was removed using a 20% piperidine DMF solution, followed by washing with DMF to remove impurities, and a DMF solution of Fmoc-Glu-OtBu was added. HATU and DIPEA were added for reaction and condensation, and ninhydrin developed a light yellow color. After washing with DMF to remove impurities, the Fmoc removal and condensation steps were repeated to obtain a crude resin. The product was cleaved from the resin using trifluoroacetic acid, and the protecting group was removed simultaneously to obtain a crude raw material 3, which was purified by preparative chromatography to obtain raw material 3.

[0162] Step 2: Synthesis of compound PC

[0163] Compound PC was synthesized by referring to the method of compound 7' (yield: 26.3%).

[0164] Experimental Example 1: Experimental study on the proliferation inhibition of different cells by compounds 8', 9', 10', NC (BLG-2') and PC

[0165] 1. Experimental Materials

[0166] 1.1 Cell line information

[0167] Table 1. Expression of multiple targets in different cells

[0168] The results in Table 1 showed that 293T cells did not express FOLR1, PSMA, and TRPV6; 293T-FOLR1 / PSMA cells highly expressed FOLR1 and PSMA, but did not express TRPV6; SK-OV-3 cells highly expressed FOLR1, but low expression of PSMA and TRPV6; HT29 cells expressed FOLR1, but low expression of PSMA and TRPV6.

[0169] 1.2 Main reagents: 1640 folic acid-free culture medium, fetal bovine serum, penicillin-streptomycin solution, L-glutamine, and CCK8.

[0170] 2. Experimental Procedure

[0171] 2.1 Cell plating

[0172] Prepare cells in advance, digest with trypsin, collect, and count; dilute cells to 2×10 4 Cells were plated at 100 μl of diluted cell solution per well in a 96-well plate. 100 μl of diluted cell solution was added to each well. A negative control well (without drug, other conditions were the same) and a blank control well (containing only cell culture medium) were set up on each plate. The 96-well plate with cells was placed in a 37°C, 5% CO2 incubator and cultured overnight.

[0173] 2.2 Dilution and sample addition

[0174] The sample was diluted with culture medium (initial concentration 10 μM, 5-fold gradient dilution), with a total of 9 concentration gradients. The culture medium in the well plate was discarded, and the drug solution was added to a 96-well plate at a volume of 100 μl per well, with 3 replicates. A negative control, a blank control, and a non-illumination group were set up and placed in a 37°C, 5% CO2 incubator for 24 h. The drug solution was then injected with 16 J / cm 2 The well plate was irradiated with light and then placed in a 37°C, 5% CO2 incubator for 24 hours.

[0175] 2.3 Chromogenic plate reading

[0176] Take CCK-8 colorimetric solution and add 10 μl (10% of the liquid volume in the well) to each well. Incubate at 37°C for an appropriate time (try to keep the OD value within the range of 1.0-2.5). Remove the culture plate cover from the 96-well plate and place it in a microplate reader (Molecular Devices SpectraMax iD5). Read the value at 450 nm.

[0177] 2.4 Data Processing

[0178] GraphPad Prism 8.0.2 was used to perform four-parameter fitting to obtain the IC 50 value.

[0179] 2.5 Experimental Results and Analysis

[0180] Table 2. IC values ​​of compounds under illuminated and non-illuminated conditions 50 Note: N / A means no value was fitted and no obvious inhibitory effect.

[0181] The results in Table 2 show that under light conditions, compounds 8', 9', and 10' have a significant killing effect on cells that highly express FOLR1 and PSMA; under non-light conditions, compounds 8', 9', 10', PC, and NC have no significant inhibitory effect on cells; thus, the following conclusions can be drawn:

[0182] (1) The ligand-photosensitizer conjugate of the present invention requires light conditions to exert its efficacy, so the compound NC that does not contain a photosensitizer (PS) does not show an inhibitory effect on cells;

[0183] (2) The efficacy of the drug is correlated to the expression of the drug on the cells. If the cells express the drug highly, the killing effect is higher (293T-FOLR1 / PSMA), while if the cells express the drug lowly or not, the killing effect is lower or no killing (293T, HT29). This is also in line with the concept of targeted precision diagnosis and treatment.

[0184] (3) When the drug concentrations were comparable, the two-arm dual-ligand conjugate (e.g., compound 8') showed a higher killing effect than the single-arm dual-ligand conjugate (e.g., compound 10') or the two-arm single-ligand conjugate (e.g., compound PC), whether against 293T-FOLR1 / PSMA or SK-OV-3, indicating that the two-arm dual-ligand structure can further enhance the affinity of the conjugate to the target cells and improve the drug efficacy; moreover, when achieving comparable drug efficacy, the actual dosage of the two-arm dual-ligand conjugate can also be reduced, further improving the safety of the drug.

