FUNCTIONALIZED DIBLOCK COPOLYMER AND ITS PREPARATION METHOD AND APPLICATION

Abstract

A functionalized diblock copolymer having the chemical structure shown in Formula I. The functionalized diblock copolymer or polymer particles can be widely used in tumor imaging, tumor therapy and other fields. It not only has good safety, realizes faster and adjustable degradation and removal of polymers (by changing the structure and number of functional groups) under acidic conditions, but also has excellent specific and high-quality imaging effects at the target site, with high signal-to-noise ratio, clear boundaries, long half-life, etc., which solves the problem of fluorescence imaging technology in real-time intraoperative navigation, and thus has a good industrialization prospect.

Claims

1. A functionalized diblock copolymer, wherein the chemical structure of the functionalized diblock copolymer is shown in Formula I: ##STR00050## wherein in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=0?50, p.sub.1=0.5?50, q.sub.1=0?500 and r.sub.1=0?200; s.sub.11=1?10, s.sub.12=1?10, s.sub.13=1?10, s.sub.14=1?10; t.sub.11=1?10, t.sub.12=1?10, t.sub.13=1?10, t.sub.14=1?10; L.sub.11, L.sub.12, L.sub.13 and L.sub.14 are linking groups; A.sub.1 is selected from protonatable groups; B.sub.1 is selected from degradability-regulating groups; C.sub.1 is selected from fluorescent molecular groups; D.sub.1 is selected from delivery molecular groups; E.sub.1 is selected from hydrophilic or hydrophobic groups; T.sub.1 is selected from capping groups; and EG.sub.1 is selected from capping groups.

2. The functionalized diblock copolymer of claim 1, wherein in Formula I, a molecular weight of the polyethylene glycol block is in a range of 1,000 to 50,000 Da, and a molecular weight of the polyphosphate block is in a range of 1,000 to 50,000 Da; and/or a critical micelle concentration (CMC) of the functionalized diblock copolymer is less than 50 ?g/mL.

3. The functionalized diblock copolymer of claim 1, wherein in Formula I, s.sub.11=1?5, s.sub.12=1?5, s.sub.13=1?5, s.sub.14=1?5; t.sub.11=1?6 t.sub.12=1?6, t.sub.13=1?6, t.sub.14=1?6; L.sub.11, L.sub.12, L.sub.13, L.sub.14 are independently selected from S, O, OC(O), C(O)O, SC(O), C(O), OC(S), C(S)O, SS, C(R.sub.1)?N, N?C(R.sub.2), C(R.sub.3)?NO, ON?C(R.sub.4), N(R.sub.5)C(O), C(O)N(R.sub.6), N(R.sub.7)C(S), C(S)N(R.sub.8), N(R.sub.9)C(O)N(R.sub.10), OS(O)O, OP(O)O, OP(O)N, NP(O)O, NP(O)N, wherein, R.sub.1?R.sub.10 are each independently selected from H, C1-C10 alkyl, and C3-C10 cycloalkyl; wherein A.sub.1 is ##STR00051## wherein R.sub.11 and R.sub.12 are each independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl and heteroaryl; a=1-10, and a is a positive integer; B.sub.1 is selected from C1-C18 alkyl and cation, preferably, the cation is selected from Na.sup.+, K.sup.+, Ca.sup.2+, Zn.sup.2+, Fe.sup.3+, Fe.sup.2+, Li.sup.+ and NH.sub.4.sup.+; C.sub.1 includes one or more of ICG, METHYLENE BLUE, CY3.5, CY5, CY5.5, CY7, CY7.5, BDY630, BDY650, BDY-TMR, Tracy 645 and Tracy 652; D.sub.1 is selected from fluorescence quenching group and drug molecule group, wherein the fluorescence quenching group is preferably 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 and Iowa Black FQ; wherein the drug molecule is preferably selected from chemotherapeutic drugs, more preferably selected from 5-ALA (5-Aminolevulinic acid), nucleic acid drugs, paclitaxel, cisplatin, doxorubicin, irinotecan and SN38; E.sub.1 is selected from H, C1-C18 alkyl, OR.sub.11, SR.sub.12, wherein R.sub.11?R.sub.12 are each independently selected from H, C1-C18 alkyl, C3-C10 cycloalkyl, aryl, and heteroaryl; T.sub.1 is selected from CH.sub.3 and H; EG.sub.1 is selected from YR.sub.13, wherein Y is selected from O, S, and N, and R.sub.13 is selected from H, C1-C20 alkyl, C3-C10 cycloalkyl, aryl and heteroaryl.

4. The functionalized diblock copolymer of claim 1, wherein in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=0, p.sub.1=0.5?50, q.sub.1=0, r.sub.1=0; or, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=0, p.sub.1=0.5?50, q.sub.1=0, r.sub.1=1?200; or, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=1?50, p.sub.1=0.5?50, q.sub.1=0, r.sub.1=0; or, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=1?50, p.sub.1=0.5?50, q.sub.1=0, r.sub.1=1?200; or, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=1?50, p.sub.1=0.5?50, q.sub.1=1?500, r.sub.1=0.

5. The functionalized diblock copolymer of claim 4, wherein the chemical structural formula of the functionalized diblock copolymer is shown as one of the following: ##STR00052## wherein m.sub.1=44?226, n.sub.1=50?300, p.sub.1=0.5?5; ##STR00053## wherein m.sub.1=44?226, n.sub.1=50?300, p.sub.1=0.5?5; ##STR00054## wherein m.sub.1=44?226, n.sub.1=70?300, p.sub.1=0.5?5, r.sub.1=10?100; ##STR00055## wherein m.sub.1=44?226, n.sub.1=70?300, p.sub.1=0.5?5, r.sub.1=10?100; ##STR00056## wherein m.sub.1=44?226, n.sub.1=70?300, o.sub.1=1?10, p.sub.1=0.5?5; ##STR00057## wherein m.sub.1=44?226, n.sub.1=70?300, o.sub.1=1?10, p.sub.1=0.5?5; ##STR00058## wherein m.sub.1=44?226, n.sub.1=50?300, o.sub.1=1?10, p.sub.1=0.5?5, r.sub.1=10?100; ##STR00059## wherein m.sub.1=44?226, n.sub.1=50?300, o.sub.1=1?10, p.sub.1=0.5?5, r.sub.1=10?100; ##STR00060## wherein m.sub.1=44?226, n.sub.1=50?300, o.sub.1=1?10, p.sub.1=0.5?5, q.sub.1=10?300; ##STR00061## wherein m.sub.1=44?226, n.sub.1=50?300, o.sub.1=1?10, p.sub.1=0.5?5, q.sub.1=10?300.

6. Polymer particles, prepared from the functionalized diblock copolymer according to claim 1.

7. The polymer particles of claim 6, wherein a particle size of the polymer particles is in a range of 10 to 200 nm; and/or the polymer particles are further modified with a targeting group, wherein the targeting group is selected from a group consisting of monoclonal antibody fragments, small molecule targeting groups, polypeptide molecules, and nucleic acid aptamers; and/or, the targeting group is modified on at least part of a T-terminal of the functionalized diblock copolymer.

8. The functionalized diblock copolymer according to claim 1, or polymer particles prepared from the functionalized diblock copolymer, wherein the functionalized diblock copolymer and/or the polymer particles are degradable in vivo.

9. Use of the functionalized diblock copolymer according to claim 1, or polymer particles prepared from the functionalized diblock copolymer in the preparation of an imaging probe reagent and/or a pharmaceutical preparation, wherein the imaging probe reagent and/or the pharmaceutical preparation preferably has a targeting function, wherein the imaging probe reagent and/or the pharmaceutical preparation is more preferably a targeting imaging probe.

10. A composition, comprising the functionalized diblock copolymer according to claim 1, or polymer particles prepared from the functionalized diblock copolymer.

11. A method of treating or diagnosing a tumor, comprising: administering to an individual an effective amount of the functionalized diblock copolymer according to claim 1, or administering to an individual an effective amount of the polymeric particles prepared from the functionalized diblock copolymer.

12. The method according to claim 11, wherein the functionalized diblock copolymer or the polymeric particles are administered to the individual by administration methods including bladder instillation, uterine perfusion, intestinal perfusion, local administration to the brain after craniotomy, tissue injection during breast cancer dissection surgery, topical administration during minimally invasive surgery for abdominal tumor.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 shows a schematic diagram of the pKa measurement results of different tertiary amine attached to the side chain of a polymer (mPEG-PPE90) in example 2 of the present disclosure.

[0035] FIG. 2 shows a schematic diagram of the critical micelle concentration (CMC) measurement results of PPE90-TPrB (left) and PPE200-TPrB (right) in example 3 of the present disclosure.

[0036] FIGS. 3a-3d show schematic diagrams of dynamic light scattering (DLS) and transmission electron microscopy (TEM) test results of PPE90-TPrB-ICG nanoparticles in PBS buffer solution in example 4 of the present disclosure, where FIG. 3a and FIG. 3c are the DLS and TEM test results of PBS (pH 8.0) respectively, FIG. 3b and FIG. 3d are the DLS and TEM test results of PBS (pH 6.0), respectively.

[0037] FIGS. 4a-4h show schematic diagrams of the fluorescence test results in example 5 of the present disclosure, where FIG. 4a is the summary of the relationship between the fluorescence emission intensity of PPE-TPrB-ICG3 with different degrees of polymerization (DP) at 821 nm and pH, FIGS. 4b-4h are fluorescence emission spectra of PPE-TPrB-ICG3 with different DP in various PBS buffers, FIG. 4b: DP 70, FIG. 4c: DP 90, FIG. 4d: DP 120, FIG. 4e: DP 150, FIG. 4f: DP 200, FIG. 4g: DP 250, FIG. 4h: DP 300.

[0038] FIGS. 5a-5d show schematic diagrams of the fluorescence test results in example 5 of the present disclosure, in which FIGS. 5a-5d are fluorescence emission spectra of PPE-TPrB-ICG3, PPE-TPrB-C520-ICG3, PPE-TPrB-C940-ICG3, PPE-TPrB-C980-ICG3, respectively, in various PBS buffers.

[0039] FIGS. 6a-6e show schematic diagrams of the fluorescence test results in Example 5 of the present disclosure, in which FIG. 6a shows the relationship between the normalized fluorescence intensity of PPE90-ICG3 with different tertiary amine side chains at 821 nm and the solution pH, FIGS. 6b-6e are the fluorescence emission spectra of fluorescent probes in buffer solutions with different pH, FIG. 6b: TPrB; FIG. 6c: TBB; FIG. 6d: TPePe; FIG. 6e: THH.

DETAILED DESCRIPTION

[0040] In order to make the purpose of the present disclosure, technical solutions and beneficial technical effects of the present disclosure clearer, the invention will be further described in detail below in conjunction with examples. Those skilled in the art can easily understand other advantages and effects of this invention from the content disclosed in this specification.

[0041] In the present disclosure, diblock copolymer generally refers to a polymer having two different polymer segments (as if two blocks linked together) with different chemical compositions.

[0042] In the present disclosure, the protonatable group generally refers to a group that can combine with a proton, that is, it can bind at least one proton. These groups usually have a lone pair of electrons, so that at least one proton can be combined with the protonatable group.

[0043] In the present disclosure, degradability regulating group is a type of group that can change the degradability of a compound in vivo.

[0044] In the present disclosure, fluorescent molecular group generally refers to a type of group corresponding to fluorescent molecules. Compounds containing these groups can usually have characteristic fluorescence in the ultraviolet-visible-near infrared regions, and their fluorescent properties (excitation and emission wavelengths, intensity, lifetime, polarization, etc.) can change with the nature of the environment.

