A functionalized diblock copolymer and its preparation method and use

Abstract

The present application relates to the fields of organic chemistry and polymer chemistry, and in particular to a functionalized diblock copolymer and its preparation method and use. The present application provides a functionalized diblock copolymer, the chemical structure of which is shown in Formula III. The functionalized diblock copolymer or polymer particles provided in the present application can be widely used in the fields of tumor imaging, tumor treatment, etc., and it not only has good safety, but also realizes faster and adjustable degradation and removal of polymers under acidic conditions (by changing the structure and number of functional groups), but also has excellent specific high-quality imaging effects at the target site, with high signal-to-noise ratio, clear boundaries, long half-life and other characteristics, which solves the problem of real-time intraoperative navigation of fluorescence imaging technology, and thus has good industrialization prospects.

Description

Technical Field

[0001] The present application relates to the field of organic chemistry, and in particular to a functionalized diblock copolymer and a preparation method and uses thereof, which mainly include tumor imaging probe reagents and tumor therapeutic drug preparations. Background Art

[0002] Malignant tumors (cancer) have become one of the main threats to human life and are increasing year by year.

[0003] At present, cancer treatment includes surgical resection, chemotherapy, radiotherapy, immunotherapy and other treatment methods. Surgical resection is the most effective means of treating early solid tumors. Surgeons usually rely on preoperative imaging diagnosis, intraoperative clinical experience (including visual discrimination and touch sensation, etc.), and other clinical auxiliary means to judge the tumor boundary and perform resection of the lesion during the surgical operation. However, since tumors are basically heterogeneously distributed tissues and different types of tumors have different boundary characteristics, it is difficult to accurately judge the tumor boundary during surgery. Therefore, excessive surgical resection may seriously affect the patient's postoperative quality of life (for example, total mastectomy for breast cancer; failure to retain healthy parathyroid glands during thyroid cancer surgery; anal retention problems caused by low rectal cancer surgery, etc.), and insufficient resection is prone to recurrence (for example, high recurrence rate caused by incomplete resection of non-invasive bladder cancer transurethral resection). Therefore, accurately judging the boundary of the tumor lesion during surgery has become a key factor for the success of surgery.

[0004] During the tumor resection operation, surgeons usually need to decide whether to perform lymph node dissection and remove the cancerous tissue that may metastasize based on the preoperative imaging diagnosis and the patient's pathological stage. Usually, the doctor will choose to remove the patient's tissue, and during the operation (the patient is still under anesthesia), send the specimen to the pathology department for sampling, and after a rapid frozen pathological diagnosis, the results will be fed back to the surgeon so that he can decide the scope and extent of the relevant tissue removal. Generally speaking, the entire rapid frozen pathological examination process takes about 45 minutes to several hours. During this period, the medical team and medical resources in the operating room are all on standby, and the patient's waiting in the operating room also increases the risk of infection and prolonged anesthesia time. Therefore, in addition to the judgment of the tumor boundary, clinically, a faster and more accurate pathological judgment method for tumor spread tissue during the operation is also needed to shorten the operation time, accurately remove the cancer spread tissue, reduce late recurrence or spread, and prolong the patient's postoperative survival.

[0005] In summary, intraoperative imaging technology for solid tumors and cancer metastasis tissues has great clinical significance. However, intraoperative specific imaging of cancer tissues is still a big challenge. The main difficulties and corresponding current clinical development strategies are as follows:

[0006] 1) The hardware should meet the requirements for use in an operating room.

[0007] Currently, widely used imaging technologies in clinical practice, such as X-ray scanning, CT (computed tomography), MRI (magnetic resonance imaging), ultrasound, and PET-CT (positron emission computed tomography) are mainly used for preoperative tumor imaging diagnosis. Due to many reasons such as hardware requirements (such as volume) and application requirements (such as electromagnetic fields, etc.), these imaging technologies are limited to real-time imaging diagnosis on the operating table and during surgery. In the prior art, intraoperative ultrasound imaging technology is limited in its application in open tumor surgery because it requires contact for imaging. Moreover, its imaging technology itself is based on tissue morphology, and both false negatives and false positives are high. In brain tumor surgery, MRI preoperative scanning and construction of surgical coordinate information are also used intraoperatively in clinical practice. However, this technology may affect the navigation quality of the surgery due to deformation or displacement of the tissue from image acquisition to surgery.

[0008] Compared with the above-mentioned imaging technologies, technologies based on fluorescence imaging have the advantage of better real-time surgical applications. First, the near-infrared light source commonly used in fluorescence imaging technology has a stronger penetration ability in tissues than light sources such as visible light and ultraviolet light, and is less affected by the main absorption chromophores inside the tissue, such as hemoglobin, oxyhemoglobin, and water. It can penetrate about 1 cm of tissue and has very important application value in tissue optical detection, especially in superficial tissues. Secondly, the hardware implementation of fluorescence imaging can be relatively flexible. It can be designed as a movable white light and fluorescence operating table imaging system, or it can be designed as a small sterile probe with an external display screen, which can realize white light and fluorescence endoscopic imaging systems for minimally invasive surgery in the body. Both hardware designs have been approved by the FDA and EMA (e.g., SPYImaging system; Endoscopic fluorescence imaging system; da Vinci surgical robot system) has been successfully applied in clinical surgery. Using the fluorescence microscope system, after intravenous injection of indocyanine green (ICG) during surgery, within 20 minutes, angiography (neurosurgery, vascular surgery, ophthalmology, etc.) can be performed using the characteristics of ICG that can excite fluorescence under near-infrared light. Methylene blue is also an approved fluorescent imaging agent and is used in some surgical operations.

[0009] 2) The technology used should be specific for tumor tissue.

[0010] The main requirements for achieving tumor specificity are: first, the targeted tumor type must have some specific characteristics. Some of the most widely recognized characteristics are: specific surface receptors of cancer cells corresponding to specific tumors (such as folic acid, Her2 / Neu, EGFR, PSMA and other receptors); characteristics of the tumor microenvironment (specific metabolites, proteases; or the acidic characteristics of the cancer cell interior (pHi: 5.0-6.0) or the interstitial fluid between cells (pHe: 6.4-6.9), which originates from the lactic acid metabolites produced after the cancer cells quickly take up glucose). Secondly, the above-mentioned specific characteristics should be used as targets for precise positioning by the developed imaging technology to effectively achieve specific aggregation of imaging agents at the tumor site. The usual means of achieving aggregation at the tumor site are: using the specific receptors of cancer cells to achieve specific binding of imaging agents to them; using the acidity or other characteristics of the tumor microenvironment to retain and enrich imaging agents at the tumor site through chemical means; using the high permeability and retention effect (EPR) of tumor tissue to achieve selective local enrichment of some nanoparticles.

[0011] 3) The imaging agent used must be safe and can be degraded or cleared from the body within a short period of time after use. There should be little tissue residue and no adverse reactions. If a metabolic reaction occurs, the metabolites of the imaging agent should be harmless to the body.

[0012] The main clinical transformation of intraoperative imaging technology for solid tumors uses the following technical means:

[0013] 1) Folic acid-fluorescent imaging molecule conjugates: On Target Laboratories has currently started clinical trials for intraoperative imaging of lung cancer and ovarian cancer. Its advantage is that for the selected tumor type, the target selection strategy is clear (except for individual tissues, the expression level of folate receptors in normal tissues is very low, but it is overexpressed on the surface of some tumor cells). Its disadvantage is that the application range is relatively narrow (it can only be used for specific tumors with high expression of folate receptors), and from the perspective of its imaging principle and clinical data, the quality of tumor-specific imaging is somewhat defective (background contrast; the boundary between tumor and healthy tissue cannot be clearly imaged). The reason may be that the imaging molecules that normally circulate in the body (not bound to tumor receptors) can fluoresce under the irradiation of the excitation light source, causing background fluorescence, or false positive images of non-tumor sites ("off-target" phenomenon, for example, some healthy tissues such as kidneys also have different degrees of folate receptors), or due to the heterogeneity of tumors mentioned above, the folate expression level of tumor tissues may not be completely uniform, thus causing image quality defects. Judging from clinical data, background clearance is related to the dosage, and it basically takes 24 hours to 4 days to clear the background. The effect of tumor imaging (cancer / normal tissue ratio, TNR, is 2-3 times) is average.

[0014] 2) Antibody (mAB)-fluorescent imaging molecule conjugates: There are currently several clinical studies for intraoperative imaging navigation of brain gliomas (mAB targeting EGFR receptors, Cetuximab) and colorectal cancer, lung cancer, etc. (targeting CEA receptors). Compared with the design of folic acid-fluorescent imaging molecule conjugates, the antibody molecules used for targeting have good biocompatibility, a very long in vivo circulation cycle (3-7 days), and a clear target and binding mechanism for the selected tumor type. Its disadvantages are also obvious. The very long circulation time of antibody molecules will also cause high background fluorescence. There are also other problems, such as a relatively narrow application range (can only be used for tumors with high expression of specific receptors), false positive images of non-tumor sites (the selected target may exist in healthy tissues), and the heterogeneous characteristics of tumors mentioned above. From the clinical and animal research data, the effect of tumor imaging of this technology (cancer / normal tissue ratio, TNR, is 2-5 times) is acceptable, but the image is usually accompanied by strong background fluorescence.

[0015] 3) Peptide-fluorescent imaging molecule conjugates: In view of the characteristics of several tumor cells and tumor microenvironment mentioned above, peptides can be used to selectively target fluorescent imaging molecules to the tumor site. Currently, there are several designs in the direction of research and development and clinical transformation: R.Tsien and Avelas Biosciences, Inc. use a special U-shaped peptide combination design, in which one end of the peptide is positively charged under physiological conditions (the end of this peptide segment is linked to the fluorescent imaging molecule), and the other end of the peptide is negatively charged under physiological conditions. The two segments of the peptide are connected by a connector, which can be cut by the protease present in the tumor microenvironment. After the disconnection, the peptide with the fluorescent imaging molecule presents a positive charge, which can be attracted by the negative charge on the surface of the cancer cell and adsorbed on the surface. Later, it enters the cancer cell through the cell endocytosis mechanism, and the imaging agent molecules that enter the cancer cell can emit fluorescence under the irradiation of the excitation light source. It can be seen that this type of imaging agent needs to enter the body within a limited time (even after adding a long-circulating PEG molecule, the half-life is only more than 20 minutes), and the time window for completing this series of actions is not sufficient, resulting in poor imaging results (the cancer / normal tissue ratio is 2-3 times). Donald M. Engelman's team at Yale University proposed a different design, which conjugates fluorescent molecules with a polypeptide. The signal targeted by the polypeptide is the acidic characteristics of the tumor microenvironment. Under normal physiological conditions, the polypeptide is negatively charged and becomes neutral in an acidic environment. Under neutral conditions, the lipophilicity of the polypeptide increases, driving the polypeptide to deposit on the surface of cancer cells, transmembrane and other behaviors, and achieving specific enrichment of fluorescent molecules at the tumor site. From the results of in vivo imaging, this technology achieves tumor imaging quality (TNR is about 6), but the error range of the reported data is too large and the effect is poor. Lumicell's design is to connect the fluorescent imaging molecule and another molecule that can absorb fluorescence through a polypeptide. The selected polypeptide can be cut under the catalysis of some common proteases in the tumor microenvironment (such as Cathepsin K, L, S), so that the fluorescent molecule and the molecule that actively absorbs fluorescence are separated and then fluoresce in the presence of an excitation light source. Such a design can reduce the background fluorescence during the circulation process, because the entire imaging agent molecule does not fluoresce before reaching the tumor microenvironment. By connecting a PEG, the circulation time can be achieved to about 24 hours, and the quality of tumor imaging (TNR ratio is 3-5) is poor. In addition, another disadvantage of this technology is whether the selected polypeptide sequence can achieve highly specific tumor targeting.