[0185] Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are illustrative and should not be construed as limiting the present invention. Without departing from the principles and purpose of the present invention, those skilled in the art may make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention, and such changes, modifications, substitutions, and variations are intended to be within the scope of the present invention.

[0186] Experimental Example 2: In vivo pharmacodynamics study of compound 8'

[0187] 1. Experimental Methods

[0188] SK-OV-3 cells were cultured in vitro in McCoy's 5A medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator. Routine manipulation and passage were performed twice weekly. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0189] 10*10 6 The cells (inoculation volume 0.1 mL) were subcutaneously inoculated on the right dorsal flank of each mouse. When the average tumor volume reached 150 mm 3 The day of grouping was set as D0, and the day of first administration was set as D1.

[0190] Animal body weight and tumor size were measured on the day of grouping. Thirty-three animals were randomly assigned to 11 groups based on tumor size using grouping: a blank control group; high-, medium-, and low-dose groups of compound 8' (45 mg / kg, 15 mg / kg, and 5 mg / kg, respectively), each with 4, 6, and 8-hour post-dose illumination (administered once every two weeks for three times), and a 5 mg / kg group of compound 8' with 4-hour post-dose illumination (administered once weekly for five times). No manipulation was performed on the blank control group. Animal grouping and illumination conditions are shown in Table 3.

[0191] The medication is as follows:

[0192] Route of administration: intravenous administration (iv);

[0193] Dosing frequency: once every two weeks and once a week.

[0194] Table 3. Animal groups and lighting conditions for in vivo pharmacodynamics experiments in mice

[0195] 2. Experimental Results

[0196] The body weight and weight changes of the experimental mice at different time points are shown in Figures 10 and 11. No significant changes were observed in the body weight of the animals in each group. One mouse in Group 11 became emaciated after four doses of the drug.

[0197] Figures 12 and 13 show the tumor volumes and changes in tumor volume at different time points in the experimental mice. Data from the groups exposed to light every 4 hours after dosing (Groups 1, 4, 7, and 11) were relatively impressive and dose-related. The 45 mg / kg dose (Group 7) exposed to light every two weeks had a significant tumor inhibitory effect. The 5 mg / kg dose (Group 11) exposed to light once weekly and the 15 mg / kg dose (Group 4) exposed to light once every two weeks showed similar tumor inhibitory effects. No significant tumor inhibitory effect was observed at the 5 mg / kg dose (Group 1) exposed to light once every two weeks.

Claims

1. A conjugate compound comprising a photosensitizer and 1 to 6 targeting ligands that specifically bind to cell surface proteins.

2. The coupled compound according to claim 1, characterized in that The photosensitizer is formed of porphyrin, phthalocyanine, cyanine dye or Bodipy compound, preferably formed of phthalocyanine compound, more preferably formed of silicon phthalocyanine or zinc phthalocyanine compound.

3. The coupled compound according to claim 2, characterized in that The photosensitizer is formed by any one of the following photosensitizer compounds or optical isomers thereof:

4. The coupled compound according to any one of claims 1 to 3, characterized in that The conjugate compound comprises a photosensitizer and 2 or 4 targeting ligands.

5. The coupled compound according to any one of claims 1 to 4, characterized in that Each targeting ligand in the conjugate compound independently binds to any one of the following cell surface proteins: PSMA, FOLR1 and TRPV6.

6. The coupled compound according to claim 4 or 5, characterized in that When the conjugate compound comprises 2 or 4 targeting ligands, the conjugate compound binds to any one of the following cell surface protein combinations: PSMA / FOLR1, FOLR1 / TRPV6 and PSMA / TRPV6, preferably PSMA / FOLR1 and FOLR1 / TRPV6, and more preferably PSMA / FOLR1.

7. The coupled compound according to any one of claims 1 to 6, characterized in that Each targeting ligand in the conjugate compound is independently formed by a polypeptide, an antibody or a small molecule.

8. The coupled compound according to claim 7, characterized in that Each targeting ligand in the coupled compound is independently formed by any one of the ligand compounds of formula LG-I, LG-II and LG-III, In formula LG-I, R LG1 For hydroxyl, Preferably, R LG1 For hydroxyl, Formula LG-II is pteroic acid, folic acid or an analog thereof; preferably, the folic acid analog is selected from 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, methotrexate, aminopterin and raltitrexed; Formula LG-III comprises all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; preferably, formula LG-III comprises 9 to 27 amino acids in the above polypeptide; more preferably, formula LG-III has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the polypeptide KEFLHPSKVDLPR; further preferably, formula LG-III is the polypeptide KEFLHPSKVDLPR.