[0045] In the present disclosure, delivery molecular group usually means various molecules that can be chemically bonded to the main chain of the block copolymer through a side chain, or interact with the hydrophobic side chain groups of the block copolymer through physical force (such as charge forces, hydrogen bonding, van der Waals force, hydrophobic interaction, etc.) and can be delivered by nanoparticles formed by self-assembly of the block polymer in aqueous solution.

[0046] In the present disclosure, hydrophilic/hydrophobic group generally refers to a group with a certain degree of hydrophilicity or lipophilicity.

[0047] In the present disclosure, alkyl usually refers to a saturated aliphatic group, which can be linear or branched. For example, C1-C20 alkyl usually refers to alkyl groups with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atom(s). Specific alkyl groups can include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl.

[0048] In the present disclosure, alkenyl generally refers to an unsaturated aliphatic group with C?C bond(s) (carbon-carbon double bonds, ethylenic bonds), which can be straight or branched. For example, C2-C10 alkenyl generally refers to alkenyl groups of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific alkenyl groups may include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl.

[0049] In the present disclosure, alkynyl generally refers to an unsaturated aliphatic group with C?C bond (s) (carbon-carbon triple bonds, acetylene bonds), which can be straight or branched. For example, C2-C10 alkynyl generally refers to alkynyl groups of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific alkynyl groups may include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.

[0050] In the present disclosure, 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, or 10 carbon atoms. Specific cycloalkyl groups may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl. The term cycloalkyl in the present disclosure also includes saturated cycloalkyls in which optionally at least one carbon atom can be replaced by a heteroatom, which can be selected from S, N, P, and O. In addition, a monounsaturated or polyunsaturated (preferably monounsaturated) cycloalkyl group without heteroatoms in the ring should belong to the term cycloalkyl group as long as it is not an aromatic system.

[0051] In the present disclosure, aromatic group generally refers to a ring system with at least one aromatic ring and no heteroatoms. The aromatic group may be substituted or unsubstituted. The specific substituent 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, aniline, and the like.

[0052] In the present disclosure, heteroaryl generally refers to a ring system having at least one aromatic ring and optionally one or more (for example, 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be substituted or unsubstituted, and the specific substituent may be selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, hydroxyl, halogen and the like. 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.

[0053] In the present disclosure, targeting agents generally refer to agents that can specifically direct a specific compound to a desired site of action (target area), which may be in the form of polymeric particles that typically have relatively low, no, or almost no interaction with non-target tissues.

[0054] In the present disclosure, imaging probe generally refers to a class of substances that can enhance the effect of image observation after being injected (or taken) into human tissues or organs.

[0055] In the present disclosure, individual generally includes humans and non-human animals, such as mammals, dogs, cats, horses, sheep, pigs, cows, and the like.

[0056] After a lot of practical research, the inventors of the present disclosure has provided a class of functionalized diblock copolymers. These diblock copolymers can be pH-responsive and degradable under corresponding pH conditions through innovative chemical modification strategies. Therefore, it can be used as in various fields utilizing such said features, and the present disclosure has been completed on this basis.

[0057] The first aspect of the present disclosure provides a functionalized diblock copolymer having the chemical structural formula shown below:

##STR00002##

[0058] In formula I, m.sub.1=22?1136, n.sub.1=30?500, o.sub.1=0?50, p.sub.1=0.5?50, q.sub.1=0?500 and r.sub.1=0?200; [0059] s.sub.11=1?10, s.sub.12=1?10, s.sub.13=1?10, s.sub.14=1?10; [0060] t.sub.11=1?10, t.sub.12=1?10, t.sub.13=1?10, t.sub.14=1?10; [0061] L.sub.11, L.sub.12, L.sub.13 and L.sub.14 are linking groups; [0062] A.sub.1 is selected from protonatable groups; [0063] B.sub.1 is selected from degradability-regulating groups; [0064] C.sub.1 is selected from fluorescent molecular groups; [0065] D.sub.1 is selected from delivery molecular groups; [0066] E.sub.1 is selected from hydrophilic/hydrophobic groups; [0067] T.sub.1 is selected from capping groups; [0068] EG.sub.1 is selected from capping groups.

[0069] The compound of formula I is a diblock copolymer of polyethylene glycol-polylactone, wherein the side chain structure of the polylactone block is randomly distributed, and the general formula is represented by ran.

[0070] In the compound of formula I, L.sub.11, L.sub.12, L.sub.13, L.sub.14 are usually linking groups, which is mainly used to link the main chain of the functionalized diblock copolymer and its pendant side chains. In a specific example of the present disclosure, L.sub.11, L.sub.12, L.sub.13, L.sub.14 can be independently selected from S, O, OC(O), C(O)O, SC(O), C(O), OC(S), C(S)O, SS, C(R.sub.1)?N, N?C(R.sub.2), C(R.sub.3)?NO, ON?C(R.sub.4), N(R.sub.5)C(O), C(O)N(R.sub.6), N(R.sub.7)C(S), C(S)N(R.sub.8), N(R.sub.9)C(O)N(R.sub.10), OS(O)O, OP(O)O, OP(O)N, NP(O)O, NP(O)N, wherein, R.sub.1?R.sub.10 are each independently selected from H, C1-C10 alkyl, and C3-C10 cycloalkyl.

[0071] In another specific embodiment of the present disclosure, L.sub.11, L.sub.12, L.sub.13, and L.sub.14 may be independently S.

[0072] In the compound of formula I, A.sub.1 is usually selected from protonatable groups, and this group and the block of the polymer in which this group is located are mainly used to adjust the pH response of the polymer. In an embodiment of the present disclosure, A.sub.1 can be

##STR00003##

wherein, R.sub.11 and R.sub.12 are each independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and aryl. In another embodiment of the present disclosure, A.sub.1 can be

##STR00004##

wherein, a=1-10, and a is a positive integer.

[0073] In another embodiment of the present disclosure, A.sub.1 can be

##STR00005##

wherein R.sub.11 is n-propyl, R.sub.12 is n-butyl. In another embodiment of the present disclosure, A.sub.1 can be

##STR00006##

wherein, a=1-10, and a is a positive integer.

[0074] In the compound of formula I, B.sub.1 is usually a degradability-regulating group, and this group and the block of the polymer in which this group is located are mainly used to regulate the in vivo degradability of the polymer. In a specific embodiment of the present disclosure, B.sub.1 can be selected from C1-C18 alkyl groups, cations and the like, and the cations can be Li.sup.+, Na.sup.+, K.sup.+, Ca.sup.2+, Zn.sup.2+, Fe.sup.2+, Fe.sup.3+, Mg.sup.2+, Zn.sup.2+, NH.sup.4+ and the like.

[0075] In another embodiment of the present disclosure, B.sub.1 may be methyl.

[0076] In the compound of formula I, C.sub.1 is usually a fluorescent molecular group, and this group and the block of the polymer in which this group is located are mainly used to introduce fluorescent molecular groups. The fluorescent molecular group may specifically include, but is not limited to, one or a combination of organic reagents, metal chelate and the like. In an embodiment of the present disclosure, C.sub.1 may include fluorescent molecules such as ICG (Indocyanine Green), METHYLENE BLUE, CY3.5, CY5, CY5.5, CY7, CY7.5, BDY630, BDY650, BDY-TMR, Tracy 645, and Tracy 652.

[0077] In another embodiment of the present disclosure, C.sub.1 may include indocyanine green (ICG), and ICG may be connected to the side chain of the block through an amide bond.

[0078] In the compound of formula I, D.sub.1 can be a delivery molecular group, and this group and the block of the polymer in which this group is located are mainly used to introduce various molecular groups that can be delivered through a block copolymer. These molecular groups may include, but are not limited to, fluorescence quenching groups, drug molecule groups (for example, photodynamic therapy precursor molecules, chemotherapeutic drug molecules, biopharmaceutical molecules, etc.) and the like. In an embodiment of the present disclosure, 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 an embodiment of the present disclosure, the drug molecule group can be a group corresponding to chemotherapeutic drugs, which can specifically be nucleic acid drugs, paclitaxel, cisplatin, doxorubicin, irinotecan, SN38 and other groups corresponding to drug molecules. In another embodiment of the present disclosure, the drug molecule group can be a group corresponding to photodynamic therapy chemical drugs, and may specifically be a group corresponding to 5-ALA and its derivative structure (lipidation or fatty chaining, etc.). The specific chemical structure of the group is as follows:

##STR00007##

[0079] In the compound of formula I, E.sub.1 can be a hydrophilic/hydrophobic group, and this group and the block of the polymer in which this group is located are mainly used to adjust the hydrophobicity/hydrophilicity of the hydrophobic block of the polymer. In an embodiment of the present disclosure, E.sub.1 can be selected from H, C1-C18 alkyl, OR.sub.11, SR.sub.12, wherein R.sub.11?R.sub.12 are each independently selected from H, C1-C18 alkyl, C3-C10 cycloalkyl, and aryl.

[0080] In an embodiment of the present disclosure, E.sub.1 can be selected from n-pentyl and n-nonyl.

[0081] In the compound of formula I, T.sub.1 can usually be selected from end groups of polyethylene glycol (PEG) initiators. In an embodiment of the present disclosure, T.sub.1 can be selected from CH.sub.3, and H.

[0082] In the compound of formula I, EG.sub.1 can usually be produced by different capping agents added after polymerization. In a specific embodiment of the present disclosure, EG.sub.1 can be YR.sub.13, wherein Y is selected from O, S, and N, and R.sub.13 is selected from H, C1-C20 alkyl, C3-C10 cycloalkyl, and aryl.

[0083] In another embodiment of the present disclosure, EG.sub.1 can be OH.

[0084] In the compound of formula I, the molecular weight of polyethylene glycol (PEG) block can be in a range of 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 polyphosphate (PPE) block can generally be in a range of 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?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. In the present disclosure, the molecular weight of a block usually refers to the molecular weight of the main chain molecule in this block, and the molecular weight is usually the number-average molecular weight (Mn).

[0085] In a specific embodiment, the molecular weight of the polyethylene glycol block can be in a range of 2000?10000 Da, and the molecular weight of the polyphosphate block can be in a range of 6000?37000 Da.

[0086] In the compound of formula I, m.sub.1 can be in a range of 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.

[0087] n.sub.1 can be in a range of 10?500, 10?15, 15?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.

[0088] o.sub.1 can be in a range of 0?50, 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, or 45?50.

[0089] p1 can be in a range of 0.5?50, 0.5-1, 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, or 45?50.

[0090] q.sub.1 can be in a range of 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.

[0091] r.sub.1 can be in a range of 0?200, 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, or 180?200.

[0092] s.sub.11 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0093] s.sub.12 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0094] s.sub.13 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0095] s.sub.14 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0096] t.sub.11 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0097] t.sub.12 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0098] t.sub.13 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0099] t.sub.14 can be in a range of 1?10, 1?2, 2?3, 3?4, 4?5, 6?7, 6?7, 7?8, 8?9, or 9?10.