[0016] 4) Nanoparticle-fluorescent molecule imaging agent: In the field of medical imaging, nanoparticles are widely used, and the main categories are liposome nanoparticles, inorganic nanoparticles, and polymer nanoparticles. Definity(R) is a phospholipid liposome approved by Lantheus Medical (now BMS) in 2001, which is used to stabilize perfluoropropane (C3F8) bubbles and is used as an ultrasound imaging agent. There are many types of inorganic nanoparticles (silicon dioxide; iron oxide; quantum dots; carbon nanotubes, etc.). The difficulty in the clinical application of inorganic nanoparticles is usually safety, and it is usually difficult to achieve specific tumor fluorescence imaging by introducing fluorescent groups only through chemical modification of the surface of nanoparticles. U.Wiesner et al. successfully promoted several early clinical studies, using small-size (5-20nm) SiO2 nanoparticles so that the nanoparticles used can be cleared from the kidneys to improve safety, and the core of the nanoparticles is embedded with fluorescent molecules, and the surface of the nanoparticles introduces specific targeting groups, which can achieve specific tumor fluorescence imaging. The fluorescent molecules introduced by this method can overcome the possible defects of fluorescence quenching due to aggregation of conventional nanoparticle-fluorescent molecule conjugates, but the reported half-life is short (10-30 minutes), the tumor imaging effect is acceptable, and the TNR is 5-10 (the reported data has a large error range), but the liver absorption is very high (the tumor / liver ratio is about 2). The author believes that although small-sized nanoparticles (less than 20nm) can be cleared by the kidneys, their clinical risks (such as diffusion through the BBB to the brain, etc.) cannot be ruled out. The typical structure of polymer nanoparticles is the use of amphiphilic diblock polymers, such as PEG-PLGA, PEG-PEG-Glutamate, and PEG-Aspartate, which are several types of removable (PEG) / degradable (another block) polymers that are currently being carried out in clinical work. Based on the previous work of Langer et al. on pH-responsive polymer microspheres (the polymer main chain contains amino groups that can be protonated at around pH 6.5), Kim et al. introduced PEG blocks to construct pH-responsive amphiphilic diblock copolymers, which achieved the dissolution of nanoparticles in the weakly acidic environment of the tumor (the inner core of the nanoparticles ionizes in an acidic environment, generating charge repulsion that destroys the energy balance of the amphiphilic assembly). Summary of the invention

[0017] In view of the above-mentioned shortcomings of the prior art, the purpose of the present application is to provide a functionalized diblock copolymer and a preparation method and use thereof, so as to solve the problems in the prior art.

[0018] To achieve the above objectives and other related objectives, the present application provides a functionalized diblock copolymer having a chemical structure as shown in Formula III:

[0019]

[0020] In formula III, m3=22-1136, n3=10-500, p3=0.5-50, q3=0-500, r3=0-200;

[0021] s 31 =1~10,s 32 =1~10,s 33 =1~10,s 34 =1~10;

[0022] L 31 , L 32 , L 33 , L 34 is a connecting group;

[0023] R'1, R'2, R'3, R'4 are each independently selected from H, C1-C20 alkyl, C3-C10 cycloalkyl;

[0024] A3 is selected from protonatable groups;

[0025] C3 is selected from a fluorescent molecular group;

[0026] D3 is selected from the group of delivery molecules;

[0027] E3 is selected from hydrophilic / hydrophobic groups;

[0028] T3 is selected from a capping group;

[0029] EG3 is selected from a capping group.

[0030] Another aspect of the present invention provides polymer particles prepared from the functionalized diblock copolymer.

[0031] Another aspect of the present invention provides the use of the functionalized diblock copolymer or the polymer particles in the preparation of imaging probe agents and pharmaceutical preparations.

[0032] Another aspect of the present invention provides a composition comprising the functionalized diblock copolymer or the polymer particles. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Fluorescence intensity of the polymer (IB015-038-01) nano-imaging agent solution of Example 6.1.5 measured at different solution pH values ​​(left) and the corresponding fluorescence intensity normalized against solution pH value (right)

[0034] Figure 2Fluorescence intensity of the polymer (IB015-055-01) nano-imaging agent solution of Example 11.1.5 measured at different solution pH values ​​(left) and the corresponding fluorescence intensity normalized against solution pH value (right)

[0035] Figure 3 The fluorescence intensity of the polymer (IB015-055-01) nano-imaging agent solution of Example 11.1.5 measured at different solution pH values ​​is combined with the fluorescence intensity of the nano-imaging agent solution added to the solvent DMF to plot

[0036] Figure 4 The fluorescence intensity of the polymer (IB015-050-01) nano-imaging agent solution of Example 10.1.5 measured at different solution pH

[0037] Figure 5 Upper left: Fluorescence intensity of the nano-imaging agent solution of polymer IB015-059-01 (Example 11.2.5) at different pH (aqueous solution); Upper right: Fluorescence intensity of the nano-imaging agent solution of polymer IB015-059-01 (Example 11.2.5) at different pH (aqueous solution) (and in DMF and EtOH); Lower left: The nano-imaging agent solution of polymer IB015-059-01 (Example 11.2.5) shows a blue shift in the fluorescence emission peak (normalization of the fluorescence emission intensity)

[0038] Figure 6 These are 24-hour in vivo imaging and fluorescence imaging photos of ex vivo organs and lymph nodes of 4T1 subcutaneous model Balb / c tumor-bearing mice after injection of the nano fluorescent imaging agent of Example 11.1.5 (IB015-055-01).

[0039] Figure 7 for Figure 6 Quantitative fluorescence intensity values ​​of isolated organs.

[0040] Figure 8 These are 24-hour in vivo imaging and fluorescence imaging photos of ex vivo organs and lymph nodes of 4T1 subcutaneous model Balb / c tumor-bearing mice after injection of the nano fluorescent imaging agent of Example 6.1.5 (IB015-038-01).

[0041] Fig. 9 for Figure 8 Quantitative fluorescence intensity values ​​of isolated organs.

[0042] Fig.10 These are fluorescent imaging photos of the ex vivo organs and lymph nodes of 4T1 subcutaneous model Balb / c tumor-bearing mice injected with the nano fluorescent imaging agent of Example 10.1.5 (IB015-050-01) (24 hours after injection).

[0043] Fig.11 for Fig.10 Quantitative fluorescence intensity values ​​of isolated organs. DETAILED DESCRIPTION

[0044] In order to make the invention objectives, technical solutions and beneficial technical effects of the present application clearer, the present application is further described in detail below in conjunction with embodiments. People familiar with this technology can easily understand other advantages and effects of the present application from the contents disclosed in this specification.

[0045] In the present application, "diblock copolymer" generally refers to a polymer formed by linking two polymer segments with different properties.

[0046] In the present application, "protonatable group" generally refers to a group that can combine with a proton, that is, can bind at least one proton. These groups generally have a lone pair of electrons, so that at least one proton can be bound through the protonatable group.

[0047] In the present application, "degradation modulating group" generally refers to a group that can change the degradability of a compound in vivo.

[0048] In the present application, "fluorescent molecule group" generally refers to a class of groups corresponding to fluorescent molecules. Compounds containing these groups usually have characteristic fluorescence in the ultraviolet-visible-near infrared region, and their fluorescence properties (excitation and emission wavelength, intensity, lifetime, polarization, etc.) can change with the nature of the environment.

[0049] In the present application, "delivery molecule group" generally refers to various molecules that can be connected to the main chain of the block copolymer through the side chain in the form of chemical bonding, or interact with the hydrophobic end side chain group of the block copolymer through physical forces (such as charge force, hydrogen bond, van der Waals force, hydrophobic force, etc.), and can be delivered through nanoparticles formed by self-assembly of the block polymer in aqueous solution.

[0050] In the present application, "hydrophilic / hydrophobic group" generally refers to a group having a certain hydrophilicity or lipophilicity.

[0051] In the present application, "alkyl" generally refers to a saturated aliphatic group, which may be straight or branched. For example, C1-C20 alkyl generally refers to an alkyl group of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms. Specific alkyl groups may include, but are not limited to, methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl.

[0052] In the present application, "alkenyl" generally refers to an unsaturated aliphatic group and includes a C=C bond (carbon-carbon double bond, olefinic bond), which may be straight chain or branched. For example, C2-C10 alkenyl generally refers to alkenyl groups of 2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Specific alkenyl groups may include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl.

[0053] In the present application, "alkynyl" generally refers to an unsaturated aliphatic group, and includes a C≡C bond (carbon-carbon triple bond, acetylenic bond), and can be straight or branched. For example, C2-C10 alkynyl generally refers to an alkynyl group of 2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Specific alkynyl groups may include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.

[0054] In the present application, "cycloalkyl" generally refers to saturated and unsaturated (but not aromatic) cyclic hydrocarbons. For example, C3-C10 cycloalkyl generally refers to cycloalkyl groups of 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Specific cycloalkyl groups may include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl. For cycloalkyl, the term also includes saturated cycloalkyl in which optionally at least one carbon atom can be replaced by a heteroatom, and the heteroatom can be selected from S, N, P or O. In addition, monounsaturated or polyunsaturated (preferably monounsaturated) cycloalkyl without heteroatoms in the ring should belong to the term cycloalkyl as long as it is not an aromatic system.

[0055] In the present application, "aromatic group" generally refers to a group having at least one aromatic ring system and no heteroatoms, and the aromatic group may be substituted or unsubstituted, and the specific substituents may be selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, hydroxyl, halogen, etc. Specific aromatic groups may include but are not limited to phenyl, phenol, phenylamino, etc.

[0056] In the present application, "heteroaryl" generally refers to a group having at least one aromatic ring and optionally containing one or more (e.g., 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur, and the heteroaryl group may be substituted or unsubstituted, and specific substituents may be selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, hydroxyl, halogen, etc. Specific heteroaryl groups may include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole, or quinazoline.

[0057] In the present application, "targeted preparations" generally refer to preparations that can specifically direct a particular compound to the desired site (target area) where it is required to act. These preparations can use polymer particles as carriers and generally have relatively low, no, or almost no interaction with non-target tissues.

[0058] In the present application, "imaging probe" generally refers to a class of substances that can enhance the imaging observation effect after being injected (or taken) into human tissues or organs.

[0059] In this application, "individual" generally includes humans, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cows, etc.

[0060] After extensive practical research, the inventors of the present application have provided a class of functionalized diblock copolymers. These diblock copolymers can be modified through innovative chemical modification strategies to make the polymers pH-responsive and degradable under corresponding pH conditions, so that they can be used as targeting agents in various fields. The present invention was completed on this basis.

[0061] The first aspect of the present application provides a functionalized diblock copolymer, wherein the functionalized diblock copolymer has the chemical structural formula shown below:

[0062]

[0063] In formula III, m3=22-1136, n3=10-500, p3=0.5-50, q3=0-500, r3=0-200;

[0064] s 31 =1~10,s 32 =1~10,s 33 =1~10,s 34 =1~10;

[0065] t 31 =1~10,t 32=1~10,t 33 =1~10,t 34 =1~10;

[0066] L 31 , L 32 , L 33 , L 34 is a connecting group;

[0067] R'1, R'2, R'3, R'4 are each independently selected from H, C1-C10 alkyl, C3-C10 cycloalkyl;

[0068] A3 is selected from protonatable groups;

[0069] C3 is selected from a fluorescent molecular group;

[0070] D3 is selected from the group of delivery molecules;

[0071] E3 is selected from hydrophilic / hydrophobic groups;

[0072] T3 is selected from a capping group;

[0073] EG3 is selected from a capping group.

[0074] The compound of formula III is a diblock copolymer of polyethylene glycol and polylactide, wherein the side chain structure of the polylactide block is randomly distributed, which is represented by ran in the general formula.

[0075] In the compound of formula III, L 31 , L 32 , L 33 , L 34 It is usually a linking group, which is mainly used to connect the main chain of the functionalized diblock copolymer and its side chain. 31 , L 32 , L 33 , L 34 can be independently selected from S, O, N, -OC(O)-, -C(O)O-, SC(O)-, -C(O)-, -OC(S)-, -C(S)O-, -SS, C(R1)=N-, -N=C(R2), C(R3)=NO, -ON=C(R4), -N(R5)C(O)-, -C(O)N(R6), -N(R7)C(S), C(S)N(R8)-, -N(R9)C(O)N(R 10 ), -OS(O)O-, -OP(O)O-, -OP(O)N-, -NP(O)O-, -NP(O)N-, among which, R1~R 10 Each is independently selected from H, C1-C10 alkyl, and C3-C10 cycloalkyl.

[0076] In another specific embodiment of the present application, L 31 , L 32 , L 33 , L 34 can be independently selected from S.