9. The coupled compound according to claim 8, characterized in that Each targeting ligand in the conjugate compound is independently a targeting ligand formed by a ligand compound of formula LG-I or an optical isomer thereof and binds to a cell surface protein PSMA; A targeting ligand formed by a ligand compound of formula LG-II or an optical isomer thereof and binds to the cell surface protein FORL1; or, a targeting ligand formed by a ligand compound of formula LG-III or an optical isomer thereof and binds to the cell surface protein TRPV6.

10. The coupled compound according to claim 8, characterized in that Each targeting ligand in the conjugate compound is independently formed by any one of the following ligand compounds or their optical isomers:

11. The coupled compound according to any one of claims 1 to 10, characterized in that It also comprises a connecting part; the connecting part is used to connect the photosensitizer and the targeting ligand and / or connect multiple targeting ligands.

12. The coupled compound according to claim 11, characterized in that The connecting part comprises a linker and a spacer; the linker is used to connect the photosensitizer and the targeting ligand; the spacer is used to connect a plurality of the targeting ligands.

13. A coupled compound having a structure as shown in Formula I, in, LG indicates targeting ligand; S represents a spacer; L represents a linker; PS indicates photosensitizer; n is 1 or 2; and The two LGs are identical to or different from each other; When n is 2, two The same as or different from each other.

14. The coupled compound according to claim 13, characterized in that: It has a structure as shown in Formula IA, wherein LG, S, L and PS are as defined in claim 13.

15. The coupled compound according to claim 13, characterized in that: It has a structure as shown in Formula IB, wherein LG, S, L and PS are as defined in claim 13.

16. The coupled compound according to any one of claims 13 to 15, characterized in that Each LG independently binds to any of the following cell surface proteins: PSMA, FOLR1, and TRPV6.

17. The coupled compound according to claim 16, characterized in that: The conjugate compound binds to any one of the following cell surface protein combinations: PSMA / FOLR1, FOLR1 / TRPV6 and PSMA / TRPV6, preferably PSMA / FOLR1 and FOLR1 / TRPV6, and more preferably PSMA / FOLR1.

18. The coupled compound according to any one of claims 13 to 17, characterized in that Each LG is independently formed by a peptide, an antibody or a small molecule.

19. The coupled compound according to claim 18, characterized in that: Each LG is independently formed by any one of the ligand compounds of formula LG-I, LG-II and LG-III, In formula LG-I, R LG1 For hydroxyl, Preferably, R LG1 For hydroxyl, Formula LG-II is pteroic acid, folic acid or an analog thereof; preferably, the folic acid analog is selected from 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, methotrexate, aminopterin and raltitrexed; Formula LG-III comprises all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; preferably, formula LG-III comprises 9 to 27 amino acids in the above polypeptide; more preferably, formula LG-III has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the polypeptide KEFLHPSKVDLPR; further preferably, formula LG-III is the polypeptide KEFLHPSKVDLPR.

20. The coupled compound according to claim 18, characterized in that Each LG is independently a targeting ligand formed by a ligand compound of formula LG-I or an optical isomer thereof and binds to the cell surface protein PSMA; a targeting ligand formed by a ligand compound of formula LG-II or an optical isomer thereof and binds to the cell surface protein FORL1; or, a targeting ligand formed by a ligand compound of formula LG-III or an optical isomer thereof and binds to the cell surface protein TRPV6.

21. The coupled compound according to claim 18, characterized in that Each LG is independently formed by any of the following ligand compounds or their optical isomers:

22. The coupled compound according to any one of claims 13 to 21, characterized in that Each S is independently formed by any of the following spacer compounds or their optical isomers:

23. The conjugate compound according to claim 22, characterized in that: Each S is independently formed by any one of the spacer compounds of S-1, S-2, S-3 and S-4 or its optical isomers and an additional amino acid or amino acid combination or its optical isomers, wherein the additional amino acid or amino acid combination is selected from Lys, Cys, Glu, Lys-Cys, Cys-Cys, Lys-Cys-Lys, Arg-Arg, Ala-Ser-Asn, Ala-Ala-Ala, Ser-Ser-Arg, Pro-Arg, Asp-Asp-Lys-Cys and Pro-Leu-Gly, and the additional amino acid or amino acid combination is optionally amidated.