[0100] In a specific embodiment, in Formula I, m.sub.1=22-1136, n.sub.1=10-500, o.sub.1=0, p.sub.1=0.5-50, q.sub.1=0 and r.sub.1=0. For products prepared by these polymers (for example, polymer particles), the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (e.g., with NIR as the excitation light source) due to the FRET (Fluorescence Resonance Energy Transfer) effect. However, after being administered to an individual, the polymer particles can be enriched at the target site (for example, tumor site) through EPR (Enhanced Permeation and Retention) passive targeting (or other tissue uptake methods). Because the target site has a special pH environment (for example, acidic environment), the protonatable group (i.e., the A.sub.1 group) can be protonated in this pH range, and the charge repulsion generated by its protonation and the increase in polymer solubility drive the disintegration of the polymer particles. The FRET effect of the fluorescent group on the molecular segment is reduced or even completely eliminated. The polymer molecules in the dispersed state enriched in the target site can emit fluorescence under certain excitation conditions (for example, with the near-infrared ray as the excitation light source).

[0101] In a preferred embodiment, the chemical structural formula of the functionalized diblock copolymer is shown as one of the following:

##STR00008##

[0102] In another preferred embodiment of the present disclosure, m.sub.1=44-226, n.sub.1=50-300, and p.sub.1=1-5.

[0103] In a specific embodiment of the present disclosure, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=0, p1=0.5?50, q.sub.1=0, and r.sub.1=1?200. For the products prepared by these polymers (for example, polymer particles), the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (for example, in the case of near infrared ray as the excitation light source) due to the FRET effect. The addition of hydrophilic/hydrophobic groups (i.e., E1 groups) increases the stability of polymer particles, enhances the FRET effect of polymer particles (more complete fluorescence quenching), and changes the acidity sensitivity of polymer particles. However, after being administered to an individual, the polymer particles can be enriched at the target site (for example, tumor site) through EPR passive targeting (or other tissue uptake methods). Because the target site has a special pH environment (for example, acidic environment), the protonatable group (i.e., the A.sub.1 group) can be protonated in this pH range, and the charge repulsion generated by its protonation and the increase in polymer solubility drive the disintegration of the polymer particles. The FRET effect of the fluorescent group on the molecular segment is reduced or even completely eliminated. The polymer molecules in the dispersed state enriched in the target site can emit fluorescence under certain excitation conditions (for example, with the near-infrared ray as the excitation light source).

[0104] In a preferred embodiment, the chemical structural formula of the functionalized diblock copolymer is shown as one of the following:

##STR00009##

[0105] In another preferred embodiment, m.sub.1=44?226, n.sub.1=70?300, p.sub.1=0.5?5, and r.sub.1=10?100.

[0106] In a specific embodiment, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=1?50, p.sub.1=0.5?50, q.sub.1=0, and r.sub.1=0. For the products prepared by these polymers (for example, polymer particles), the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (for example, in the case of near infrared ray as the excitation light source) due to the FRET effect. The addition of the degradability-regulating group (i.e., B.sub.1 group) can adjust the degradation performance of the polymer in vivo. However, after being administered to an individual, the polymer particles can be enriched at the target site (for example, tumor site) through EPR passive targeting (or other tissue uptake methods). Because the target site has a special pH environment (for example, acidic environment), the protonatable group (i.e., the A1 group) can be protonated in this pH range, and the charge repulsion generated by its protonation and the increase in polymer solubility drive the disintegration of the polymer particles. The FRET effect of the fluorescent group on the molecular segment is reduced or even completely eliminated. The polymer molecules in the dispersed state enriched in the target site can emit fluorescence under certain excitation conditions (for example, with the near-infrared ray as the excitation light source).

[0107] In a preferred embodiment, the chemical structural formula of the functionalized diblock copolymer is shown as one of the following:

##STR00010##

[0108] In another preferred embodiment, m.sub.1=44?226, n.sub.1=70?300, o.sub.1=1?10, and p.sub.1=0.5?5.

[0109] In a specific embodiment, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=1?50, p.sub.1=0.5?50, q.sub.1=0, and r.sub.1=1?200. For the products prepared by these polymers (for example, polymer particles), the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (for example, in the case of near infrared ray as the excitation light source) due to the FRET effect. The addition of hydrophilic/hydrophobic groups (i.e., E.sub.1 groups) increases the stability of polymer particles, enhances the FRET effect of polymer particles (more complete fluorescence quenching), and changes the acidity sensitivity of polymer particles. The introduction of the degradability-regulating group (i.e., B1 group) can adjust the degradation performance of the polymer in vivo. However, after being administered to an individual, the polymer particles can be enriched at the target site (for example, tumor site) through EPR passive targeting (or other tissue uptake methods). Because the target site has a special pH environment (for example, acidic environment), the protonatable group (i.e., the A1 group) can be protonated in this pH range, and the charge repulsion generated by its protonation and the increase in polymer solubility drive the disintegration of the polymer particles. The FRET effect of the fluorescent group on the molecular segment is reduced or even completely eliminated. The polymer molecules in the dispersed state enriched in the target site can emit fluorescence under certain excitation conditions (for example, with the near-infrared ray as the excitation light source).

[0110] In a preferred embodiment, the chemical structural formula of the functionalized diblock copolymer is shown as one of the following:

##STR00011##

[0111] In another preferred embodiment, m.sub.1=44?226, n.sub.1=50?300, o.sub.1=1?10, p.sub.1=0.5?5, and r.sub.1=10?100.

[0112] In a specific embodiment, in Formula I, m.sub.1=22?1136, n.sub.1=10?500, o.sub.1=1?50, p.sub.1=0.5?50, g.sub.1=1?500, and r.sub.1=0. For the products prepared by these polymers (for example, polymer particles), the fluorescent molecules distributed in the hydrophobic core do not emit light under certain excitation conditions (for example, in the case of near infrared ray as the excitation light source) due to the FRET effect. The addition of the degradability-regulating group (i.e., B.sub.1 group) can adjust the degradation performance of the polymer in vivo. The delivery molecular group (i.e., the D.sub.1 group) is connected to the main chain of the functionalized diblock copolymer. However, after being administered to an individual, the polymer particles can be enriched at the target site (for example, tumor site) through EPR passive targeting (or other tissue uptake methods). Because the target site has a special pH environment (for example, acidic environment), the protonatable group (i.e., the A.sub.1 group) can be protonated in this pH range, and the charge repulsion generated by its protonation and the increase in polymer solubility drive the disintegration of the polymer particles. The FRET effect of the fluorescent group on the molecular segment is reduced or even completely eliminated. The polymer molecules in the dispersed state enriched in the target site can emit fluorescence under certain excitation conditions (for example, with the near-infrared ray as the excitation light source). In addition to the fluorescent molecular groups carried by the polymer particles, the delivery molecular groups attached to the side chains can continue to be hydrolyzed to the corresponding molecules under specific pH conditions at the target site after polymer dissolution. These molecules can play a corresponding role at the target site. For example, the delivery molecular group can be the group corresponding to 5-ALA, which can provide 5-ALA molecules after hydrolysis. 5-ALA can be efficiently enriched inside cancer cells with accelerated metabolism within a few hours and complete biosynthesis to form Protoporphyrin. At this time, fluoresce can be efficiently emitted under the irradiation of near-infrared excitation. Together with ICG fluorescent molecules, the effect of fluorescence image enhancement or boundary confirmation at the tumor site can be realized. Moreover, 5-ALA is an approved 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 at tumor sites at the same time. In addition to the fluorescent molecular groups carried by the polymer particles, the insoluble anticancer drugs connected to the side chains can form a good water-soluble, safe and stable pharmaceutical injection preparation. On the one hand, this pharmaceutical preparation greatly increases the solubility of hydrophobic drugs in the blood and reduces their direct contact with the blood, which improves the stability of the drug in the body, reduces the toxic and side effects of the drug, and retains the high anti-tumor activity characteristics of the drugs. After the polymer is disintegrated, the delivery molecular groups attached to the side chains can continue to be hydrolyzed to the corresponding molecules under specific pH conditions at the target site. These molecules can play a corresponding role at the target site. For example, the delivery molecule group can be the group corresponding to SN-38, which can provide SN-38 after hydrolysis, which overcomes the shortcomings of conventional hydrophobic antitumor drug delivery systems such as low drug loading capacity and strong side effects, thus improving drug safety and achieving the effect of killing cancer cells. In addition, the side chains can also be chemically connected to nucleic acid drugs or deliver nucleic acid drugs through physical action, forming a nano-formulation of nucleic acid drugs, which can significantly improve the in vivo stability of nucleic acid drugs. After the polymer particle is disintegrated, the delivery molecular groups attached to the side chains can continue to be hydrolyzed (corresponding to chemical linkage) or released (corresponding to physical interaction delivery) into the corresponding nucleic acid drug molecules under specific pH conditions at the target site to exert the drug efficacy at the site of the lesion.

[0113] In a preferred embodiment, the chemical structural formula of the functionalized diblock copolymer is shown as one of the following:

##STR00012##

[0114] In another preferred embodiment, m.sub.1=44?226, n.sub.1=50?300, o.sub.1=1?10, p.sub.1=0.5?5, and q.sub.1=10?300.

[0115] The functionalized diblock copolymer provided in the present disclosure usually has a low critical micelle concentration (CMC), thereby reducing the difficulty of preparing polymer self-assembled particles, thereby ensuring that the prepared polymer particles have good stability in solution and blood. For example, the critical micelle concentration (CMC) of the functionalized diblock copolymer may be <50 ?g/mL, <45 ?g/mL, <40 ?g/mL, <35 ?g/mL, <30 ?g/mL, <25 ?g/mL, <20 ?g/mL, <16 ?g/mL, <14 ?g/mL, <12 ?g/mL, <10 ?g/mL, ?9 ?g/mL, ?8 ?g/mL, ?7 ?g/mL, ?6 ?g/mL, ?5 ?g/mL, ?4 ?g/mL, or smaller critical micelle concentration.

[0116] The second aspect of the present disclosure provides polymer particles prepared from the functionalized diblock copolymer provided in the first aspect of the present disclosure. The functionalized diblock copolymers described above 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, in the case of near infrared as the excitation light source) due to the FRET effect. However, after being administered to an individual, the polymer particles can be enriched at the target site (for example, tumor site) through EPR passive targeting (or other tissue uptake methods). Because the target site has a special pH environment (for example, acidic environment), the protonatable group can be protonated in this pH range, and the charge repulsion generated by its protonation and the increase in polymer solubility drive the disintegration of the polymer particles. The FRET effect of the fluorescent group on the molecular segment is reduced or even completely eliminated. The polymer molecules in the dispersed state enriched in the target site can emit fluorescence under certain excitation conditions (for example, with the near-infrared ray as the excitation light source). For example, the PH values in the aforementioned pH environment can be 6.5-6.8, which can correspond to the interstitial fluid of tumor tissue, and at least part of the polymer particles can reach the target site and stay in the interstitial fluid of the cells; for another example, the PH values in the aforementioned pH environment can also be 4.5-6.5, which correspond to endosomes or lysosomes in tumor cells, and at least part of the polymer particles can interact with cells (for example, tumor cells) at the target site and enter into the cells through the endocytosis mechanism, thus reaching the above pH environment. The polymer particles prepared by the functionalized diblock copolymer provided in the present disclosure can be sufficiently diffused at the target site to achieve a clear fluorescence margin, and the functionalized diblock copolymer and/or polymer particles are bio-degradable in vivo. After being administered to an individual, polymer particles or nano-particles that fail to be targeted to the tumor site through the EPR effect cycle may be up-taken by the body's immune system (mainly macrophages, etc.) and then degraded (although PEG cannot be completely degraded in the body, PEG molecules with a molecular weight of less than 40,000 Da (for example, Roche's long-acting interferon, PEGASYS?, has been approved for safe clinical use for more than ten years, and its molecular weight is 40,000 Da) can be effectively eliminated by the kidneys after circulating in the body; PPE can be enzymatically degraded by protein hydrolases, such as phosphodiesterase, and gradually metabolized after the molecular weight gradually decreases, and partly can be cleared by the kidneys). The polymer particles targeted to the target site through the EPR effect are disintegrated into free functionalized diblock copolymer molecules, which, under the pH conditions of the target site and the presence of a variety of enzymes, can be degraded into PEG (which can be cleared by the kidney after circulation) and degradable block (PPE) polymers with gradually smaller molecular weights (which can be subsequently metabolized by circulation and partially 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 administered in single or multiple doses. Imaging observation results of live animals show that the block copolymer used can quickly achieve clear fluorescence imaging of tumor tissue after being injected into the living body. After about ten days of follow-up observation, it was found that the fluorescence presented at other sites (liver, kidney, pancreas, etc.) upon injection (this fluorescence appeared in these organs probably because some of the nanoparticles were captured by the reticuloendothelial system (RES) and then phagocytosed by macrophages and other cells, after that, the nanoparticles were protonated and finally disassembled into individual polymer chain segments) almost completely disappeared, providing strong evidence of the biodegradation and clearance performance of the present disclosure.