[0077] In the compound of formula III, A3 is usually selected from a protonatable group, and the group and the polymer block in which the group is located are mainly used to adjust the pH response of the polymer. In a specific embodiment of the present application, A3 can be selected from Among them, R 11 and R 12 Each is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and aromatic. In another specific embodiment of the present application, A3 can be selected from Wherein, a=1-10, and a is a positive integer.

[0078] In another specific embodiment of the present application, A3 can be selected from Among them, R 11 Selected from ethyl, R 12 In another specific embodiment of the present application, A3 can be selected from Wherein, a=1-10, and a is a positive integer.

[0079] In another specific embodiment of the present application, A3 can be selected from Among them, R 11 Selected from ethyl, R 12 Selected from ethyl.

[0080] In another specific embodiment of the present application, A3 can be selected from Among them, R 11 Selected from n-propyl, R 12 Selected from n-propyl.

[0081] In another specific embodiment of the present application, A3 can be selected from Among them, R 11 Selected from n-propyl, R 12 Selected from n-butyl.

[0082] In another specific embodiment of the present application, A3 can be selected from Among them, R 11 Selected from n-butyl, R 12 Selected from n-butyl.

[0083] In the compound of formula III, C3 is usually selected from fluorescent molecular groups, and the group and the block of the polymer where the group is located are mainly used to introduce fluorescent molecular groups. The fluorescent molecular groups can specifically include but are not limited to one or more combinations of organic reagents, metal chelates, etc. In a specific embodiment of the present application, C3 can include fluorescent molecules such as ICG, METHYLENE BLUE, CY3, CY3.5, CY5, CY5.5, CY7, CY7.5, BDY630, BDY650, BDY-TMR, Tracy 645, Tracy 652, etc.

[0084] In another specific embodiment of the present application, C3 may include indocyanine green (ICG), and ICG may be connected to the side chain of the block via an amide bond.

[0085] In the formula III compound, D3 can be selected from a delivery molecule group, and the block of the polymer where the group and the group are located is mainly used to introduce various molecular groups that can be delivered by block copolymers. These molecular groups can be, but are not limited to, fluorescence quenching groups, drug molecule groups (e.g., precursor molecules of photodynamic therapy, chemotherapeutic drug molecules, biopharmaceutical molecules, etc.). In a specific embodiment of the present application, the fluorescence quenching group can be selected from BHQ-0, BHQ-1, BHQ-2, BHQ-3, BHQ-10, QXL-670, QXL-610, QXL-570, QXL 520, QXL-490, QSY35, QSY7, QSY21, QXL 680, Iowa Black RQ, Iowa Black FQ. In a specific embodiment of the present application, the drug molecule group can be selected from chemotherapeutics, specifically groups corresponding to drug molecules such as nucleic acid drugs, paclitaxel, cisplatin, doxorubicin, irinotecan, SN38, etc. In another specific embodiment of the present application, the drug molecule group can be selected from chemical drugs for photodynamic therapy, specifically, the group corresponding to 5-ALA and its derivative structure (fat chain, etc.), and the specific chemical structure of the group is as follows:

[0086]

[0087] In the compound of formula III, E3 can be selected from a hydrophilic / hydrophobic group, and the group and the polymer block where the group is located are mainly used to adjust the hydrophobic / hydrophilic degree of the polymer hydrophobic block. In a specific embodiment of the present application, E3 can be selected from H, C1-C18 alkyl, -OR 11 , -SR 12 , where R 11 ~R 12Each is independently selected from H, C1-C18 alkyl, C3-C10 cycloalkyl, aromatic group, heteroaryl group, and the hydrophilic / hydrophobic group may also be preferably selected from -(CH2-CH2-O)nH (n=1-30), -(R 14 )-NH2,-(R 15 )-OH, where R 14 is selected from a methylene group (-CH2)n (n=1-18) with a length of 1-18, R 15 Independently selected from methylene (-CH2-)n (n=1-18) with a length of 1-18, glycosyl, the glycosyl is preferably a monosaccharide and / or a polysaccharide, the hydrophilic / hydrophobic group can also be preferably selected from cholesterol and cholesterol derivatives, hydrophobic vitamins, the hydrophobic vitamins are preferably selected from vitamin E and / or vitamin D, - zwitterionic group (chemical structure is as follows), the hydrophilic / hydrophobic group can also be preferably selected from the above groups used alone or in combination of two or more different groups, when used in combination, compared with the general formula of formula II, r3 is the total number of hydrophilic / hydrophobic groups, r 3,A is the total number of hydrophilic groups, r 3,B is the total number of hydrophobic groups.

[0088] The chemical structural formula of the cholesterol and cholesterol derivatives, vitamin D and vitamin E can be as shown in one of the following:

[0089]

[0090] The chemical structural formula of the zwitterionic group can be as shown below:

[0091]

[0092] In another specific embodiment of the present application, E3 can be selected from n-nonyl group.

[0093] In another specific embodiment of the present application, E3 can be selected from n-octyl group.

[0094] In another specific embodiment of the present application, E3 can be selected from n-butane.

[0095] In another specific embodiment of the present application, E3 can be selected from n-propyl.

[0096] In another specific embodiment of the present application, E3 can be selected from ethyl group.

[0097] In another specific embodiment of the present application, E3 can be selected from methyl.

[0098] In another specific embodiment of the present application, E3 can be selected from n-octadecyl.

[0099] In another specific embodiment of the present application, E3 can be selected from n-heptadecanyl.

[0100] In another specific embodiment of the present application, E3 can be selected from cholesterol.

[0101] In another specific embodiment of the present application, E3 can be selected from cholesterol derivatives.

[0102] In another specific embodiment of the present application, E3 can be selected from hydroxyethyl.

[0103] In another specific embodiment of the present application, E3 can be selected from hydroxymethyl.

[0104] In another specific embodiment of the present application, E3 can be selected from hydroxypropyl.

[0105] In another specific embodiment of the present application, E3 can be selected from hydroxybutyl.

[0106] In another specific embodiment of the present application, E3 can be selected from zwitterionic groups.

[0107] In another specific embodiment of the present application, E3 can be selected to be a mixture of a zwitterionic group and a n-nonyl group.

[0108] In another specific embodiment of the present application, E3 can be selected to be a mixture of a zwitterionic group and an n-octyl group.

[0109] In the compound of formula III, T3 can generally be the end group of different PEG initiators. In a specific embodiment of the present application, T3 can be selected from -CH3, H.

[0110] In the compound of formula III, EG3 can generally be produced by adding different end-capping agents after polymerization. In a specific embodiment of the present application, EG3 can be selected from -YR 13 , wherein Y is selected from O, S, N, R 13 Selected from H, C1-C20 alkyl, C3-C10 cycloalkyl, and aromatic group.

[0111] In another specific embodiment of the present application, EG3 can be selected from -OH.

[0112] In the compound of formula III, the molecular weight of the polyethylene glycol (PEG) block can be 1000-50000 Da, 1000-2000 Da, 2000-3000 Da, 3000-4000 Da, 4000-5000 Da, 5000-6000 Da, 6000-7000 Da, 7000-8000 Da, 8000-9000 Da, 9000-10000 Da, 10000-12000 Da, 12000-14000 Da, 14000-16000 Da, 16000-18000 Da, 18000-20000 Da, 22000-24000 Da, 24000-26000 Da, 26000-28000 Da, 28000-30000 Da, 30000-32000 Da, 32000-34000 Da, 34000-36000 Da, 36000-38000 Da, 38000-40000 Da, 40000-42000 Da, 42000-44000 Da, 44000-46000 Da, 46000-48000 Da, or 48000-50000 Da,The molecular weight of the polylactide block can generally be 5000-50000 Da, 5000-6000 Da, 6000-7000 Da, 7000-8000 Da, 8000-9000 Da, 9000-10000 Da, 10000-12000 Da, 12000-14000 Da, 14000-16000 Da, 16000-18000 Da, 18000-20000 Da, 22000-24000 Da, 24000-26000 Da, 26000-28000 Da, 28000-30000 Da, 30000~32000Da, 32000~34000Da, 34000~36000Da, 36000~38000Da, 38000~40000Da, 40000~42000Da, 42000~44000Da, 44000~46000Da, 46000~48000Da, 48000~50000Da, 52500~55000Da, 57500~60000Da, 60000~62500Da, 62500~65000Da, 67500~70000Da, 72500~75000Da, 77500~80000Da, 82500~8500Da, 85000~87500Da, 87500~90000Da, 90000~92500Da, 92500~95000Da, 95000~97500Da, 97500~100000Da, 100000~102500Da, 102500~105000Da, 105000~107500Da, 107500~110000Da, 110000~112500Da, 112500-115000 Da, 115000-117500 Da, 117500-120000 Da, 120000-122500 Da, 122500-125000 Da, 125000-127500 Da, or 127500-130000 Da. ,

[0113] In a specific embodiment of the present application, the molecular weight of the polyethylene glycol block may be 2000-10000 Da, and the molecular weight of the polylactide block may generally be 4000-26000 Da, 20000-40000 Da, or 40000-60000 Da.

[0114] In the compound of formula III, m3 can be 22-1136, 22-32, 32-42, 42-52, 52-62, 62-72, 72-82, 82-92, 92-102, 102-122, 122-142, 142-162, 162-182, 182-202, 202-242, 242-282, 282-322, 322-362, 362-402, 402-442, 442-482, 482-522, 522-562, 562-602, 602-642, 642-682, 682-722, 722-762, 762-802, 802-842, 842-882, 882-902, 902-942, 942-982, or 982-1136.

[0115] n3 may be 10 to 500, 10 to 15, 15 to 20, 20 to 25, 25 to 30, 30 to 35, 35 to 40, 40 to 45, 45 to 50, 45 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100, 100 to 120, 120 to 140, 140 to 160, 160 to 180, 180 to 200, 200 to 220, 220 to 240, 240 to 260, 260 to 280, 280 to 300, 300 to 320, 320 to 340, 340-360, 360-380, 380-400, 400-420, 420-440, 440-460, 460-480, or 480-500.

[0116] p3 can be 0.5-50, 0-0.5, 0.5-1, 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-25, 25-30, 30-35, 35-40, 40-45, or 45-50.

[0117] q3 can be 0-500, 0-1, 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-120, 120-140, 140-160, 160-180, 180-200, 200-220, 220-240, 240-260, 260-280, 280-300, 300-320, 320-340, 340-360, 360-380, 380-400, 400-420, 420-440, 440-460, 460-480, or 480-500.

[0118] r3 may be 0-200, 0-1, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, 9-10, 10-15, 15-20, 25-30, 30-35, 35-40, 40-45, 45-50, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-120, 120-140, 140-160, 160-180, 180-200, or 200-220.

[0119] r3 can be the total number of hydrophilic / hydrophobic groups, r 3,A can be the total number of hydrophilic groups, r 3,B can be the total number of hydrophobic groups, correspondingly, (r 3,A +r 3,B )=1-200, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, 9-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-120, 120-140, 140-160, 160-180, or 180-200, r 3,AIt can be <151, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, 9-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-120, 120-140, or 140-150.

[0120] s 31 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0121] s 32 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0122] s 33 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0123] s 34 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0124] t 31 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0125] t 32 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0126] t 33 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0127] t 34 It may be 1-10, 1-2, 2-3, 3-4, 4-5, 6-7, 6-7, 7-8, 8-9, or 9-10.

[0128] In a specific embodiment of the present application, in formula III, m3 = 22 to 1136, n3 = 10 to 500, p3 = 1 to 50, q3 = 0, and r3 = 0. In the products (e.g., polymer particles) prepared by these polymers, the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (e.g., when near-infrared is used as the excitation light source) due to the FRET (Fluorescence Resonance Energy Transfer) effect. After administration to an individual, the drug can be enriched in a target site (e.g., a tumor site) through EPR (Enhanced Permeation and Retention) passive targeting (or other tissue uptake methods). Since the target site has a special pH environment (e.g., an acidic environment), the protonable group (i.e., the A3 group) can be protonated within this pH range, and the charge repulsion generated by the protonation and the increase in the solubility of the polymer drive the dispersion of the polymer particles. The FRET effect of the fluorescent group carried by the discrete single polymer chain segment is weakened or even completely eliminated, and the polymer molecules in a discrete state enriched in the target site can emit fluorescence under certain excitation conditions (e.g., when near-infrared is used as the excitation light source).