24. The conjugate compound according to any one of claims 13 to 23, characterized in that Each L is independently formed by any one of the linker compounds of formula LI and L-II, In formula LI, s is any integer from 1 to 8, preferably any integer from 3 to 5, more preferably 4 or 5; R L1 is amino, carboxyl or Where W is and the two ends are connected to other fragments through amide bonds; t is 0 or 1; u is any integer from 1 to 4, preferably 2 or 3, more preferably 3; v is any integer from 1 to 4, preferably 1 or 2, more preferably 2; preferably, R L1 For amino, carboxyl, In Formula L-II, p is any integer from 1 to 4, preferably any integer from 1 to 3, more preferably 2 or 3; q is any integer from 0 to 3, preferably any integer from 0 to 2, more preferably 0 or 1; r is 0 or 1; Preferably, when p is 2, q is 1, and r is 1; or Preferably, when p is 3, q ​​is 0 or 1, and r is 0.

25. The conjugate compound according to claim 24, characterized in that: Each L is independently formed by any one of the following linker compounds or their optical isomers:

26. The conjugate compound according to claim 25, characterized in that When S is formed by any one of the spacer compounds S-1 and S-2, L is formed by any one of the linker compounds L-2A, L-2B and L-2C, and the two are connected to each other through a cycloaddition reaction between an alkynyl group and an azide group.

27. The conjugate compound according to claim 25, characterized in that When S is formed by any spacer compound among S-3 and S-4, L is formed by any linker compound among L-1A, L-1B, L-1C, L-1D, L-1E and L-1F, and the two are connected to each other through the double bond addition reaction between the alkenyl group in the maleimide ring and the thiol group.

28. The conjugate compound according to any one of claims 13 to 27, characterized in that PS is formed of a porphyrin, phthalocyanine, cyanine dye or Bodipy compound, preferably a phthalocyanine compound, more preferably a silicon phthalocyanine or zinc phthalocyanine compound.

29. The conjugate compound according to claim 28, characterized in that PS is formed by any of the following photosensitizer compounds or their optical isomers:

30. The conjugate compound according to claim 29, characterized in that When PS is formed by any photosensitizer compound of PS-1 and PS-3, L is formed by any linker compound of L-1A and L-2B, and the two are connected to each other through an amidation reaction between a carboxyl group and a primary amino group.

31. The conjugate compound according to claim 29, characterized in that When PS is formed by a PS-2 photosensitizer compound, L is formed by an L-2A linker compound, and the two are connected to each other through an etherification reaction of two hydroxyl groups.

32. The conjugate compound according to claim 29, characterized in that When PS is formed by any photosensitizer compound among PS-4, PS-7 and PS-8, L is formed by any linker compound among L-1B, L-1F and L-2C, and the two are connected to each other through an esterification reaction between a hydroxyl group and a carboxyl group.

33. The conjugate compound according to claim 29, characterized in that When PS is formed by any photosensitizer compound among PS-5 and PS-6, L is formed by any linker compound among L-1C, L-1D and L-1E, and the two are connected to each other through a nucleophilic substitution reaction between a silanol group and a silyl ether group.

34. A conjugate compound, which is any one of the following compounds: Preferably, it is any one of the following compounds or their optical isomers:

35. A pharmaceutical composition comprising the conjugate compound according to any one of claims 1 to 34; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

36. Use of the conjugate compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 35 in the preparation of a medicament for diagnosing, preventing and / or treating a disease or condition; Preferably, the disease or condition is cancer or a precancerous lesion; More preferably, the cancer or precancerous lesion occurs in a cavity, lumen or body surface; Further preferably, the cancer is selected from skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer and bladder cancer.

37. The conjugate compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 35 for use in diagnosing, preventing and / or treating a disease or condition; Preferably, the disease or condition is cancer or a precancerous lesion; More preferably, the cancer or precancerous lesion occurs in a cavity, lumen or body surface; Further preferably, the cancer is selected from skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer and bladder cancer.

38. A method for diagnosing, preventing and / or treating a disease or condition comprising: administering a diagnostically, prophylactically and / or therapeutically effective amount of the conjugate compound according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 35 to an individual in need thereof; Preferably, the disease or condition is cancer or a precancerous lesion; More preferably, the cancer or precancerous lesion occurs in a cavity, lumen or body surface; Further preferably, the cancer is selected from skin cancer, esophageal cancer, colorectal cancer, lung cancer, cervical cancer and bladder cancer.

39. A biligand compound, which is any one of the following compounds: Preferably, it is any one of the following compounds or their optical isomers:

40. A coupled compound intermediate, which is any one of the following compounds: Preferably, it is any one of the following compounds or their optical isomers:

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