[0117] The polymer particles provided in the present disclosure can be nano-sized. For example, the particle size of the polymer particles can be 10?200 nm, 10?20 nm, 20?30 nm, 30?40 nm, 40?60 nm, 60?80 nm, 80 nm?100 nm, 100?120 nm, 120?140 nm, 140?160 nm, 160?180 nm, or 180?200 nm.

[0118] In the polymer particles provided in the present disclosure, the polymer particles can also be modified with targeting groups, and these targeting groups can usually be modified on the surface of the polymer particles. Suitable methods for modifying the targeting group on the polymer particles should be known to those skilled in the art. For example, in general, the targeting group can be attached to the T end of the molecular structure of the functionalized diblock copolymer. These targeting groups can usually increase the efficiency of targeting nanoparticles to liver tumors based on the EPR effect. These targeting groups can include but are not limited to various functional molecules such as (monoclonal) antibody fragments (for example, Fab, etc.), small molecule targeting groups (for example, folic acid, carbohydrates), polypeptide molecules (for example, cRGD, GL2P), and aptamers, and these functional molecules may have a targeting function (for example, a function of targeting tumor tissue). In a specific embodiment of the present disclosure, the targeting group is selected from -GalNac (N-acetylgalactosamine).

[0119] The third aspect of the present disclosure provides a method for preparing the polymer particles provided in the second aspect of the present disclosure. Based on the knowledge of the chemical structure of the functionalized diblock copolymer, a suitable method for forming polymer particles shall be known to those skilled in the art. For example, the method may include: dispersing an organic solvent including the above-mentioned functionalized diblock copolymer in water for self-assembling to provide the polymer particles; or conversely, dispersing water in an organic solvent including the functionalized diblock copolymer. In the above dispersion process, proper operations can be used to make the system fully mixed, for example, it can be carried out under ultrasonic conditions. For another example, the self-assembly process can usually be carried out by removing the organic solvent in the reaction system. The organic solvent removal method may specifically be a solvent volatilization method, an ultrafiltration method, and the like. For another example, the critical micelle concentration (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 the CMC. When E.sub.1, E.sub.2, E.sub.3 are long-chain hydrophobic side chains, their content is inversely proportional to the value of CMC; when E.sub.1, E.sub.2, E.sub.3 are hydrophilic side chains, their content is directly proportional to the value of CMC. For another example, the particle size of polymer particles can usually be adjusted by an extrusion instrument (NanoAssemblr).

[0120] The fourth aspect of the present disclosure provides the uses of the functionalized diblock copolymer provided in the first aspect of the present disclosure or the polymer particles provided in the second aspect of the present disclosure in the preparation of pharmaceutical preparations and/or reagents. Polymer nanoparticles formed as a drug delivery system allow the delivery of drugs or imaging probe molecules using polymer particles as carriers. As mentioned above, the products (for example, polymer particles) prepared by the functionalized diblock copolymers provided in the present disclosure have a passive targeting (enriched at the tumor sites through the general EPR effect of nanoparticles) or active targeting (enriched at the tumor sites by specific binding of nanoparticle surface-modified targeting groups to tumor surface-specific receptors) function. After administration to the individual, because the target site has a special pH environment (for example, acidic environment), the protonatable group can be protonated in this pH range. The charge repulsion generated by the protonation and the increase in polymer solubility drive the disintegration of polymer particles, and the FRET effect of the fluorophore on the dispersed single polymer segment is reduced or even completely eliminated, allowing the polymer molecules in the dispersed state enriched in the target site to emit fluorescence under certain excitation conditions (for example, in the case of near-infrared ray as the excitation light source). In this case, the target site (for example, the tumor site) can emit light specifically, which can be used for targeted imaging probing. In addition to imaging probe applications, these polymer particles can be used to prepare targeting agents. In a specific embodiment of the present disclosure, the above polymer particles can be used to prepare polymer particle-based drug delivery systems to deliver various drug molecules.

[0121] In the pharmaceutical preparations or reagents provided by the present disclosure, 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 can be combined with other active components to collectively form the active ingredient for the aforementioned uses.

[0122] The fifth aspect of the present disclosure provides a composition including the functionalized diblock copolymer provided in the first aspect of the present disclosure or the polymer particles provided in the second aspect of the present disclosure. As mentioned above, the aforementioned composition may be a targeting agent, and in a specific embodiment of the present disclosure, the aforementioned composition may be an imaging probe.

[0123] The composition provided in the present disclosure may also include at least one pharmaceutically acceptable carrier, which usually refers to a carrier for administration, which does not induce the production of antibodies harmful to the individual receiving the composition, and are not excessively toxic after administration. These carriers are well-known to those skilled in the art. For example, Remington's Pharmaceutical Sciences (Mack Pub. Co., N. J. 1991) discloses related content about pharmaceutically acceptable carriers. Specifically, the carrier may include one or more of saline, buffer, glucose, water, glycerol, ethanol, and adjuvant.

[0124] In the composition provided in the present disclosure, the functionalized diblock copolymer may serve as a single active ingredient, or may be combined with other active components for joint use. The other active components can be various other drugs and/or agents, which can usually act on the target site together with the above-mentioned functionalized diblock copolymer. The content of the active ingredient in the composition is usually a safe and effective amount, and the safe and effective amount should be adjustable for those skilled in the art. For example, the dosage of the active ingredient usually depends on the body weight of the subject to whom it is administered, the type of application, and the condition and severity of the disease.

[0125] The composition provided in the present disclosure can be adapted to any form of administration. It can be parenterally administered, for example, it can be pulmonary, nasal, rectal and/or intravenous injection, more specifically intradermal, subcutaneous, intramuscular, intraarticular, intraperitoneal, lung, oral, sublingual, nasal, percutaneous, vaginal, bladder instillation, uterine perfusion, intestinal perfusion, topical administration after craniotomy, or parenteral administration. Those skilled in the art can choose a suitable preparation form according to the mode of administration. For example, the preparation form suitable for parenteral administration may include, but is not limited to, a solution, a suspension, a reconstitutable dry preparation or a spray, etc. For another example, it may be in the form of a preparation administered by inhalation in the form of an inhalant.

[0126] The sixth aspect of the present disclosure provides a method of treatment or diagnosis, including: administering to an individual an effective amount of the functionalized diblock copolymer provided in the first aspect of the present disclosure, or the polymer particles provided in the second aspect of the present disclosure, or the composition provided by the fifth aspect of the present present disclosure. The effective amount generally refers to an amount that can achieve the desired effect after a proper administration period, for example, imaging, treatment of diseases, etc. The above-mentioned are pH-responsive and can be degraded under corresponding pH conditions. Chemical modifications on the functionalized diblock copolymers can also bring synergistic effect from co-delivered molecules, which are bonded to polymer molecules through degradable chemical bonds, and can be combined with a unique end group (targeting group, a group that can improve the immunogenicity of the system) to become a unique block copolymer-delivery bonded complex. In a specific embodiment of the present disclosure, after use, better intraoperative tumor boundary discrimination, and more precise removal of tumor lesions and metastatic tissue can be achieved. During the intraoperative imaging, the local delivery molecules can be used to better kill cancer cells, reduce the recurrence rate, and improve the patient's postoperative survival.

[0127] The functionalized diblock copolymers or polymer particles provided in the present disclosure can significantly improve the safety of tumor imaging probe reagents and/or tumor drug preparations (tumor imaging probe reagents are mostly for single use; and tumor drugs are usually administered multiple times). For the diblock copolymer provided by the present disclosure (the compound of formula I, or PEG-PPE diblock copolymer), PEG can be safely removed from the human body (ADEGEN?, ONCASPAR?, etc., are clinically approved to use PEG with a molecular weight of 5K in multi-site modified therapeutic enzymes; biological macromolecules such as interferon, granulocyte colony stimulating factor, and antibody Fab fragments modified with 12-40K PEG have been safely used in clinical practice for more than ten years), another block PPE can be gradually degraded under physiological conditions (hydrolysis; enzyme). In addition, the design in which the PPE main chain can be actively severed under acidic conditions allows for faster and adjustable (by changing the number of functional groups) degradation and removal of the polymer under acidic conditions.

[0128] The functionalized diblock copolymers or polymer particles provided in the present disclosure can achieve high-quality imaging with tumor imaging probe reagents specific to solid tumor sites, and can be sensitive to pH changes at the tumor site (fluorescence signal changes ?pH10-90% only need about 0.2-0.3 pH unit), with high signal-to-noise ratio, clear boundary, and long half-life. Live imaging data show that the imaging probe used can have a long intratumoral retention and duration (several days or more) once enriched into the tumor, giving a longer observation window for tumor imaging surgery, and solving the problem of fluorescence imaging technology in real-time intraoperative navigation.

[0129] The functionalized diblock copolymers, polymer particles, or compositions provided in the present disclosure can be conveniently administered locally, for example, bladder instillation, uterine perfusion, intestinal perfusion, local administration to the brain after craniotomy. The polymer particles used can be absorbed by the tumor tissue after sufficient contact with the tumor tissue, thereby achieving imaging and treatment of the tumor tissue.

[0130] The functionalized diblock copolymers or polymer particles provided in the present disclosure can introduce, based on the feature that the nanoparticles can accumulate sufficiently into the solid tumor microenvironment, precursor molecules (e.g., precursor molecules for photodynamic therapeutics, more specifically precursor molecules of 5-ALA) to the polymers, where these precursor molecules can be cleaved and released to the tumor microenvironment (weak acids, tumor microenvironment-specific proteases, etc.). The side chains can be cleaved from the polymer backbone and converted to the clinically approved drug molecules (e.g., 5-ALA, etc.), enabling intraoperative image enhancement of tumor sites. At the same time as the implementation of imaging, the designed imaging probe reagent utilizes the light source of intraoperative imaging to realize the photodynamic therapy of tumor tissue during tumor resection surgery, and reduce the damage of other photodynamic therapy on normal tissue, kill the uncut cancer tissue in the process of resection of the tumor tissue, reduce postoperative recurrence and prolong survival time.

[0131] In summary, the functionalized diblock copolymers or polymer particles provided in the present disclosure can be widely used in tumor imaging, tumor therapy and other fields. It not only has good safety, realizes faster and adjustable degradation and removal of polymers (by changing the structure and number of functional groups) under acidic conditions, but also has excellent specific and high-quality imaging effects at the target site, with high signal-to-noise ratio, clear boundaries, long half-life, etc., which solves the problem of fluorescence imaging technology in real-time intraoperative navigation, and thus has a good industrialization prospect.