[0129] In a preferred embodiment of the present application, the chemical structural formula of the functionalized diblock copolymer is shown as one of the following:

[0130]

[0131]

[0132] Wherein, m3=22-1136, preferably 44-226, n3=10-500, preferably 30-200, p3=0.5-5;

[0133] In a specific embodiment of the present application, in formula III, m3=22-1136, n3=10-500, p3=0.5-50, q3=0, and r3=1-200. In the products (e.g., polymer particles) prepared by these polymers, the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (e.g., when near-infrared is used as the excitation light source) due to the FRET effect. The addition of hydrophilic / hydrophobic groups (i.e., E3 groups) increases the stability of the polymer particles, enhances the FRET effect of the polymer particles (more complete fluorescence quenching), and changes the acidity sensitivity of the polymer particles. After administration to an individual, the target site (e.g., tumor site) can be enriched through EPR passive targeting (or other tissue uptake methods). Since the target site has a special pH environment (e.g., acidic environment), the protonable group (i.e., A3 group) can be protonated within this pH range. The charge repulsion generated by its protonation and the increase in the solubility of the polymer drive the dispersion of the polymer particles. The fluorescent groups carried by the discrete single polymer chain segments have a weakened or even completely eliminated FRET effect. The polymer molecules in the discrete state enriched in the target site can emit fluorescence under certain excitation conditions (e.g., when near infrared is used as the excitation light source). The experimental results show that compared with the polymer without the hydrophobic group E3, Example 6.1.5 introduces 20 -C9H 19 The polymer (IB015-038-01) of this embodiment achieved highly specific tumor fluorescent labeling (TNR=13) of tumors in tumor-bearing mice in the in vivo imaging experiment. Figure 8 and 9 Other experimental results show that after the introduction of the hydrophilic side chain -C2H4-OH (Example 11.2.5), the emission of the polymer connected with ICG undergoes a large blue shift (as shown in the attached Figure 5 The reason is that the hydroxyl groups of the hydrophilic side chains improve the relative hydrophilicity of the hydrophobic block and provide a hydrogen bond with the oxygen of the -C(=O)- of the ester bond on the polymer main chain, which makes the polymer more compact in the core. This compact aggregation state causes the change of the molecular state of ICG, which in turn causes the change of its emission wavelength. In the in vivo imaging experiment, the polymer of Example 11.1.5 (IB015-055-01, the number of -C2H4-OH modifications is 24) was used to achieve highly specific tumor fluorescent labeling (TNR=21) of tumors in tumor-bearing mice, as shown in the attached figure. Figure 6 and7 shown.

[0134] In a preferred embodiment of the present application, the chemical structure of the functionalized diblock copolymer is as follows:

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] Among them, m3=22~1136, preferably 44~226, n3=10~500, preferably 30~200, p3=0.5~5, r3=1~200.

[0151] In a preferred embodiment of the present application, the chemical structure of the functionalized diblock copolymer is as follows:

[0152]

[0153]

[0154] Wherein, m3=22-1136, preferably 44-226, n3=10-500, preferably 30-200, p3=0.5-5, (r 3,A

[0155] +r 3,B )=1~200.

[0156] In another preferred embodiment of the present application, m3=44-226, n3=50-200, p3=0.5-5, r3=10-40.

[0157] In a specific embodiment of the present application, in formula III, m3 = 22 to 1136, n3 = 10 to 500, p3 = 0.5 to 50, q3 = 1 to 500, and r3 = 0. In the products (e.g., polymer particles) prepared by these polymers, the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (e.g., when near infrared is used as the excitation light source) due to the FRET effect, and the delivery molecule group (i.e., the D3 group) is connected to the main chain of the functionalized diblock polymer. After being administered to an individual, the drug can be enriched in the target site (e.g., tumor site) through EPR passive targeting (or other tissue uptake methods). Since the target site has a special pH environment (e.g., acidic environment), the protonable group (i.e., A3 group) can be protonated within this pH range. The charge repulsion generated by the protonation and the increase in the solubility of the polymer drive the dispersion of the polymer particles. The fluorescent groups carried by the discrete single polymer chain segments have a weakened or even completely eliminated FRET effect. The polymer molecules in the discrete state enriched in the target site can emit fluorescence under certain excitation conditions (e.g., when near-infrared is used as the excitation light source). In addition to the fluorescent molecular groups carried by the polymer particles, the delivery molecular groups connected to the side chains can continue to hydrolyze into corresponding molecules under the specific pH conditions of the target site after the polymer is disintegrated. These molecules can play a corresponding role in the target site. For example, the delivery molecule group can be a group corresponding to 5-ALA, which can provide 5-ALA molecules after hydrolysis. 5-ALA can be efficiently enriched in cancer cells with accelerated metabolism within a few hours, complete biosynthesis to form Protoporphyrin (after Protoporphyrin enters cancer cells, it stays / "traps" in cancer cells for a long time because its metabolism process is blocked). At this time, under the irradiation of near-infrared or 400nm excitation light, it can efficiently emit fluorescence. On the basis of the existing ICG fluorescent molecules (780nm excitation), dual wavelengths are separately excited for fluorescence, and the fluorescence image of the tumor site is enhanced or the boundary is confirmed or whether it is cancerous or not. In addition, 5-ALA is a proven precursor of photodynamic therapy drugs. In this embodiment, we creatively introduce and deliver 5-ALA, which not only enhances the effect of tumor-specific imaging, but also performs photodynamic therapy of the tumor site while implementing tumor imaging. In addition to the fluorescent molecular groups carried by the polymer particles, the water-insoluble anticancer drugs connected to the side chains form a water-soluble, safe and stable drug injection preparation. On the one hand, this drug preparation greatly increases the solubility of hydrophobic drugs in the blood and reduces their direct contact with the blood, thereby improving the stability of the drug in the body, reducing the toxic side effects of the drug in the body, and retaining the high anti-tumor activity of the drug itself.After the polymer dissolves, it can continue to hydrolyze into corresponding molecules under the specific pH conditions of the target site. These molecules can play a corresponding role at the target site. For example, the delivery molecule group can be a group corresponding to SN-38, which can provide SN-38 after hydrolysis, overcoming the shortcomings of low drug loading and strong side effects of traditional hydrophobic anti-tumor drug delivery systems, improving drug safety and achieving the effect of killing cancer cells. In addition, nucleic acid drugs can also be chemically connected or delivered by physical action on the side chain to form a nano-preparation of nucleic acid drugs, which can significantly improve the in vivo stability of nucleic acid drugs. After the polymer dissolves, it can continue to hydrolyze (corresponding to chemical connection) or release (corresponding to physical action delivery) into corresponding nucleic acid drug molecules under the specific pH conditions of the target site to exert drug efficacy at the lesion site.

[0158] In a preferred embodiment of the present application, the chemical structure of the functionalized diblock copolymer is as follows:

[0159]

[0160]

[0161]

[0162] Among them, m3=22~1136, preferably 44~226, n3=10~500, preferably 30~200, p3=0.5~5, q3=0~500,

[0163] It is preferably 10 to 200.

[0164] In another preferred embodiment of the present application, m3=44~226, n3=50~200, p3=0.5~5, q3=50~200.

[0165] The functionalized diblock copolymer provided in the present application usually has a lower critical micelle concentration, thereby reducing the difficulty of preparing the polymer self-assembled particles, thereby ensuring that the obtained polymer particles have good solution stability and blood stability. For example, the critical micelle concentration (CMC) of the functionalized diblock copolymer can be <50μg / mL, <45μg / mL, <40μg / mL, <35μg / mL, <30μg / mL, <25μg / mL, <20μg / mL, <16μg / mL, <14μg / mL, <12μg / mL, <10μg / mL, ≤9μg / mL, ≤8μg / mL, ≤7μg / mL, ≤6μg / mL, ≤5μg / mL, ≤4μg / mL, or a smaller critical micelle concentration.

[0166] The second aspect of the present application provides a polymer particle, which is prepared by the functionalized diblock copolymer provided by the first aspect of the present invention. The above-mentioned functionalized diblock copolymer can be used to form polymer particles. The fluorescent molecules distributed in the hydrophobic core of the polymer particles do not emit light under certain excitation conditions (for example, when near infrared is used as an excitation light source) due to the FRET effect. After being administered to an individual, it can be enriched in the target site (for example, a tumor site) through EPR passive targeting (or other tissue uptake methods). Since the target site has a special pH environment (for example, an acidic environment), the protonatable group can be protonated within this pH range, and the charge repulsion and water solubility generated by its protonation become stronger, driving the discreteness of the polymer particles. The fluorescent groups carried on the discrete single polymer chain segments have a weakened FRET effect or even completely eliminated. The polymer molecules in a discrete state enriched in the target site can emit fluorescence under certain excitation conditions (for example, when near infrared is used as an excitation light source). For example, the pH environment can be 6.5-6.8, which can correspond to the interstitial fluid of tumor cells, and at least part of the polymer particles can reach the target site and be in the interstitial fluid of the cells; for another example, the pH environment can also be 4.5-6.5, which can correspond to the endosomes or lysosomes in tumor cells, and at least part of the polymer particles can interact with the cells (e.g., tumor cells) in the target site, and enter the interior of the cells through the endocytosis mechanism, thereby reaching the above-mentioned pH environment. The polymer particles prepared by the functionalized diblock copolymer provided in the present application can be fully diffused in the target site to achieve clear fluorescent edges, and the functionalized diblock copolymers and / or polymer particles can be degraded in vivo. After implementation in an individual, the polymer particles or nanoparticles that fail to be targeted to the tumor site through the EPR effect cycle can be engulfed and degraded by the body's immune system (mainly macrophages, etc.) (although PEG cannot be completely degraded in vivo, PEG molecules with a molecular weight lower than 40,000Da (e.g., Roche's long-acting interferon, The Chinese product name is Pegasys, which has been approved for safe clinical use for more than ten years. The PEG involved has a molecular weight of 40,000 Da, which can be effectively cleared by the kidneys after circulating in the body, while polylactide can be gradually metabolized through hydrolysis, and some of it can be cleared by the kidneys. The polymer particles targeted to the target site through the EPR effect are dissolved into free functionalized diblock copolymer molecules. Under the pH conditions of the target site and the presence of various enzymes, they can be degraded into PEG (which can be circulated and cleared by the kidneys) and degradable block (polylactide) polymers with gradually smaller molecular weights (subsequently gradually circulated and metabolized, and some polymers can be cleared by the kidneys). These degradation pathways can improve the safety of the drug system for imaging probe applications or drug delivery system applications that are implemented (dosing) in a single or multiple times. We provided the results of in vivo animal imaging observations, showing that the block copolymers used achieved clear fluorescent imaging of tumor tissues soon after injection into the living body. After about ten days of follow-up observations, we found that the fluorescence (it is inferred that the reason for the appearance of fluorescence is that some nanoparticles are captured by the reticuloendothelial system (RES), engulfed by macrophages and other cells, and then protonated and dissolved into separate polymer segments) presented during injection into other parts (liver, kidney, pancreas, etc.) almost completely disappeared, which strongly demonstrated the biodegradation and clearance performance we designed.

[0167] The polymer particles provided in the present application may be nanosized. For example, the particle size of the polymer particles may be 10-200 nm, 10-20 nm, 20-30 nm, 30-40 nm, 40-60 nm, 60-80 nm, 80-100 nm, 100-120 nm, 120-140 nm, 140-160 nm, 160-180 nm, or 180-200 nm.

[0168] In the polymer particles provided in the present application, the polymer particles can also be modified with targeting groups, and these targeting groups can generally be modified on the surface of the polymer particles. Suitable methods for modifying the targeting groups on polymer particles should be known to those skilled in the art. For example, generally speaking, the targeting group can be connected to the T end of the functionalized diblock copolymer molecular structure. These targeting groups can generally increase the targeting efficiency of nanoparticles to liver tumors based on the EPR effect (or other tissue uptake methods). These targeting groups can be various functional molecules including but not limited to (monoclonal) antibody fragments (e.g., Fab, etc.), small molecule targeting groups (e.g., folic acid, carbohydrate compounds), polypeptide molecules (e.g., cRGD, GL2P), nucleic acid aptamers (aptamers), etc., and these functional factors can have targeting functions (e.g., functions targeted to tumor tissues). In a specific embodiment of the present application, the targeting group is selected from -GalNac (N-acetylgalactosamine).

[0169] The third aspect of the present application provides a method for preparing polymer particles provided in the second aspect of the present application. Based on the knowledge of the chemical structure of the functionalized diblock copolymer, a suitable method for forming polymer particles should be known to those skilled in the art, for example, it may include: dispersing an organic solvent including the above-mentioned functionalized diblock copolymer in water, self-assembling to provide the polymer particles; or reversing this process, dispersing water in the organic solvent of the above-mentioned functionalized diblock copolymer. During the above-mentioned dispersion process, appropriate operations can be performed to fully mix the system, for example, it can be performed under ultrasonic conditions. For another example, during the self-assembly process, it can usually be performed by removing the organic solvent from the reaction system, and the method for removing the organic solvent can specifically be a solvent volatilization method, an ultrafiltration method, etc. For another example, the CMC of a polymer is related to the ratio of the hydrophobic block to the hydrophilic block of the polymer. The higher the ratio of the hydrophobic block, the smaller its CMC. When E1, E2, and E3 are long-chain hydrophobic side chains, their content is inversely proportional to the size of the CMC; when E1, E2, and E3 are hydrophilic side chains, their content is proportional to the size of the CMC. For another example, the particle size of polymer particles can usually be adjusted by using an extrusion instrument or a microfluidic device (equipment such as a homogenizer and NanoAssemblr).

[0170] The fourth aspect of the present application provides the use of the functionalized diblock copolymer provided in the first aspect of the present application, or the polymer particles provided in the second aspect of the present application in the preparation of pharmaceutical preparations and / or reagents, so that the formed polymer nanoparticles are used as a drug delivery system, and the polymer particles can be used as a carrier to deliver drugs or imaging probe molecules. As described above, the product (e.g., polymer particles) prepared by the functionalized diblock copolymer provided in the present application has passive (enriched at the tumor site through the general EPR effect of nanoparticles) or active targeting (enriched at the tumor site through the targeting groups modified on the surface of the nanoparticles and the specific binding effect with the specific receptors on the tumor surface) function. After administration to an individual, since the target site has a special pH environment (e.g., an acidic environment), the protonable groups can be protonated within this pH range, and the charge repulsion and water solubility generated by the protonation become stronger, driving the discreteness of the polymer particles. The fluorescent groups carried by the discrete single polymer chain segments have a weakened or even completely eliminated FRET effect. The polymer molecules in a discrete state enriched at the target site can emit fluorescence under certain excitation conditions (e.g., when near-infrared light is used as the excitation light source), thereby achieving specific luminescence of the target site (e.g., the tumor site), and can thus be used as targeted imaging probes. In addition to the application of imaging probes, these polymer particles can be used to prepare targeting agents. In a specific embodiment of the present application, the above-mentioned polymer particles can be used to prepare a polymer particle-based drug delivery system to deliver various drug molecules.

[0171] In the pharmaceutical preparation or reagent provided by the present invention, polymer particles can usually be used as carriers to deliver drugs or imaging probe molecules. The functionalized diblock copolymer can be used as a single active ingredient or combined with other active components to jointly constitute an active ingredient for the above-mentioned purposes.

[0172] The fifth aspect of the present application provides a composition, comprising the functionalized diblock copolymer provided in the first aspect of the present application, or the polymer particles provided in the second aspect of the present application. As described above, the composition can be a targeting agent, and in a specific embodiment of the present application, the composition can be an imaging probe.

[0173] The composition provided in the present application may also include at least one pharmaceutically acceptable carrier, which generally refers to a carrier for administration, which itself does not induce the production of antibodies harmful to the individual receiving the composition, and has no excessive toxicity after administration. These carriers are well known to those skilled in the art, for example, relevant content about pharmaceutically acceptable carriers is disclosed in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ 1991). Specifically, the carrier can be a combination of one or more including but not limited to saline, buffer, glucose, water, glycerol, ethanol, adjuvants, etc.

[0174] In the composition provided by the present application, the functionalized diblock copolymer can be a single active ingredient, or it can be combined with other active ingredients and used in combination. The other active ingredients can be various other drugs and / or agents, which can usually act together with the above-mentioned functionalized diblock copolymer at the target site. The content of the active ingredient in the composition is usually a safe and effective amount, which should be adjustable for those skilled in the art. For example, the amount of the active ingredient applied usually depends on the weight of the subject, the type of application, the condition and severity of the disease.

[0175] The composition provided in the present application can be adapted to any form of administration, and can be parenteral administration, for example, can be pulmonary, nasal, rectal and / or intravenous injection, more specifically can be intradermal, subcutaneous, intramuscular, intraarticular, intraperitoneal, pulmonary, oral, sublingual, nasal, transdermal, vaginal, bladder perfusion, uterine perfusion, intestinal perfusion, local application after craniotomy, or parenteral administration. Those skilled in the art can select a suitable formulation form according to the administration mode, for example, the formulation form suitable for parenteral administration can include but is not limited to solution, suspension, reconstituted dry preparation or spray, etc., and for another example, the formulation form can be administered by inhalation in the form of an inhalant.

[0176] The sixth aspect of the present application provides a treatment or diagnosis method, comprising: administering to an individual an effective amount of the functionalized diblock copolymer provided in the first aspect of the present application, or the polymer particles provided in the second aspect of the present application, or the composition provided in the fifth aspect of the present application. The "effective amount" generally refers to an amount that can achieve the desired effect after an appropriate administration period, for example, imaging, treatment of diseases, etc. The above-mentioned function of pH response and degradation under corresponding pH conditions, further extended chemical modification of the functionalized diblock copolymer, can also bring about a delivery molecule with a coordinated effect, which is bonded to the polymer molecule through a degradable chemical bond, and can be matched with a unique terminal group (targeting group, a group that can improve systemic immunogenicity) to become a unique (block copolymer-transporter bond). In a specific embodiment of the present application, after use, better intraoperative tumor boundary identification, more precise removal of tumor lesions and metastatic tissues can be achieved, and during the implementation of intraoperative imaging, the local delivery of the transporter can be used to better kill cancer cells, reduce the recurrence rate, and improve the patient's postoperative survival rate.

[0177] The functionalized diblock copolymers or polymer particles provided in the present application can significantly improve the safety of tumor imaging probe agents and / or tumor drug preparations (tumor imaging probe agents are mostly used once; while tumor drug preparations are usually administered multiple times). For the diblock copolymers (Formula III compound PEG-PLA copolymers) provided by the present invention, PEG can be safely removed from the human body (Adegen (R), Oncaspar (R) and other therapeutic enzymes modified with PEG with a molecular weight of 5K for multi-site modification, and interferon, granulocyte colony stimulating factor, antibody Fab fragments and other biomacromolecules modified with PEG with a molecular weight of 12-40K have been clinically approved and have been safely used clinically for more than ten years), and the component polymer (PLGA) of the other block can be gradually degraded under physiological conditions (hydrolysis; enzymes).

[0178] The functionalized diblock copolymer or polymer particle provided in the present application can realize high-quality imaging of tumor imaging probe reagents specific to the site of solid tumors, and is sensitive to pH changes in the tumor site (a change in fluorescence signal ΔpH10–90% only requires about 0.2-0.3 pH units), with a high signal-to-noise ratio, clear boundaries, and a long half-life. In vivo imaging data show that once the imaging probe used is enriched into the tumor, it can have a very long intratumoral retention and duration (more than several days), giving tumor imaging surgery a longer observation window and solving the problem of real-time intraoperative navigation using fluorescence imaging technology.

[0179] The functionalized diblock copolymer or polymer particles provided in the present application can achieve in vivo labeling of cancerous lymph nodes after administration, and in vivo imaging and ex vivo dissection can show significantly fluorescent lymph nodes. This discovery is of great significance for the intraoperative determination of lymph node cancer metastasis during future tumor resection surgery, and can have a significant positive impact on the patient's surgical prognosis and survival. In addition to intravenous injection, the specific mode of administration can be local injection, such as local injection around the areola or subcutaneous tissue in breast cancer resection, local injection of intraperitoneal tissue in abdominal tumor surgery, and local subcutaneous or intramuscular injection in melanoma resection and treatment surgery.

[0180] The functionalized diblock copolymers, polymer particles, or compositions provided in the present application can be conveniently administered locally, for example, by bladder instillation, uterine instillation, intestinal instillation, local administration to the brain after craniotomy, etc. After the polymer particles used are in sufficient contact with the local tumor tissue, the polymer particles can be absorbed by the tumor tissue, thereby achieving imaging and treatment of the tumor tissue.

[0181] The functionalized diblock copolymer or polymer particle provided in the present application can introduce precursor molecules (for example, precursor molecules of photodynamic therapy drugs, more specifically 5-ALA precursor molecules, etc.) that can be cut off by the tumor microenvironment (for example, weak acid, microenvironment-specific protease, etc.) on the polymer based on the characteristics that nanoparticles can fully diffuse into the microenvironment of solid tumors. The side chain is cut off from the main chain of the polymer and restored to a clinically approved drug molecule (for example, 5-ALA, etc.), thereby achieving intraoperative image enhancement of the tumor site. While implementing imaging, the designed imaging probe reagent utilizes the light source for implementing intraoperative imaging, realizes photodynamic therapy of tumor tissue during tumor resection surgery, reduces the damage of other photodynamic therapies to normal tissues, kills uncut cancer tissues during tumor tissue resection, reduces postoperative recurrence, and prolongs survival time.

[0182] In summary, the functionalized diblock copolymer or polymer particles provided in the present application can be widely used in the fields of tumor imaging, tumor treatment, etc. It not only has good safety, but also realizes faster and adjustable (by changing the number of tubular energy groups) degradation and clearance of polymers under acidic conditions, but also has excellent specific high-quality imaging effects at the targeted site, with the characteristics of high signal-to-noise ratio, clear boundaries, long half-life, etc., which solves the problem of real-time intraoperative navigation of fluorescence imaging technology, and thus has good industrialization prospects.

[0183] The present invention is further described below by way of examples, but the scope of the present invention is not limited thereby.

[0184] The reaction route of the preparation method of the series of compounds of formula III in the embodiment is as follows:

[0185]

[0186] Example 1

[0187] Synthesis of mPEG5k-PLA monomers and polymers

[0188] 1.1 Monomer synthesis:

[0189]

[0190] Step 1: Synthesis of 2-hydroxypent-4-enoic acid (IB004-069-01)

[0191] Glyoxylic acid (3.7 g, 0.05 mol) was dissolved in 100 ml THF, cooled to 0 ° C in an ice bath, and zinc particles (6.5 g, 0.1 mol) and BiCl3 (22 g, 0.07 mol) were added respectively, stirred at 0 ° C for 3 h, and then 3-bromo-propylene (8.47 g, 0.07 mol) was added, and stirred at room temperature under argon protection overnight. 100 ml of 1N HCl was added to quench the reaction, filtered, and the filtrate was extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated. Drying gave 4.6 g of crude product, which was directly used in the next step without further purification, and the yield was 80%. 1 H NMR (500MHz, CDCl3, ppm): δ5.75-5.85(m,1H,CH=CH2), 5.20(m,2H,CH2=CH), 4.34(m,1H,HOCHCH2, 2.46-2.64(m,2H,CH2CH=CH2).

[0192] Step 2: Synthesis of 2-(2-bromo-propionyloxy)-pent-4-enoic acid (IB004-082-01)

[0193] DMAP (0.24 g, 0.002 mol) was dissolved in 50 ml of dichloromethane, protected by argon, and cooled to 0°C in an ice bath. 2-bromo-propionyl bromide (4.32 g, 0.02 mol), 2-hydroxypent-4-enoic acid (2.32 g, 0.02 mol) and Et3N (2.02 g, 0.02 mol) were dissolved in 10 ml of dichloromethane, and then slowly added to the above solution. After the addition was completed, the reaction was stirred at room temperature overnight. The solvent was concentrated, and the crude product was separated and purified by column (EA: PE = 1: 15) to obtain 963 mg of 2-(2-bromo-propionyloxy)-pent-4-enoic acid, which was a colorless transparent oil with a yield of 19%. 1H NMR (500MHz, CDCl3, ppm): δ1.86 (m, 3H, CH3CHBr), 2.66-2.71 (m, 2H, CH2CH=CH2), 4.38-4.48 (m, 1H, CH3CHBr), 5.18-5.24 (m, 3H, CH=CH2 andHOOCCHOCO),5.78-5.83(m,1H,CH=CH2).