[0132] The following embodiments further illustrate the present disclosure, but do not limit the scope of the present disclosure.

[0133] The reaction route of the preparation method of the compound of formula I series in the embodiment is as follows:

##STR00013## ##STR00014##

EXAMPLE 1

Synthesis of mPEG-PPE Copolymer

1.1 Synthesis of Monomer:

Synthesis of AEP (IB001-077-01):

[0134] ##STR00015##

[0135] Allyl alcohol (11.6 g, 0.2 mol) was dissolved in 250 ml of dry DCM, dry triethylamine (20.2 g, 0.2 mol) was added, and then the mixture was cooled to 0? C. in an ice-salt bath. Argon displacement was performed three times.

2-Chloro-2-oxo-1,3,2-dioxaphospholane (28.4 g, 0.2 mol) was added slowly dropwise to the above reaction solution, and the temperature was kept below 5? C. After the dropwise adding, the reaction system continued to be stirred at 0? C. for 3 h. Most of the DCM was concentrated off, then 200 ml of dry methyl tert-butyl ether was added. A white solid was precipitated, filtered, washed with 20 ml of methyl tert-butyl ether, and the filtrate was concentrated. Finally, the obtained concentrate was distilled under reduced pressure (0.1 torr, 92? C.) to give 13.7 g of product, which was a colorless and transparent liquid with a yield of 41.7%. The product was stored at ?20? C. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.97 (ddt, J=16.4, 10.9, 5.7 Hz, 1H), 5.46-5.36 (m, 1H), 5.29 (dd, J=10.4, 1.4 Hz, 1H), 4.69-4.58 (m, 2H), 4.50-4.33 (m, 4H).

1.2 Polymerization:

[0136] ##STR00016##

1.2.1 General Polymerization Method, PPE70(n=70, IB004-030-01):

[0137] In a glove box with H.sub.2O and O.sub.2 indexes less than 0.1 ppm, mPEG-5000 (100 mg, 0.02 mmol) was place in a polymerization reaction tube, and 0.5 ml of benzene was added. Then, the polymerization reaction tube was sealed and removed from the glove box, heated to 50? C., stirred for 10 min. After the reagents were all dissolved, the tube was cooled down to room temperature, and then moved back into the glove box. AEP (328 mg, 2 mmol) was added. Finally, TBD (2.78 mg, 0.02 mmol) was added, and the mixture was rapidly stirred to react for 5 min. The polymerization reaction tube was removed from the glove box, the reaction was terminated by adding benzoic acid solution (30 mg of benzoic acid dissolved in 1 ml of DCM). The reaction was stirred for 5 min, then 50 ml of methyl tert-butyl ether was added slowly. A white precipitate appeared. The stirring was continued for 10 min, and filtration was performed to obtain 268 mg of white solid polymer with a yield of 78.2%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.00-5.90 (m, 70H), 5.36 (d, J=17.1, 1.7 Hz, 70H), 5.27 (d, J=10.6, 1.5 Hz, 70H), 4.58 (dd, J=8.1, 5.8 Hz, 140H), 4.32-4.20 (m, 280H), 3.64 (s, 448H), 3.38 (s, 3H). Mw: 18045, Mn: 12600, PDI: 1.432.

1.2.2 PPE90 (n=90)

[0138] Synthesis and purification of PPE90 was carried out according to the process as in Example 1.2.1 above, to obtain 386 mg of white solid polymer in 90.2% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.99-5.90 (m, 90H), 5.37 (d, J=17.1, 1.7 Hz, 90H), 5.26 (d, J=10.6, 1.5 Hz, 90H), 4.54 (dd, J=8.1, 5.8 Hz, 180H), 4.30-4.20 (m, 360H), 3.64 (s, 448H), 3.38 (s, 3H). Mw: 18945, Mn: 14127, PDI: 1.341.

1.2.3 PPE120 (n=120)

[0139] Synthesis and purification of PPE120 was carried out according to the process as in Example 1.2.1 above, to obtain 479 mg of white solid polymer in 89.8% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.99-5.91 (m, 123H), 5.35 (d, J=17.1, 1.7 Hz, 123H), 5.25 (d, J=10.6, 1.5 Hz, 123H), 4.54 (dd, J=8.1, 5.8 Hz, 246H), 4.28-4.24 (m, 492H), 3.64 (s, 448H), 3.37 (s, 3H). Mw: 21479, Mn: 14461, PDI: 1.485.

1.2.4 PPE150 (n=150)

[0140] Synthesis and purification of PPE150 was carried out according to the process as in Example 1.2.1 above, to obtain 577 mg of white solid polymer in 95.3% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.99-5.90 (m, 146H), 5.36 (d, J=17.1, 1.7 Hz, 146H), 5.26 (d, J=10.6, 1.5 Hz, 146H), 4.54 (dd, J=8.1, 5.8 Hz, 292H), 4.27-4.24 (m, 584H), 3.64 (s, 448H), 3.38 (s, 3H). Mw: 33489, Mn: 22443, PDI: 1.492.

1.2.5 PPE200 (n=200)

[0141] Synthesis and purification of PPE200 was carried out according to the process as in Example 1.2.1 above, to obtain 638 mg of white solid polymer in 92.4% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.94 (ddt, J=16.4, 10.9, 5.7 Hz, 87H), 5.38 (dd, J=17.1, 1.6 Hz, 89H), 5.27 (dd, J=10.5, 1.4 Hz, 88H), 4.58 (dd, J=8.1, 5.9 Hz, 180H), 4.36-4.17 (m, 367H), 3.64 (s, 448H).3.38(s, 3H). Mw: 39356, Mn: 21908, PDI: 1.796.

1.2.6 PPE250 (n=250)

[0142] Synthesis and purification of PPE250 was carried out according to the process as in Example 1.2.1 above, to obtain 769 mg of white solid polymer in 93.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.99-5.91 (m, 258H), 5.36 (d, J=17.1, 1.7 Hz, 258H), 5.26 (d, J=10.6, 1.5 Hz, 258H), 4.54 (dd, J=8.1, 5.8 Hz, 516H), 4.28-4.25 (m, 1032H), 3.64 (s, 448H), 3.38 (s, 3H). Mw: 39902, Mn: 22993, PDI: 1.735.

1.2.7 PPE300 (n=300)

[0143] Synthesis and purification of PPE300 was carried out according to the process as in Example 1.2.1 above, to obtain 1048 mg of white solid polymer in 97.0% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.99-5.91 (m, 290H), 5.36 (d, J=17.1, 1.7 Hz, 290H), 5.26 (d, J=10.6, 1.5 Hz, 290H), 4.54 (dd, J=8.1, 5.8 Hz, 580H), 4.27-4.25 (m, 1160H), 3.65 (s, 448H), 3.38 (s, 3H). Mw: 43351, Mn: 24337, PDI: 1.781.

1.2.8 HO-PPE90 (n=90)

##STR00017##

Step One, Bn-PPE90:

[0144] Synthesis and purification of Bn-PPE90 was carried out according to the process as in Example 1.2.1 above (m-PEG-5000 was replaced with an equimolar amount of Bn-PEG-5000), to obtain 605 mg of white solid polymer in 92.1% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.30 (m, 5H), 5.99-5.90 (m, 90H), 5.37 (d, J=17.1, 1.7 Hz, 90H), 5.26 (d, J=10.6, 1.5 Hz, 90H), 4.58 (dd, J=8.1, 5.8 Hz, 182H), 4.31-4.22 (m, 360H), 3.66 (s, 448H). Mw: 19744, Mn: 15217, PDI: 1.297.

Step Two, OH-PPE90

[0145] In a 25 mL high-pressure reactor, 500 mg of Bn-PPE90 was added, fully dissolved in 5 mL of methanol, then 50 mg of Pd/C was added. The reactor was pressurized to 500 PSI, and the temperature was raised to 50? C. After 48 h, the reaction was stopped and filtration was performed, and the filtrate was slowly added with 50 ml of methyl tertiary-butyl ether, which resulted in the appearance of a white precipitate. The reaction was stirred for 10 min, and filtration was performed to obtain 370 mg of white solid polymer with a yield of 74.4%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.99-5.89 (m, 90H), 5.38 (d, J=17.1, 1.7 Hz, 90H), 5.26 (d, J=10.6, 1.5 Hz, 90H), 4.55 (dd, J=8.1, 5.8 Hz, 182H), 4.30-4.19 (m, 360H), 3.64 (s, 450H), 3.38. Mw: 19046, Mn: 14088, PDI: 1.352.

1.3 Synthesis of Side Chains:

1.3.1 Synthesis of TEPr:

[0146] ##STR00018##

[0147] N-ethyl-n-propylamine (34.8 g, 0.4 mol) and 500 ml of dichloromethane were added to a 1 L three-necked flask sequentially and the system was replaced with N.sub.2 three times, then thiirane (48 g, 0.8 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The reaction was terminated, and the organic solvent was removed by concentration. Finally, the obtained concentrate was distilled under reduced pressure (0.2 torr, 38? C.) to obtain 24 g of product, which was a colorless and transparent liquid with a yield of 40.8%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.81 (d, J=8.5 Hz, 4H), 2.67-2.46 (m, 6H), 2.37 (dd, J=8.6, 6.5 Hz, 2H), 1.51-1.37 (m, 2H), 1.00 (t, J=7.1 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H).

1.3.2 Synthesis of TPrPr:

[0148] ##STR00019##

[0149] Di-n-propylamine (40.4 g, 0.4 mol) and 500 ml of dichloromethane were added to a 1 L three-necked flask sequentially and the system was replaced with N.sub.2 three times, then thiirane (48 g, 0.8 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The reaction was terminated, and the organic solvent was removed by concentration. Finally, the obtained concentrate was distilled under reduced pressure (0.2 torr, 42? C.) to obtain 21 g of product, which was a colorless and transparent liquid with a yield of 32.6%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 2.69-2.54 (m, 4H), 2.39 (dd, J=8.5, 6.6 Hz, 4H), 1.46 (h, J=7.4 Hz, 4H), 0.89 (t, J=7.4 Hz, 6H).

1.3.3 Synthesis of TPrB:

[0150] ##STR00020##

Step 1: Synthesis of n-butyl Propionamide (IB001-183-01)

[0151] N-butylamine (40.15 g, 0.55 mol) and Et.sub.3N(101 g, 1 mol) were dissolved in 500 ml DCM, cooled to 0? C. in ice bath, and subjected to nitrogen replacement three times. Propionyl chloride (46.25 g, 0.5 mol) was slowly dropped into the above solution. After dropping, the solution was stirred at room temperature overnight. The salt of Et 3 N was removed by filtration, the solvent was removed by concentration, and the crude product was distilled under reduced pressure (80? C./0.4 torr) to obtain 45 g of product, which was a colorless and transparent liquid with a yield of 69.7%.

Step 2: Synthesis of Butyl Propylamine (IB001-186-01)

[0152] N-butyl propionamide (38.7 g, 0.3 mol) was dissolved in 500 ml THF, and LiAlH.sub.4(12.54 g, 0.33 mol) was added in batches with stirring, and the reaction was refluxed overnight. The reaction solution was cooled, and was slowly added with 98 ml of 1 mol/L NaOH solution under stirring, then, the solution was filtered through diatomaceous earth, and the filtrate was concentrated, then extracted by EA (50 ml?3). The organic phases were combined, washed with H.sub.2O (50 ml?1), NaCl (50 ml?1), respectively, and dried with anhydrous Na.sub.2SO.sub.4, then filtered, and concentrated to obtain crude product. The crude product was distilled under reduced pressure (65? C./0.4 torr) to obtain 12.5 g of butyl propylamine, which was a colorless transparent liquid with a yield of 36.2%.