[0194] Step 3: Synthesis of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione (IB004-084-01)

[0195] NaHCO3 (181 mg, 1.72 mmol) was dispersed in 10 ml DMF, and argon was used as protection. 2-(2-bromo-propionyloxy)-pent-4-enoic acid (963 mg, 3.8 mmol) was dissolved in 5 ml DMF and then slowly added dropwise to the above reaction solution. After the addition was complete, the reaction was stirred at room temperature overnight. DMF was concentrated, and the crude product was separated and purified by column (EA:PE=1:10) to obtain 200 mg of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, which was a colorless transparent oil with a yield of 30.6%. 1 H NMR (500MHz, CDCl3, ppm): δ1.67-1.71(m,3H,CH3CH),2.72-2.86(m,2H,CH2CH=CH2), 4.95-5.01(m,1H,CHCH2CH=CH2), 5.02-5.09(m,1H,CH3CH), 5.23-5.33(m,2H,CH2CH=CH2), 5.83-5.88(m,1H,CH2CH=CH2).

[0196] 1.2 Aggregation:

[0197]

[0198] PLA100(IB004-132-01)

[0199] In a glove box with H2O and O2 index less than 0.1ppm, m-PEG-5000 (50mg, 0.01mmol) and 3-allyl-6-methyl-[1,4]dioxane-2,5-dione (170mg, 1mmol) were weighed and placed in a polymerization reaction tube. Sn(Oct)2 (40.5mg, 0.1mmol) was dissolved in 200μL toluene, 20μL was added to the reaction tube, sealed, removed from the glove box, heated to 130℃, and stirred for 1h. Cooled to room temperature, 1ml DCM was added, stirred to dissolve, transferred to a 100ml eggplant-shaped bottle, 50ml methyl tert-butyl ether was slowly added under stirring, and white solid precipitated. Stirring continued for 10min, stopped stirring, poured out methyl tert-butyl ether, and the residual solid was pumped dry with an oil pump to obtain a total of 187mg of polymer, which was a white solid with a yield of 85%.

[0200] Example 2

[0201] General method for modification of hydrophilic / hydrophobic groups

[0202]

[0203] Add the polymer to be modified into the photochemical reactor. According to the solubility of the polymer, choose solvents such as dichloromethane or water. The reaction system should be completely dissolved. The reaction concentration is 100mg polymer / 1000μL. Add the hydrophilic / hydrophobic group to be modified and 0.2mol equivalent of 2,2-dimethoxy-2-phenylacetophenone. The reaction solution is irradiated with 365nm ultraviolet light and reacted at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution. Wash the precipitate with n-heptane. Filter to obtain the polymer precipitate, and the product is a white solid.

[0204] Example 3

[0205] General method for modification of protonatable groups

[0206]

[0207] Add the polymer to be modified into the photochemical reactor. According to the solubility of the polymer, choose a solvent such as dichloromethane or water. The reaction system should be completely dissolved. The reaction concentration is 100mg polymer / 1000μL. Add the protonatable group to be modified, 0.2mol equivalent of 2,2-dimethoxy-2-phenylacetophenone, and the reaction solution is irradiated with 365nm ultraviolet light at room temperature for 2 hours. Use NMR to monitor the reaction until the reaction is complete. After the reaction is completed, concentrate the reaction solution. Wash the precipitate with n-heptane. Filter to obtain the polymer precipitate, and the product is a white solid.

[0208] Example 4

[0209] General Methods for Modification of Fluorophores

[0210]

[0211] Add the polymer to be modified into a single-necked flask. Select solvents such as dichloromethane or water according to the solubility of the polymer. The reaction system should be completely dissolved. The reaction concentration is 50mg polymer / 1000μL. Add the fluorescent group to be modified and react overnight at room temperature. After the reaction is completed, concentrate the reaction solution. Dissolve the precipitate with ethanol. Dialyze the solution using a dialysis bag to remove small molecules. Concentrate to obtain a green solid polymer.

[0212] Example 5

[0213] General method for modification of delivery molecule groups

[0214]

[0215] Add the polymer to be modified into the photochemical reactor. According to the solubility of the polymer, choose a solvent such as dichloromethane or water. The reaction system should be completely dissolved. The reaction concentration is 100mg polymer / 1000μL. Add the protonatable group to be modified, 0.2mol equivalent of 2,2-dimethoxy-2-phenylacetophenone, and the reaction solution is irradiated with 365nm ultraviolet light at room temperature for 2 hours. Use NMR to monitor the reaction until the reaction is complete. After the reaction is completed, concentrate the reaction solution. Wash the precipitate with n-heptane. Filter to obtain the polymer precipitate, and the product is a white solid.

[0216] Example 6

[0217] Example series containing n-nonyl group

[0218] 6.1 PLA110-C9-TEE-ICG

[0219] 6.1.1 Synthesis route of PLA110-C9-TEE-ICG

[0220]

[0221] 6.1.2 Synthesis of PLA110 (IB008-026-01)

[0222] Synthesis and purification of Example 6.1.2 According to the process of Example 1.2 (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1HNMR (400 MHz, Chloroform-d) δ5.85–5.67(m,109H),5.28–5.08(m,452H),3.63(s,448H),2.67(m,240H),1.55(m,343H).

[0223] 6.1.3 Synthesis of PLA110-C9 (IB008-036-01)

[0224] Synthesis and purification of Example 6.1.3 According to the process of Example 2 above, dichloromethane was used as the solvent to obtain 52 mg of white solid polymer with a yield of 91%. 1 H NMR(400MHz,Chloroform-d)δ5.85–5.67(m,89H),5.28 –5.08(m,432H),3.63(d,J=1.2Hz,448H),2.75-2.56(m,220H),2.46–2.39(m,41H), 1.90-1.78(m,40H),1.61-1.44(m,447H),1.29-1.26(m,210H),0.89-0.87(m,62H).

[0225] 6.1.4 Synthesis of PLA110-C9-TEE (IB008-037-01)

[0226] Synthesis and purification of Example 6.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 65 mg of white solid polymer with a yield of 89%. 1 H NMR (400MHz, Chloroform-d) δ5.14 (s, 332H), 3.60 (d, J= 1.2Hz,448H),3.10-2.57(m,1238H),1.90-1.78(m,241H),1.58-1.43(m,549H),0.92-0.89(m,59H).

[0227] 6.1.5 Synthesis of PLA110-C9-TEE-ICG (IB008-038-01)

[0228] Synthesis and purification of Example 6.1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 32 mg of green solid polymer with a yield of 76%. 1H NMR(400MHz,Chloroform-d)δ8.12-7.31(m,19H),5.14(s, 322H), 3.62 (d, J = 1.2Hz, 448H), 3.09-2.58 (m, 1207H), 1.90-1.77 (m, 238H), 1.57-1.44 (m, 579H), 1.29-1.26 (m, 218H), 0.89-0.86 (m, 63H).

[0229] Example 7

[0230] Example series containing octadecyl

[0231] 7.1 PLA110-C18-TEE-ICG

[0232] 7.1.1 Synthesis route of PLA110-C18-TEE-ICG

[0233]

[0234] 7.1.2 Synthesis of PLA110 (IB008-026-01)

[0235] Synthesis and purification of Example 7.1.2 According to the process of Example 1.2 (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400MHz, Chloroform-d) δ5.84–5.66(m,109H),5.28–5.08(m,452H),3.62(s,448H),2.67(m,240H),1.54(m,343H).

[0236] 7.1.3 Synthesis of PLA110-C18 (IB015-039-01)

[0237] Synthesis and purification of Example 7.1.3 According to the process of Example 2 above, dichloromethane was used as the solvent to obtain 56 mg of white solid polymer with a yield of 93%. 1H NMR(400MHz,Chloroform-d)δ5.85-5.67(m,89H),5.30- 5.07(m,432H),3.63(d,J=1.2Hz,448H),2.75-2.56(m,208H),2.46-2.38(m,40H), 1.90-1.76(m,39H),1.58-1.44(m,442H),1.29-1.24(m,565H),0.89-0.87(m,58H).

[0238] 7.1.4 Synthesis of PLA110-C18-TEE (IB015-040-01)

[0239] Synthesis and purification of Example 7.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 60 mg of white solid polymer with a yield of 85%. 1 H NMR (400MHz, Chloroform-d) δ5.13 (s, 337H), 3.63 (d, J = 1.2Hz, 448H), 3.12-2.57 (m, 1122H), 2.44-2.38 (m, 41H), 1.91-1.76 (m, 239H), 1.57-1.44 (m, 543H),0.89-0.87(m,61H).

[0240] 7.1.5 Synthesis of PLA110-C18-TEE-ICG (IB015-041-01)

[0241] Synthesis and purification of Example 7.1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 33 mg of green solid polymer with a yield of 72%. 1 H NMR(400MHz,Chloroform-d)δ8.14-7.30(m,27H),5.14(s, 327H), 3.63 (d, J = 1.2Hz, 448H), 3.09-2.58 (m, 1172H), 2.47-2.39 (m, 42H), 1.90-1.78 (m, 240H), 1.57-1.44 (m, 543H), 0.89-0.87 (m, 61H).

[0242] Example 8

[0243] Example series containing n-butyl

[0244] 8.1 PLA110-C4-TEE-ICG

[0245] 8.1.1 Synthesis route of PLA110-C4-TEE-ICG

[0246]

[0247] 8.1.2 Synthesis of PLA110 (IB008-026-01)

[0248] Synthesis and purification of Example 8.1.2 According to the process of Example 1.2 (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400MHz, Chloroform-d) δ5.85-5.67 (m, 109H), 5.28-5.08 (m, 452H), 3.63 (s, 448H), 2.67 (m, 240H), 1.55 (m, 343H). 8.1.3 Synthesis of PLA110-C4 (IB015-042-01)

[0249] Synthesis and purification of Example 8.1.3 According to the process of Example 2 above, dichloromethane was used as the solvent to obtain 51 mg of white solid polymer with a yield of 89%. 1 H NMR(400MHz,Chloroform-d)δ5.85–5.67(m,89H),5.28 -5.08(m,432H),3.63(d,J=1.2Hz,448H),2.75-2.56(m,223H),2.46–2.3 9(m,38H),1.90-1.78(m,40H),1.61-1.44(m,442H),0.92-0.89(m,61H).

[0250] 8.1.4 Synthesis of PLA110-C4-TEE (IB015-043-01)

[0251] Synthesis and purification of Example 8.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 54 mg of white solid polymer with a yield of 91%. 1 H NMR (400MHz, Chloroform-d) δ5.14 (s, 332H), 3.63 (s, 448H), 3.09-2.58 (m, 1238H), 1.90-1.78 (m, 240H), 1.57-1.44 (m, 549H), 0.92-0.89 (m, 60H).

[0252] 8.1.5 Synthesis of PLA110-C4-TEE-ICG (IB015-044-01)

[0253] Synthesis and purification of Example 8.1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 36 mg of green solid polymer with a yield of 75%. 1 H NMR(400MHz,Chloroform-d)δ8.09-7.28(m,24H),5.14(s, 333H),3.63(s,448H),3.07-2.56(m,1238H),1.91-1.80(m,243H),1.58-1.43(m,548H),0.92-0.88(m,59H).

[0254] Example 9

[0255] Example series containing ethyl

[0256] 9.1 PLA110-C2-TEE-ICG

[0257] 9.1.1 Synthesis route of PLA110-C2-TEE-ICG

[0258]

[0259] 9.1.2 Synthesis of PLA110 (IB008-026-01)

[0260] Synthesis and purification of Example 9.1.2 According to the process of Example 1.2 (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400MHz, Chloroform-d) δ5.85–5.68(m,109H),5.28–5.08(m,452H),3.62(s,448H),2.67(m,240H),1.56(m,343H).

[0261] 9.1.3 Synthesis of PLA110-C2 (IB015-045-01)

[0262] Synthesis and purification of Example 9.1.3 According to the process of Example 2 above, dichloromethane was used as the solvent to obtain 55 mg of white solid polymer with a yield of 89%. 1H NMR(400MHz,Chloroform-d)δ5.85-5.67(m,89H),5.28- 5.08(m,432H),3.63(d,J=1.2Hz,448H),2.75-2.56(m,208H),2.50-2.4 6(m,42H),1.90-1.78(m,40H),1.61-1.55(m,363H),1.17-1.12(m,63H).