Step 1: Synthesis of 2-(butylpropylamino)-ethanethiol (IB001-190-01)

[0153] Butyl propylamine (11.5 g, 0.1 mol) was dissolved in 100 ml DCM, and subjected to nitrogen replacement three times. Then, thiirane (12 g, 0.2 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The solvent was removed by concentration, and the crude product was distilled under reduced pressure (73? C./0.4 torr) to obtain 2-(butylpropylamino)-ethanethiol, which was a colorless and transparent liquid with a yield of 34.2%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 2.69-2.54 (m, 4H), 2.46-2.39 (dd, J=8.2, 6.6 Hz, 4H), 1.63-1.39 (m, 4H), 1.34 (h, J=7.4 Hz, 2H), 0.91-0.85 (m, 6H).

1.3.4 Synthesis of TBB:

[0154] ##STR00021##

[0155] Di-n-butylamine (25.8 g, 0.2 mol) and 300 ml of dichloromethane were added to a 500 mL three-necked flask sequentially and the system was subjected to nitrogen replacement three times, then thiirane (24 g, 0.4 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The reaction was terminated, and the organic solvent was removed by concentration. Finally, the obtained concentrate was distilled under reduced pressure (0.2 torr, 49? C.) to obtain 11.4 g of product, which was a colorless and transparent liquid with a yield of 30.1%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 2.63 (dd, J=16.1, 6.2 Hz, 4H), 2.45 (t, J=7.4 Hz, 4H), 1.45 (p, J=7.3 Hz, 4H), 1.34 (p, J=7.2 Hz, 4H), 0.93 (t, J=7.2 Hz, 6H).

1.3.5 Synthesis of TBPe:

[0156] ##STR00022##

Step 1: Synthesis of Butyramide Valerate (IB001-176-01)

[0157] N-butylamine (16.06 g, 0.22 mol) and Et.sub.3N(40.4 g, 0.4 mol) were dissolved in 2800 ml DCM, cooled to 0? C. in ice bath, and subjected to nitrogen replacement three times. Valeryl chloride (24 g, 0.2 mol) was slowly dropped into the above solution. After dropping, the solution was stirred at room temperature overnight.

[0158] The salt of Et.sub.3N was removed by filtration, the solvent was removed by concentration, and the crude product was distilled under reduced pressure (82? C./0.4 torr) to obtain 16.3 g of product, which was a colorless and transparent liquid with a yield of 52%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 3.24 (td, J=7.2, 5.7 Hz, 2H), 2.16 (t, J=7.7 Hz, 2H), 1.61 (dq, J=8.9, 7.5 Hz, 2H), 1.55-1.42 (m, 2H), 1.34 (h, J=7.3 Hz, 4H), 0.92 (td, J=7.3, 3.0 Hz, 6H).

Step 2: Synthesis of Butyl Amylamine (IB001-179-01)

[0159] Butyramide valerate (15.7 g, 0.1 mol) was dissolved in 200 ml THF, and LiAlH.sub.4 (4.18 g, 0.11 mol) was added in batches under stirring, and the reaction was refluxed overnight. The reaction solution was cooled, and was slowly added with 98 ml of 1 mol/L NaOH solution under stirring, then the solution was filtered through diatomaceous earth, and the filtrate was concentrated, then extracted by EA (50 ml?3). The organic phases were combined, washed with H.sub.2O (50 ml?1), NaCl (50 ml?1), respectively, and dried with anhydrous Na.sub.2SO.sub.4, then filtered, and concentrated to obtain crude product. The crude product was distilled under reduced pressure (68? C./0.4 torr) to obtain 5.4 g of butyl amylamine, which was a colorless transparent liquid with a yield of 38%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 62.57 (m, 4H), 1.25-1.55(m, 11H), 0.89 (m, 6H).

Step 3: Synthesis of 2-(butylpentylamino)-ethanethiol (IB001-180-01)

[0160] Butyl amylamine (10 g, 0.07 mol) was dissolved in 50 ml DCM, and subjected to nitrogen replacement three times. Then, thiirane (8.4 g, 0.14 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The solvent was removed by concentration, and the crude product was distilled under reduced pressure (76? C./0.4 torr) to obtain 4.4 g 2-(butylpentylamino)-ethanethiol, which was a colorless and transparent liquid with a yield of 31%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 2.70-2.53 (m, 4H), 2.42 (td, J=7.5, 3.5 Hz, 4H), 1.52-1.20 (m, 10H), 0.92 (q, J=7.1 Hz, 6H).

1.3.6 Synthesis of TPePe (IB001-172-01):

[0161] ##STR00023##

[0162] Diamylamine (15.7 g, 0.1 mol) was dissolved in 200 ml DCM, and subjected to nitrogen replacement three times. Then, thiirane (12 g, 0.2 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The solvent was removed by concentration, and the crude product was distilled under reduced pressure (83? C./0.4 torr) to obtain 9.1 g 2-(dipentylamino)-ethanethiol, which was a colorless and transparent liquid with a yield of 42%.

[0163] .sup.1H NMR (400 MHz CDCl.sub.3) ? 2.68-2.54 (m, 4H), 2.49-2.36 (m, 4H), 1.44 (p, J=7.3 Hz, 4H), 1.39-1.20 (m, 8H), 0.91 (t, J=7.0 Hz, 6H).

1.3.7 Synthesis of THH (IB001-172-01):

[0164] ##STR00024##

[0165] Diamylamine (15.7 g, 0.1 mol) was dissolved in 200 ml DCM, and subjected to nitrogen replacement three times. Then, thiirane (12 g, 0.2 mol) was added slowly dropwise to the above solution. After completion of the dropwise adding, the system was stirred and reacted overnight at room temperature. The solvent was removed by concentration, and the crude product was distilled under reduced pressure (83? C./0.4 torr) to obtain 9.1 g 2-(dipentylamino)-ethanethiol, which was a colorless and transparent liquid with a yield of 42%.

[0166] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 2.68-2.54 (m, 4H), 2.49-2.36 (m, 4H), 1.44 (p, J=7.3 Hz, 4H), 1.39-1.20 (m, 8H), 0.91 (t, J=7.0 Hz, 6H).

1.3.8 Synthesis of 5-ALA Side Chain

[0167] ##STR00025##

Step 1: Synthesis of 6-triphenylmercaptohexan-1-ol (IB004-045-01)

[0168] Triphenylmethyl mercaptan (8.29 g, 0.03 mol) was dissolved in 30 ml EtOH and 30 ml water, then K.sub.2CO.sub.3 (4.14 g, 0.03 mol) was added. The mixture was stirred for 30 min at room temperature under argon protection, then bromohexanol (5.43 g, 0.03 mol) was added, and the temperature was raised to 80? C. and the mixture was stirred for reaction overnight. The reaction was terminated, and the mixture was filtered and concentrated to remove EtOH. 50 ml of water was added, EA extraction (50 ml?3) was performed, the organic phases were combined, washed with water (50 ml?1), washed with saturated NaCl (50 ml?1), dried with anhydrous Na.sub.2SO.sub.4, filtered, concentrated, and dried by an oil pump to obtain 10.92 g of white solid in 96.4% yield, which was not further purified and will be used directly in the next step of the reaction. .sup.1H-NMR (500 MHz, Chloroform-d) ? 7.49-7.39 (m, 6H), 7.29 (t, J=7.7 Hz, 6H), 7.25-7.18 (m, 3H), 3.58 (t, J=6.6 Hz, 2H), 2.16 (t, J=7.3 Hz, 2H), 1.54 (s, 1H), 1.53-1.45 (m, 2H), 1.45-1.38 (m, 2H), 1.34-1.18 (m, 4H).

Step 2: Synthesis of 6-triphenylmercaptohexyl 5-Fmoc-5-amino-4-oxopentanoate (IB004-055-01)

[0169] 6-Triphenylmercaptohexan-1-ol (3.77 g, 0.01 mol) was dissolved in 30 ml THF, then SOCl.sub.2 (1.67 g, 0.014 mol) was added. The mixture was stirred for 10 min, then 5-Fmoc-5-aminolevulinic acid hydrochloride (1.67 g, 0.01 mol) was added, and the system was stirred and reacted overnight at room temperature. 50 ml saturated NaHCO.sub.3 solution was added slowly, the resulting solution was subjected to EA extraction (50 ml?3), the organic phases were combined, washed with water (50 ml?1), washed with saturated NaCI (50 ml?1), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was separated and purified on silica gel column (EA:PE=1:25), and a total of 4.17 g of product was obtained, which was colorless and transparent oil in nature with 58.7% yield. .sup.1H-NMR (500 MHz, Chloroform-d) ? 7.89 (m, 2H), 7.73-7.65 (m, 4H), 7.49-7.39 (m, 8H), 7.29 (t, J=7.7 Hz, 6H), 7.25-7.18 (m, 3H), 4.07 (2H, br s), 3.58 (t, J=6.6 Hz, 2H), 2.87 (2H, t, J=6.5 Hz),2.63 (2H, t, J=6.5 Hz), 2.16 (t, J=7.3 Hz, 2H), 1.53-1.45 (m, 2H), 1.45-1.38 (m, 2H), 1.34-1.18 (m, 4H).

Step 3: Synthesis of 6-mercaptohexyl 5-Fmoc-5-amino-4-oxopentanoate (IB004-063-01)

[0170] 6-triphenylmercaptohexyl 5-Fmoc-5-amino-4-oxopentanoate (3.56 g, 5 mmol) was dissolved in 50 ml DCM, then Et.sub.3SiH (3.41 g, 29.4 mmol) and TFA (6.7 g, 58.8 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration, 50 ml of water was added, 50 ml of saturated NaHCO.sub.3 solution was added slowly, and the resulting solution was subjected to EA extraction (50 ml?3). The organic phases were combined, washed with water (50 ml?1), washed with saturated NaCI (50 ml?1), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was separated and purified on silica gel column (EA:PE=1:5), and a total of 1.05 g product was obtained, which was colorless and transparent oil in nature with 44.8% yield. .sup.1H-NMR (500 MHz, Chloroform-d) ? 7.89 (m, 2H), 7.73-7.65 (m, 4H), 7.45 (m, 2H), 4.31-4.25 (m, 3H), 4.07 (m, 4H), 3.57 (t, J=6.6 Hz, 2H), 2.87 (2H, t, J=6.5 Hz), 2.63 (2H, t, J=6.5 Hz), 2.16 (t, J=7.3 Hz, 2H), 1.54 (s, 1H), 1.53-1.45 (m, 2H), 1.45-1.38 (m, 2H), 1.32-1.15 (m, 4H).