[0263] 9.1.4 Synthesis of PLA110-C2-TEE (IB015-047-01)

[0264] Synthesis and purification of Example 9.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 64 mg of white solid polymer with a yield of 91%. 1 H NMR(400MHz,Chloroform-d)δ,5.14(s,322H),3.63(d,J= 1.2Hz,448H),3.09-2.58(m,1198H),2.50-2.46(m,42H),1.90-1.78(m,240H),1.55(m,473H),1.17-1.13(m,63H).

[0265] 9.1.5 Synthesis of PLA110-C2-TEE-ICG (IB015-049-01)

[0266] Example 9.1.5 Synthesis and Purification According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 40 mg of green solid polymer with a yield of 75%. 1 H NMR(400MHz,Chloroform-d)δ,8.08-7.28(m,20H),5.14 (s,320H),3.63(d,J=1.2Hz,448H),3.09-2.58(m,1198H),2.50-2.46(m,42H),1.90-1.78(m,240H),1.55(m,473H),1.17-1.13(m,63H).

[0267] Example 10

[0268] Example series containing cholesterol group

[0269] 10.1 PLA110-CHOL-TEE-ICG

[0270] 10.1.1 Synthesis of PLA110-CHOL-TEE-ICG

[0271]

[0272] 10.1.2 Synthesis of PLA110 (IB008-026-01)

[0273] Synthesis and purification of Example 10.1.2 According to the process of Example 1.2 (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400MHz, Chloroform-d) δ5.85-5.67 (m, 109H), 5.28-5.08 (m, 452H), 3.63 (s, 448H), 2.67 (m, 240H), 1.55 (m, 343H). 10.1.3 Synthesis of PLA110-CHOL (IB015-046-01)

[0274] Synthesis and purification of Example 10.1.3 According to the process of Example 2 above, dichloromethane was used as the solvent to obtain 61 mg of white solid polymer with a yield of 93%. 1 H NMR(400MHz,Chloroform-d)δ5.85-5.67(m,89H),5.28- 5.08(m,451H),4.40(d,J=9.8Hz,2H),3.63(d,J=1.2Hz,448H),3.02(d,J=8.2Hz,20H ), 2.75-2.56 (m, 220H), 2.12 (d, J = 8.3Hz, 20H), 1.90-0.58 (m, 1260H), 0.46 (s, 61H).

[0275] 10.1.4 Synthesis of PLA110-CHOL-TEE (IB015-048-01)

[0276] Synthesis and purification of Example 10.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 75 mg of white solid polymer with a yield of 92%. 1 H NMR(400MHz,Chloroform-d)δ5.21-5.11(m,352H),4.40 (d,J=9.8Hz,20H),3.63(d,J=1.2Hz,448H),3.09-2.58(m,1231H),2.12(d,J=8.3Hz,42H),1.90-0.58(m,1588H),0.46(s,63H).

[0277] 10.1.5 Synthesis of PLA110-CHOL-TEE-ICG (IB015-050-01)

[0278] Synthesis and purification of Example 10.1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 43 mg of green solid polymer with a yield of 85%. 1 H NMR(400MHz,Chloroform-d)δ8.12-7.28(m,21H),5.21- 5.11(m,352H),4.40(d,J=9.8Hz,20H),3.63(d,J=1.2Hz,448H),3.09-2.5 8(m,1231H),2.12(d,J=8.3Hz,42H),1.90-0.58(m,1588H),0.46(s,63H).

[0279] Embodiment 11

[0280] Example series containing hydroxyethyl

[0281] 11.1 PLA110-C2OH-TEE-ICG

[0282] 11.1.1 Synthesis route of PLA110-C2OH-TEE-ICG

[0283]

[0284] 11.1.2 Synthesis of PLA110 (IB008-026-01)

[0285] Synthesis and purification of Example 11.1.2 According to the process of Example 1.2 above (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400 MHz, Chloroform-d) δ5.85-5.67(m,109H),5.28-5.08(m,452H),3.63(s,448H),2.67(m,243H),1.55(m,343H).

[0286] 11.1.3 Synthesis of PLA110-C2OH (IB015-051-01)

[0287] Synthesis and purification of Example 11.1.3 According to the process of Example 2 above, water was used as the solvent to obtain 55 mg of white solid polymer with a yield of 85%. 1H NMR(400MHz,Chloroform-d)δ5.85-5.67(m,89H),5.28-5.08 (m,432H),3.63(d,J=1.2Hz,448H),2.75-2.56(m,265H),2.35-2.31(m,41H),1.90-1.78(m,40H),1.61-1.55(m,363H).

[0288] 11.1.4 Synthesis of PLA110-C2OH-TEE (IB015-053-01)

[0289] Synthesis and purification of Example 11.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 60 mg of white solid polymer with a yield of 80%. 1 H NMR (400MHz, Chloroform-d) δ5.14 (s, 331H), 3.63 (d, J= 1.2Hz,448H),3.09-2.58(m,1251H),,2.35-2.31(m,45H),1.90-1.78(m,238H),1.55(m,473H).

[0290] 11.1.5 Synthesis of PLA110-C2OH-TEE-ICG (IB015-055-01)

[0291] Synthesis and purification of Example 11.1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 35 mg of green solid polymer with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ8.08-7.28(m,25H),5.14 (s,331H),3.63(d,J=1.2Hz,448H),3.09-2.58(m,1251H),2.35-2.31(m,45H),1.90-1.78(m,238H),1.55(m,473H).

[0292] 11.2 PLA110-C2OH-TEE-ICG

[0293] 11.2.1 Synthesis of PLA110-C2OH-TEE-ICG

[0294]

[0295] 11.2.2 Synthesis of PLA110 (IB008-026-01)

[0296] Synthesis and purification of Example 11.2.2 According to the process of Example 1.2 above (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400 MHz, Chloroform-d) δ5.85-5.67(m,109H),5.28-5.08(m,452H),3.63(s,448H),2.67(m,243H),1.55(m,343H).

[0297] 11.2.3 Synthesis of PLA110-C2OH (IB015-057-01)

[0298] Synthesis and purification of Example 11.2.3 According to the process of Example 2 above, water was used as the solvent to obtain 52 mg of white solid polymer with a yield of 85%. 1 H NMR(400MHz,Chloroform-d)δ5.85–5.67(m,59H),5.28–5.08(m,397H),3.63(d,J=1.2Hz,448H),2.75-2.56(m,238H),2.37-2.32(m,101H),1.90-1.78 (m,99H),1.61-1.55(m,397H).

[0299] 11.2.4 Synthesis of PLA110-C2OH-TEE (IB015-058-01)

[0300] Synthesis and purification of Example 11.2.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 54 mg of white solid polymer with a yield of 80%. 1 H NMR (400MHz, Chloroform-d) δ5.14 (s, 337H), 3.63 (d, J = 1.2Hz, 448H), 3.09-2.58 (m, 938H), 2.37-2.32 (m, 105H), 1.90-1.78 (m, 241H), 1.55 (m, 468H).

[0301] 11.2.5 Synthesis of PLA110-C2OH-TEE-ICG (IB015-059-01)

[0302] Synthesis and purification of Example 11.2.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 32 mg of green solid polymer with a yield of 74%. 1H NMR(400MHz,Chloroform-d)δ8.04-7.28(m,28H),5.14(s, 337H), 3.63 (d, J = 1.2Hz, 448H), 3.09-2.58 (m, 938H), 2.37-2.32 (m, 105H), 1.90-1.78 (m, 241H), 1.55 (m, 468H).

[0303] Example 12

[0304] Example series containing amine ethyl

[0305] 12.1 PLA110-C2NH2-TEE-ICG

[0306] 12.1.1 Synthesis of PLA110-C2NH2-TEE-ICG

[0307]

[0308] 12.1.2 Synthesis of PLA110 (IB008-026-01)

[0309] Synthesis and purification of Example 12.1.2 According to the process of Example 1.2 (using 1.02 g of 3-allyl-6-methyl-[1,4]dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1 HNMR (400MHz, Chloroform-d)δ5.85–5.67 (m, 109H), 5.28–5.08 (m, 452H), 3.63 (s, 448H), 2.67 (m, 240H), 1.55 (m, 343H). 12.1.3 Synthesis of PLA110-C2NH2 (IB015-052-01)

[0310] Synthesis and purification of Example 12.1.3 According to the process of Example 2 above, water was used as the solvent to obtain 56 mg of white solid polymer with a yield of 85%. 1 H NMR(400MHz,Chloroform-d)δ5.85–5.67(m,89H),5.28-5.08(m,432H),3.63(d,J=1.2Hz, 448H),3.06-0.99(m,50H),2.75-2.56(m,270H),1.90-1.78(m,40H),1.61-1.55(m,363H).

[0311] 12.1.4 Synthesis of PLA110-C2NH2-TEE (IB015-054-01)

[0312] Synthesis and purification of Example 12.1.4 According to the process of Example 3 above, dichloromethane was used as the solvent to obtain 56 mg of white solid polymer with a yield of 80%. 1 H NMR (400MHz, Chloroform-d) δ5.14 (s, 318H), 3.63 (d, J = 1.2Hz, 448H), 3.09-2.58 (m, 1268H), 1.90-1.78 (m, 237H), 1.55 (m, 462H).

[0313] 12.1.5 Synthesis of PLA110-C2NH2-TEE-ICG (IB015-056-01)

[0314] Example 12. Synthesis and purification of 1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain 30 mg of green solid polymer with a yield of 75%. 1 H NMR (400MHz, Chloroform-d) δ 8.07-7.29 (m, 26H), 5.14 (s, 318H), 3.63 (d, J = 1.2Hz, 448H), 3.09-2.58 (m, 1270H), 1.90-1.78 (m, 238H), 1.55 (m, 462H).

[0315] Example 13

[0316] Example series containing zwitterionic groups

[0317] 13.1 PLA110-EMAA-TEE-ICG

[0318] 13.1.1 Synthesis of PLA110-EMAA-TEE-ICG

[0319]

[0320] 13.1.2 Synthesis of PLA110 (IB008-026-01)

[0321] Synthesis and purification of Example 13.1.2 According to the process of Example 1.2 above (using 1.02 g of 3-allyl-6-methyl-[1,4]-dioxane-2,5-dione, 6 mmol), a total of 1.16 g of white solid polymer was obtained with a yield of 91.3%. 1HNMR (400 MHz, Chloroform-d) δ5.85–5.67(m,109H),5.28–5.08(m,452H),3.63(s,448H),2.67(m,240H),1.55(m,343H).

[0322] 13.1.3 Synthesis of PLA110-EMAA (IB008-060-01)

[0323] Synthesis and purification of Example 6.1.3 According to the process of Example 2 above, water was used as the solvent to obtain 52 mg of white solid polymer with a yield of 90%. 1 H NMR(400MHz,Chloroform-d)δ5.85–5.67(m,88H),5.28–5.08(m, 433H),4.28(s,41H),3.81-3.77(m,42H),3.32(S,123H),3.63(d,J=1.2Hz,448H), 2.96-2.92(m,42H),2.75-2.56(m,222H),1.90-1.78(m,41H),1.61-1.55(m,368H).

[0324] 13.1.4 Synthesis of PLA110-EMAA-TEE (IB008-061-01)

[0325] Synthesis and purification of Example 6.1.4 According to the process of Example 3 above, water was used as the solvent to obtain 65 mg of white solid polymer with a yield of 85%. 1 H NMR(400MHz,Chloroform-d)δ5.14(s,335H),4.28(s,39H),3.81-3.77(m,43H),3.63(d,J =1.2Hz,448H),3.32(S,126H),3.09-2.58(m,1233H),1.90-1.78(m,243H),1.55(m,468H).

[0326] 13.1.5 Synthesis of PLA110-EMMA-TEE-ICG (IB008-062-01)

[0327] Synthesis and purification of Example 6.1.5 According to the process of Example 4 above, dichloromethane was used as the solvent to obtain a total of 32 mg of green solid polymer with a yield of 74%. 1H NMR(400MHz,Chloroform-d)δ8.21-7.30(m,27H)5.14(s, 334H),4.28(s,39H),3.81-3.77(m,38H),3.63(d,J=1.2Hz,448H),3.3 2(S,117H),3.09-2.58(m,1225H),1.90-1.78(m,241H),1.55(m,465H).