1.4 Coupling of Side Chains:

[0171] ##STR00026##

1.4.1 PPE70-TPrB (IB003-167-01)

[0172] In a glove box with H.sub.2O and O.sub.2 indexes less than 0.1 ppm, PPE70 (255 mg, 0.015 mmol) was dissolved in 4.5 mL dichloromethane, cysteamine hydrochloride (5.12 mg, 0.045 mmol) was added, and then DMPA (25 mg, 10% wt) was added. Under the irradiation of 365 nm ultraviolet lamp, the reaction was carried out under stirring for 1 h at room temperature. TPrB (222.4 mg, 1.05 mmol) was added, and then DMPA (25 mg, 10% wt) was added. Under the irradiation of 365 nm ultraviolet lamp, the reaction was carried out under stirring for 1 h at room temperature, and the reaction system was removed from the glove box. The solvent was removed by rotary evaporation, 10 mL of 50% ethanol was added, and ultrafiltration was performed by using an ultrafiltration centrifuge tube for 45 min and repeated three times. After concentration by rotary evaporation and vacuum drying, a white solid product of 434.6 mg was obtained in 90.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.31-4.22 (m, 420H), 3.63 (s, 448H), 3.34-3.31 (m, 143H), 3.14-3.08 (m, 268H), 2.89-2.87 (m, 140H), 2.70-2.68 (m, 140H), 2.00-1.97 (m, 140H), 1.61 (m, 268H), 1.29-1.26 (m, 134H), 0.87-0.81 (m, 402H).

1.4.2 PPE90-TPrB

[0173] Synthesis and purification of PPE90-TPrB were carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE90, and TPrB with a corresponding molar ratio was used, to obtain 205 mg of white solid polymer in 88.4% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.31-4.22 (m, 540H), 3.63 (s, 448H), 3.34-3.30 (m, 183H), 3.15-3.07 (m, 348H), 2.89-2.87 (m, 180H), 2.70-2.67 (m, 180H), 2.00-1.97 (m, 180H), 1.61 (m, 348H), 1.29-1.26 (m, 174H), 0.87-080 (m, 522H).

1.4.3 PPE120-TPrB

[0174] Synthesis and purification of PPE120-TPrB were carried out according to the procedure of Example 1.4.1 above, in which PPE70 was replaced by PPE120 with equal molar amount, and a proportional molar amount of TPrB was used, to obtain 104 mg of white solid polymer with a yield of 87.8%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.32-4.27 (m, 738H), 3.63 (s, 448H), 3.33-3.28 (m, 255H), 3.20-3.14 (m, 480H), 2.89-2.86 (m, 246H), 2.75-2.69 (m, 246H), 2.00-1.96 (m, 246H), 1.63-1.60 (m, 480H), 1.31-1.27 (m, 240H), 0.84-0.79 (m, 720H).

1.4.4 PPE150-TPrB

[0175] Synthesis and purification of PPE150-TPrB were carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE150, and a proportional molar amount of TPrB was used, to obtain 205 mg of white solid in 86.3% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.31-4.22 (m, 876H), 3.63 (s, 448H), 3.34-3.30 (m, 295H), 3.14-3.07 (m, 572H), 2.88-2.87 (m, 292H), 2.70-2.67 (m, 292H), 1.99-1.97 (m, 292H), 1.60 (m, 572H), 1.29-1.26 (m, 286H), 0.87-080 (m, 858H).

1.4.5 PPE200-TPrB (IB002-086-01)

[0176] Synthesis and purification of PPE200-TPrB were carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE200, and a proportional molar amount of TPrB was used, to obtain 323 mg of white solid in 84.3% yield. .sup.1H NMR (400 MHz, D.sub.2O) ? 4.14-3.89 (m, 1244H), 3.37 (s, 448H), 3.15-2.36 (m, 2292H), 1.80-0.97 (m, 1758H), 0.83 (dt, J=13.9, 7.4 Hz, 1273H).

1.4.6 PPE250-TPrB

[0177] Synthesis and purification of PPE250-TPrB were carried out according to the procedure of Example 1.4.1 above, in which PPE70 was replaced by PPE250 with equal molar amount, and a proportional molar amount of TPrB was used, to obtain 205 mg of white solid polymer with a yield of 86.3%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.30-4.21 (m, 1548H), 3.63 (s, 448H), 3.34-3.31 (m, 519H), 3.15-3.07 (m, 1020H), 2.88-2.87 (m, 516H), 2.71-2.68 (m, 516H), 2.00-1.96 (m, 516H), 1.61 (m, 1020H), 1.30-1.26 (m, 510H), 0.87-080 (m, 1530H).

1.4.7 PPE300-TPrB

[0178] Synthesis and purification of PPE300-TPrB were carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE300 and TPrB with a corresponding molar ratio was used, to obtain 526 mg of white solid polymer in 92.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.32-4.21 (m, 1740H), 3.63 (s, 448H), 3.34-3.30 (m, 583H), 3.15-3.07 (m, 1148H), 2.89-2.87 (m, 580H), 2.70-2.67 (m, 580H), 1.99-1.97 (m, 580H), 1.60 (m, 1148H), 1.29-1.26 (m, 574H), 0.87-080 (m, 1722H).

1.4.8 PPE200-TPrB-40C5

[0179] The synthetic route for PPE200-TPrB40C5 is shown below, and the synthesis and purification was carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE200, and proportional molar amounts of TPr and C.sub.5H.sub.11SH were used, to obtain 176 mg of white solid in 72.6% yield. .sup.1H NMR (400 MHz, D.sub.2O) ? 4.31-4.22 (m, 1200H), 3.68 (s, 448H), 3.35-3.30 (m, 323H), 3.16-3.12 (m, 628H), 2.91-2.88 (m, 320H), 2.70-2.67 (m, 480H), 1.99-1.95 (m, 400H), 1.64 (m, 628H), 1.33-1.28 (m, 554H), 0.86-078 (m, 1062H).

##STR00027##

[0180] The synthetic route for PPE200-TPrB40C9 is shown below, and the synthesis and purification was carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE200, and proportional molar amounts of TPr and C9H19SH were used, to obtain 191 mg of white solid in 80.2% yield. .sup.1H NMR (400 MHz, D.sub.2O) ? 4.32-4.20 (m, 1200H), 3.68 (s, 448H), 3.35-3.30 (m, 320H), 3.15-3.07 (m, 628H), 2.89-2.87 (m, 320H), 2.72-2.68 (m, 480H), 2.00-1.96 (m, 400H), 1.60 (m, 628H), 1.29-1.27 (m, 874H), 0.85-0.77 (m, 1062H).

##STR00028##

1.4.10 PPE200-TPrB-80C9

[0181] The synthetic route for PPE200-TPrB80C9 is shown below, and the synthesis and purification was carried out according to the process as in Example 1.4.1 above, wherein PPE70 was replaced with an equimolar amount of PPE200, and proportional molar amounts of TPr and C9H19SH were used, to obtain 202 mg of white solid in 83.8% yield. .sup.1H NMR (400 MHz, D.sub.2O) ? 4.32-4.20 (m, 1200H), 3.66 (s, 448H), 3.34-3.29 (m,. 243H), 3.13-3.08 (m, 468H), 2.90-2.84 (m, 240H), 2.69 (m, 560H), 2.00-1.95 (m, 400H), 1.61 (m, 468H), 1.29-1.26(m, 1354H), 0.86-0.78 (m, 942H).

##STR00029##

1.4.11 PPE90-TEPr

[0182] Synthesis and purification of PPE90-TEPr were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with an equimolar amount of TEPr, the specific chemical reaction is shown below) to give 130 mg of white solid in 60.5% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.33-4.22 (m, 540H), 3.61 (s, 448H), 3.34-3.27 (m, 183H), 3.18-3.09 (m, 348H), 2.90-2.87 (m, 180H), 2.76-2.66 (m, 180H), 2.00-1.97 (m, 180H), 1.62 (m, 174H), 1.26-1.23 (m, 126H), 0.88-0.81 (m, 261H).

##STR00030##

1.4.12 PPE90-TPrPr

[0183] Synthesis and purification of PPE90-TPrPr were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with an equimolar amount of TPrPr, the specific chemical reaction is shown below) to give 119 mg of white solid in 65.5% yield. .sup.1H NMR (400 MHz, D.sub.2O) ? 4.32-4.25 (m, 540H), 3.65 (s, 448H), 3.37-3.31 (m, 183H), 3.11-3.08 (m, 348H), 2.90-2.88 (m, 180H), 2.72-2.67 (m, 180H), 2.02-1.99 (m, 180H), 1.64-1.58 (m, 348H), 0.84-0.81, (m, 522H).

##STR00031##

1.4.13 PPE90-TBB

[0184] Synthesis and purification of PPE90-TBB were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with an equimolar amount of TBB, the specific chemical reaction is shown below) to give 150 mg of white solid in 63.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.33-4.23 (m, 540H), 3.66 (s, 448H), 3.34-3.31 (m, 183H), 3.15-3.08 (m, 348H), 2.90-2.88 (m, 180H), 2.73-2.68 (m, 180H), 2.02-1.94 (m, 180H), 1.59 (m, 348H), 1.26-1.23 (m, 348H), 0.84-0.81 (m, 522H).

##STR00032##

1.4.14 PPE90-TBPe

[0185] Synthesis and purification of PPE90-TBPe were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with an equimolar amount of TBPe, the specific chemical reaction is shown below) to give 80 mg of white solid in 63.5% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.33-4.23 (m, 540H), 3.66 (s, 448H), 3.34-3.31 (m, 183H), 3.15-3.08 (m, 348H), 2.90-2.88 (m, 180H), 2.73-2.68 (m, 180H), 2.02-1.94 (m, 180H), 1.59 (m, 348H), 1.26-1.23 (m, 348H), 0.84-0.81 (m, 522H).

##STR00033##

1.4.15 PPE90-TPePe

[0186] Synthesis and purification of PPE90-TPePe were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with an equimolar amount of TPePe, the specific chemical reaction is shown below) to give 165 mg of white solid in 73.9% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.31-4.21 (m, 540H), 3.63 (s, 448H), 3.34-3.31 (m, 183H), 3.14-3.07 (m, 348H), 2.89-2.87 (m, 180H), 2.70-2.67 (m, 180H), 2.00-1.96 (m, 180H), 1.61 (m, 348H), 1.30-1.26 (m, 696H), 0.87-0.80 (m, 522H).

##STR00034##

1.4.16 PPE90-THH

[0187] Synthesis and purification of PPE90-THH were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with an equimolar amount of THH, the specific chemical reaction is shown below) to give 176 mg of white solid in 72.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.32-4.22 (m, 540H), 3.63 (s, 448H), 3.34-3.30 (m, 183H), 3.15-3.07 (m, 348H), 2.88-2.87 (m, 180H), 2.71-2.67 (m, 180H), 2.00-1.97 (m, 180H), 1.60 (m, 348H), 1.29-1.26 (m, 1044H), 0.87-080 (m, 522H).

##STR00035##

1.4.17 OH-PPE90-TPrB

[0188] Synthesis and purification of OH-PPE90-TPrB were carried out according to the process as in Example 1.4.2 above (PPE90 was replaced with an equimolar amount of OH-PPE90 and an equimolar amount of TPrB was used, the specific chemical reaction is shown below) to give 176 mg of white solid in 72.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.31-4.22 (m, 540H), 3.62 (s, 448H), 3.34-3.31 (m, 180H), 3.12 (m, 348H), 2.88 (m, 180H), 2.70-2.66 (m, 180H), 2.01-1.98 (m, 180H), 1.61 (m, 348H), 1.29-1.26 (m, 174H) 0.87-0.79 (m, 522H).