[0328] Embodiment 14

[0329] 14.1 In vivo imaging experiment of subcutaneous breast cancer tumor in mice using imaging agents containing C2H4OH hydrophilic groups:

[0330] Animal modeling: Female Balb / c nude mice (4-6 weeks old) were injected with a certain amount of 2x10 6 ) of 4T1 cells, when the tumor volume grew to 200-400mm 3 Afterwards, take the mouse and set aside.

[0331] Injection of imaging agent: Imaging agent No. IB015-055-01 (Example 11.1.5) was used at a dose of 2.5 mg / kg and injected into mice via the tail vein.

[0332] In vivo fluorescence imaging observation: After injection, at different time points, an in vivo fluorescence imaging system (PerkinElmer, model: IVIS spectrum CT, origin: the United States, using the ICG optical filter combination pre-set by the device, and each shot is taken with fixed shooting parameters) was used to monitor the tumor enrichment and in vivo distribution of the fluorescent probe in vivo. Figure 6 As shown, 24 hours after injection, strong fluorescence signal enrichment appeared in the tumor site. After in vivo fluorescence imaging, the mice were killed and the main organs were removed for fluorescence intensity quantification to characterize their tissue distribution.

[0333] 14.2 Determination of the ratio of tumor to healthy tissue (muscle) after administration of imaging agent (IB015-055-01, structure corresponding to Example 11.1.5)

[0334] After administration and 24 hours of in vivo fluorescence imaging, the animals were sacrificed and the tumors, muscles, and major organs (heart, liver, spleen, lungs, and kidneys) were imaged for fluorescence. After imaging, the same size of image information region (ROI, Region of Interst) was used to delineate the areas of different tissues and measure the total and average values ​​of fluorescence intensity (typical imaging results and values ​​can be found in Figure 6), and then the TNR (tumor / healthy tissue ratio) was calculated using “total light intensity of tumor ROI” / “total light intensity of muscle ROI”.

[0335] The results are as follows Figure 7 (Table) It can be seen that the fluorescence intensity of the tumor increased rapidly from 0 to 24 hours after administration, and the tumor / muscle (TNR) ratio could reach 21.1 times within 24 hours after administration. The numerical values ​​in the chart can also be calculated that the ratio of lymph node / muscle with stronger fluorescence intensity is about 13.3 times.

[0336] Embodiment 15

[0337] 15.1 Contains C9H 19 In vivo imaging experiment of subcutaneous breast cancer tumor in mice using imaging agents with hydrophobic groups:

[0338] Animal modeling: Female Balb / c nude mice (4-6 weeks old) were injected with a certain amount of 2x10 6 ) of 4T1 cells, when the tumor volume grew to 200-400mm 3 Afterwards, take the mouse and set aside.

[0339] Injection of imaging agent: Imaging agent No. IB015-038-01 (Example 6.1.5) was used at a dose of 2.5 mg / kg and injected into mice via the tail vein.

[0340] In vivo fluorescence imaging observation: After injection, at different time points, an in vivo fluorescence imaging system (PerkinElmer, model: IVIS spectrum CT, origin: the United States, using the ICG optical filter combination pre-set by the device, and each shot is taken with fixed shooting parameters) was used to monitor the tumor enrichment and in vivo distribution of the fluorescent probe in vivo. Figure 8 As shown, 24 hours after injection, strong fluorescence signal enrichment appeared in the tumor site. After in vivo fluorescence imaging, the mice were killed and the main organs were removed for fluorescence intensity quantification to characterize their tissue distribution.

[0341] 16.2 Determination of the ratio of tumor to healthy tissue (muscle) after administration of imaging agent (IB015-038-01, structure corresponding to Example 6.1.5)

[0342] After administration and 24 hours of in vivo fluorescence imaging, the animals were sacrificed and the tumors, muscles, and major organs (heart, liver, spleen, lungs, and kidneys) were imaged for fluorescence. After imaging, the same size of image information region (ROI, Region of Interst) was used to delineate the areas of different tissues and measure the total and average values ​​of fluorescence intensity (typical imaging results and values ​​can be found in Figure 8), and then the TNR (tumor / healthy tissue ratio) was calculated using “total light intensity of tumor ROI” / “total light intensity of muscle ROI”.

[0343] The results are as follows Fig. 9 (Table) It can be seen that the fluorescence intensity of the tumor increased rapidly from 0 to 24 hours after administration, and the tumor / muscle (TNR) ratio could reach 13.0 times within 24 hours after administration. The numerical values ​​in the chart can also be calculated that the lymph node / muscle ratio with stronger fluorescence intensity is about 4.9 times.

[0344] Example 16

[0345] 16.1 In vivo imaging of subcutaneous breast cancer tumors in mice using imaging agents containing cholesterol (CHOL) hydrophobic groups:

[0346] Animal modeling: Female Balb / c nude mice (4-6 weeks old) were injected with a certain amount of 2x10 6 ) of 4T1 cells, when the tumor volume grew to 200-400mm 3 Afterwards, take the mouse and set aside.

[0347] Injection of imaging agent: Imaging agent No. IB015-050-01 (Example 10.1.5) was used at a dose of 2.5 mg / kg and injected into mice via the tail vein.

[0348] In vivo fluorescence imaging observation: After injection, at different time points, an in vivo fluorescence imaging system (PerkinElmer, model: IVIS spectrum CT, origin: the United States, using the ICG optical filter combination pre-set by the device, and each shot was taken with fixed shooting parameters) was used to monitor the tumor enrichment and in vivo distribution of the fluorescent probe in vivo. 24 hours after injection, strong fluorescence signal enrichment appeared in the tumor site. After in vivo fluorescence imaging, the mice were killed and the main organs were removed for fluorescence intensity quantification to characterize their tissue distribution. The results are as follows: Fig.10 shown.

[0349] 16.2 Determination of the ratio of tumor to healthy tissue (muscle) after administration of imaging agent (IB015-050-01, structure corresponding to Example 10.1.5)

[0350] After administration, mice were killed 24 hours later and samples were collected. Tumors, muscles, and major organs (heart, liver, spleen, lungs, and kidneys) were imaged for fluorescence imaging. After imaging, the same size of image information region (ROI, Region of Interst) was used to delineate the areas of different tissues and measure the total and average values ​​of fluorescence intensity (typical imaging results and values ​​can be found in Fig.10), and then the TNR (tumor / healthy tissue ratio) was calculated using “total light intensity of tumor ROI” / “total light intensity of muscle ROI”.

[0351] The results are as follows Fig.11 (Table) It can be seen that the fluorescence intensity of the tumor increased rapidly from 0 to 24 hours after administration, and the tumor / muscle (TNR) ratio can reach 12.2 times within 24 hours after administration. The numerical values ​​in the chart can also be calculated that the lymph node / muscle ratio with stronger fluorescence intensity is about 12.1 times.

[0352] In summary, the present invention effectively overcomes various shortcomings of the prior art and has high industrial utilization value.

[0353] The above embodiments are merely illustrative of the principles and effects of the present application and are not intended to limit the present application. Anyone familiar with the technology may modify or change the above embodiments without violating the spirit and scope of the present application. Therefore, all equivalent modifications or changes made by a person of ordinary skill in the art without departing from the spirit and technical ideas disclosed in the present application shall still be covered by the claims of the present application.

Claims

1. A functionalized diblock copolymer, wherein the chemical structure of the functionalized diblock copolymer is as shown in Formula III: In formula III, m3=42-242, n3=20-160, p3=1-10, q3=0-500, r3=10-50; s 31 =1~10,s 32 =1~10,s 33 =1~10,s 34 =1~10; t 31 =1~10,t 32 =1~10,t 33 =1~10,t 34 =1~10; L 31 , L 32 , L 33 , L 34 are linking groups, each independently selected from -S-, -O-; R'1, R'2, R'3, R'4 are each independently selected from H, methyl; A3 is selected from a protonatable group, and A3 is selected from in, R 11 Selected from ethyl, R 12 Selected from ethyl, or R 11 Selected from ethyl, R 12 Selected from n-propyl, or R 11 Selected from n-propyl, R 12 Selected from n-propyl, or R 11 Selected from n-propyl, R 12 Selected from n-butyl, or R 11 Selected from n-butyl, R 12 Selected from n-butyl; C3 is selected from fluorescent molecular groups, and C3 includes ICG indocyanine green, methylene blue, CY3, CY3.5, CY5, CY5.5, CY7, CY7.5, BDY630, BDY650, BDY-TMR, Tracy 645, and Tracy 652; D3 is selected from the group of delivery molecules; E3 is selected from a hydrophobic group; the hydrophobic group is selected from a C1-C18 alkyl group, the hydrophobic group is further selected from cholesterol and cholesterol derivatives, the hydrophobic group is further selected from the above groups used alone or in combination of two or more different groups, when used in combination, compared with the general formula of formula III, r3 is the total number of hydrophobic groups; T3 is selected from a capping group, and T3 is selected from -CH3 or H; EG3 is selected from a capping group, and EG3 is OH; The critical micelle concentration of the functionalized diblock copolymer is less than 50 μg / mL; the copolymer represented by formula III is a diblock copolymer of polyethylene glycol and polylactide, wherein the side chain structure of the polylactide block is randomly distributed, which is represented by ran in the general formula.

2. The functionalized diblock copolymer according to claim 1, characterized in that In formula III, s 31 =1~5,s 32 =1~5,s 33 =1~5,s 34 =1~5; t 31 =1~6,t 32 =1~6,t 33 =1~6,t 34 =1~6; The molecular weight of the polyethylene glycol block is 2000-10000 Da, and the molecular weight of the polylactide block is 1000-130000 Da.

3. The functionalized diblock copolymer according to claim 1, characterized in that s 31 =1~5,s 32 =1~5,s 33 =1~5,s 34 =1-5; in formula III, D3 is selected from a fluorescence quenching group or a drug molecule group, and the drug molecule group is selected from a chemotherapeutic drug; The chemical structural formula of cholesterol and cholesterol derivatives described in E3 is shown as one of the following: The hydrophobic group is selected from the group consisting of n-nonyl, n-octyl, n-butyl, n-propyl, ethyl, methyl, n-octadecyl and n-heptadecanyl.

4. The functionalized diblock copolymer according to claim 3, characterized in that The fluorescence quenching group is selected from BHQ-0, BHQ-1, BHQ-2, BHQ-3, BHQ-10, QXL-670, QXL-610, QXL-570, QXL 520, QXL-490, QSY35, QSY7, QSY21, QXL 680, Iowa Black RQ, Iowa Black FQ, or, the drug molecule group is selected from 5-aminolevulinic acid, nucleic acid drug, paclitaxel, cisplatin, doxorubicin, irinotecan, SN38.

5. The functionalized diblock copolymer according to claim 1, characterized in that In formula III, m3=42~242, n3=20~160, p3=1~10, q3=0, r3=10~50.

6. The functionalized diblock copolymer according to claim 1, characterized in that The chemical structural formula of the functionalized diblock copolymer is shown as one of the following: Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, r3=10~50; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500; Among them, m3=42~242, n3=20~160, p3=1~5, q3=0~500.

7. The functionalized diblock copolymer according to claim 1, characterized in that The chemical structural formula of the functionalized diblock copolymer is shown as one of the following: Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200; Among them, m3=42~242, n3=20~160, p3=1~5, q3=10~200.

8. A polymer particle prepared from the functionalized diblock copolymer according to any one of claims 1 to 7.

9. The polymer particles according to claim 8, characterized in that The particle size of the polymer particles is 10 to 200 nm; And / or, the polymer particles are further modified with a targeting group, and the targeting group is selected from a monoclonal antibody fragment, a small molecule targeting group, a polypeptide molecule, and a nucleic acid aptamer; And / or, the targeting group is modified on at least part of the T3 end of the functionalized diblock copolymer.

10. The functionalized diblock copolymer according to any one of claims 1 to 7, or the polymer particles according to any one of claims 8 to 9, characterized in that: The functionalized diblock copolymer and / or polymer particles are degradable in vivo.

11. Use of the functionalized diblock copolymer according to any one of claims 1 to 7 or the polymer particles according to any one of claims 8 to 9 in the preparation of imaging probe agents and pharmaceutical preparations.

12. The use according to claim 11, characterized in that The imaging probe reagent and / or drug preparation has a targeting function.

13. The use according to claim 11, characterized in that The imaging probe reagent and / or pharmaceutical preparation is a targeted imaging probe.

14. A composition comprising the functionalized diblock copolymer according to any one of claims 1 to 7, or the polymer particles according to any one of claims 8 to 9.

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