##STR00036##

1.4.18 PPE90-TPrB-FmocALA10

[0189] Synthesis and purification of PPE90-TEPr-FmocALA10 were carried out according to the process as in Example 1.4.2 above (TPrB was replaced with a 77 molar amount of TEPr and a 10 molar amount of 6-mercaptohexyl 5-Fmoc-5-amino-4-oxopentanoate, with the specific chemistry as shown below) to give 185 mg of white solid with a yield of 71.9%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.87 (m, 20H), 7.73-7.63 (m, 40H), 7.44 (m, 20H), 4.31-4.22 (m, 570H), 4.01 (br, 40H), 3.82-3.55 (m, 488H), 3.34-3.31 (m, 157H), 3.12 (m, 308H), 2.87 (m, 200H), 2.70-2.61 (m, 200H), 2.12 (t, J=7.2 Hz, 20H), 2.01-1.98 (m, 180H), 1.61-1.41 (m, 338H), 1.29-1.14 (m, 254H), 0.87-0.79 (m, 522H).

##STR00037##

1.5 Coupling of Fluorescent Molecules:

[0190] ##STR00038##

1.5.1 PPE70-TPrB-ICG3

[0191] Polymer PPE70-TPrB (125 mg, 0.0069 mmol) was dissolved in 2 ml DMF, ICG-Osu (25.8 mg, 0.031 mmol) and DIEA (51 mg, 0.396 mmol) were sequentially added, and then the mixture was stirred overnight at room temperature. DMF was removed by concentration, the residue was dissolved in 100 ml absolute ethanol, purified by ceramic membrane (5K) for 2 hours, and EtOH was removed by concentration. After vacuum drying, 92 mg of polymer was obtained, which was a dark green solid with a yield of 73.1%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.12-7.47 (m, 45H), 6.74-6.41 (m, 12H), 4.36-4.23 (m, 420H), 3.64 (s, 448H), 3.38-3.30 (m, 140H), 3.12-3.07 (m, 268H), 2.93-2.88 (m, 140H), 2.72-2.66 (m, 140H), 1.99-1.31 (m, 632H), 0.89-0.80 (m, 402H).

1.5.2 PPE90-TPrB-ICG3

[0192] Synthesis and purification of PPE90-TPrB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-TPrB) to give 77.2 mg of polymer as a dark green solid in 80.9% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.12-7.47 (m, 45H), 6.74-6.44 (m, 12H), 4.31-4.22 (m, 540H), 3.63 (s, 448H), 3.34-3.31 (m, 186H), 3.14-3.08 (m, 348H), 2.89-2.87 (m, 180H), 2.70-2.68 (m, 180H), 2.02-1.28 (m, 792H), 0.87-080 (m, 522H).

1.5.3 PPE120-TPrB-ICG3

[0193] Synthesis and purification of PPE120-TPrB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE120-TPrB) to give 45.3 mg of polymer as a dark green solid in 81.4% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.09-7.45 (m, 45H), 6.75-6.47 (m, 12H), 4.35-4.20 (m, 738H), 3.64 (s, 448H), 3.37-3.35 (m, 252H), 3.20-3.04 (m, 480H), 2.92-2.89 (m, 246H), 2.68-2.65 (m, 246H), 2.02-1.26 (m, 1056H), 0.88-0.79 (m, 720H).

1.5.4 PPE150-TPrB-ICG3

[0194] Synthesis and purification of PPE150-TPrB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE150-TPrB) to give 51 mg of polymer as a dark green solid in 79.8% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10-7.47 (m, 45H), 6.77-6.49 (m, 12H), 4.34-4.20 (m, 876H), 3.61 (s, 448H), 3.35-3.32 (m, 298H), 3.17-3.06 (m, 572H), 2.90-2.86 (m, 292H), 2.72-2.68 (m, 292H), 2.00-1.26 (m, 1240H), 0.85-0.79 (m, 858H).

1.5.5 PPE200-TPrB-ICG3 (IB002-091-01)

[0195] Synthesis and purification of PPE200-TPrB-20C5-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE200-TPrB) to give 60 mg of polymer as a dark green solid in 72.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.09-7.48 (m, 45H), 6.76-6.49 (m, 12H), 4.33-4.25 (m, 1218H), 3.65 (s, 448H), 3.38-3.35 (m, 415H), 3.17-3.04 (m, 800H), 2.92-2.89 (m, 406H), 2.72-2.69 (m, 406H), 2.00-1.27 (m, 1696H), 0.89-0.80 (m, 1200H).

1.5.6 PPE250-TPrB-ICG3

[0196] Synthesis and purification of PPE250-TPrB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE250-TPrB) to give 59.3 mg of polymer as a dark green solid in 79.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10-7.47 (m, 45H), 6.73-6.46 (m, 12H), 4.32-4.23 (m, 1548H), 3.63 (s, 448H), 3.33-3.29 (m, 5252H), 3.19-3.08 (m, 1020H), 2.91-2.87 (m, 516H), 2.70-2.65 (m, 516H), 2.02-1.26 (m, 2136H), 0.87-0.79 (m, 1530H).

1.5.7 PPE300-TPrB-ICG3

[0197] Synthesis and purification of PPE300-TPrB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE300-TPrB) to give 92 mg of polymer as a dark green solid in 86.7% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.12-7.51 (m, 45H), 6.734-6.42 (m, 12H), 4.36-4.22 (m, 1740H), 3.65 (s, 448H), 3.37-3.34 (m, 589H), 3.16-3.11 (m, 1148H), 2.91-2.89 (m, 580H), 2.71-2.69 (m, 580H), 2.02-1.24 (m, 2392H), 0.87-0.83 (m, 1722H).

1.5.8 PPE200-TPrB-40C5-ICG3

[0198] Synthesis and purification of PPE200-TPrB-40C5-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE200-TPrB-40C5, with the specific chemistry as shown below) to give 60 mg of polymer as a dark green solid in 72.6% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.16-7.47 (m, 45H), 6.74-6.49 (m, 12H), 4.32-4.25 (m, 1200H), 3.63 (s, 448H), 3.35-3.31 (m, 363H), 3.18-3.09 (m, 708H), 2.90-2.87 (m, 360H), 2.72-2.66 (m, 440H), 2.00-1.30 (m, 1672H), 0.88-0.78 (m, 1122H).

##STR00039##

1.5.9 PPE200-TPrB-40C9-ICG3

[0199] Synthesis and purification of PPE200-TPrB-40C9-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE200-TPrB-40C9, with the specific chemistry as shown below) to give 52.1 mg of polymer as a dark green solid in 88.1% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10-7.46 (m, 45H), 6.78-6.47 (m, 12H), 4.35-4.26 (m, 1200H), 3.63 (s, 448H), 3.39-3.30 (m, 323H), 3.20-3.12 (m, 628H), 2.91-2.86 (m, 320H), 2.72-2.66 (m, 480H), 2.04-1.28 (m, 1992H), 0.87-0.82 (m, 1062H).

##STR00040##

1.5.10 PPE200-TPrB-80C9-ICG3

[0200] Synthesis and purification of PPE200-TPrB-80C9-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE200-TPrB-80C9, with the specific chemistry as shown below) to give 77 mg of polymer as a dark green solid in 74.2% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.13-7.50 (m, 45H), 6.72-6.48 (m, 12H), 4.36-4.27 (m, 1200H), 3.63 (s, 448H), 3.36-3.33 (m, 243H), 3.14-3.04 (m, 468H), 2.90-2.88 (m, 240H), 2.72-2.69 (m, 560H), 2.04-1.29 (m, 2312H), 0.89-0.81 (m, 942H).

##STR00041##

1.5.11 PPE90-TEPr-ICG3

[0201] Synthesis and purification of PPE90-TEPr-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-TEPr, with the specific chemistry as shown below) to give 90 mg of polymer as a dark green solid in 95.4% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.11-7.51 (m, 45H), 6.72-6.47 (m, 12H), 4.29-4.20 (m, 540H), 3.61 (s, 448H), 3.33-3.30 (m, 183H), 3.15-3.10 (m, 348H), 2.89-2.87 (m, 180H), 2.70-2.65 (m, 180H), 2.02-1.25 (m, 705H), 0.84-0.79 (m, 261H).

##STR00042##

1.5.12 PPE90-TPrPr-ICG3

[0202] Synthesis and purification of PPE90-TPrPr-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-TPrPr, with the specific chemistry as shown below) to give 90 mg of polymer as a dark green solid in 56.9% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.16-7.44 (m, 45H), 6.73-6.46 (m, 12H), 4.31-4.25 (m, 540H), 3.63 (s, 448H), 3.36-3.32 (m, 183H), 3.17-3.08 (m, 348H), 2.92-2.90 (m, 180H), 2.71-2.66 (m, 180H), 2.00-1.27 (m, 618H), 0.86-0.79 (m, 522H).

##STR00043##

1.5.13 PPE90-TBB-ICG3

[0203] Synthesis and purification of PPE90-TBB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-TBB, with the specific chemistry as shown below) to give 38.2 mg of polymer as a dark green solid in 82.5% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.14-7.51 (m, 45H), 6.78-6.44 (m, 12H), 4.33-4.19 (m, 540H), 3.61 (s, 448H), 3.39-3.36 (m, 183H), 3.17-3.09 (m, 348H), 2.92-2.89 (m, 180H), 2.70-2.67 (m, 180H), 2.02-1.31 (m, 996H), 0.90-0.82 (m, 522H).

##STR00044##

1.5.14 PPE90-TBPe-ICG3

[0204] Synthesis and purification of PPE90-TBPe-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-TBPe, with the specific chemistry as shown below) to give 33.7 mg of polymer as a dark green solid in 84.7% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.16-7.52 (m, 45H), 6.72-6.46 (m, 12H), 4.34-4.24 (m, 540H), 3.66 (s, 448H), 3.31-3.27 (m, 183H), 3.13-3.10 (m, 348H), 2.92-2.87 (m, 180H), 2.70-2.66 (m, 180H), 2.00-1.31 (m, 1140H), 0.90-0.77 (m, 522H).

##STR00045##

1.5.15 PPE90-TPePe-ICG3

[0205] Synthesis and purification of PPE90-TPePe-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-TPePe, with the specific chemistry as shown below) to give 35.6 mg of polymer as a dark green solid in 73.2% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10-7.52 (m, 45H), 6.73-6.45 (m, 12H), 4.33-4.29 (m, 540H), 3.64 (s, 448H), 3.35-3.27 (m, 183H), 3.15-3.10 (m, 348H), 2.89-2.84 (m, 180H), 2.71-2.68 (m, 180H), 2.02-1.28 (m, 1314H), 0.88-0.80 (m, 522H).

##STR00046##

1.5.16 PPE90-THH-ICG3

[0206] Synthesis and purification of PPE90-THH-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of PPE90-THH, with the specific chemistry as shown below) to give 36.8 mg of polymer as a dark green solid in 75.4% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.16-7.48 (m, 45H), 6.73-6.45 (m, 12H), 4.30-4.22 (m, 540H), 3.63 (s, 448H), 3.34-3.30 (m, 183H), 3.14-3.09 (m, 348H), 2.89-2.86 (m, 180H), 2.73-2.71 (m, 180H), 2.04-1.27 (m, 1662H), 0.89-0.80 (m, 522H).

##STR00047##

1.5.17 OH-PPE90-TPrB-ICG3

[0207] Synthesis and purification of OH-PPE90-TPrB-ICG3 were carried out according to the process as in Example 1.5.1 above (PPE70-TPrB was replaced with an equimolar amount of OH-PPE90-TPrB, with the specific chemistry as shown below) to give 37.1 mg of polymer as a dark green solid in 76.5% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.17-7.53 (m, 45H), 6.72-6.45 (m, 12H), 4.33-4.23 (m, 540H), 3.66 (s, 448H), 3.31-3.28 (m, 180H), 3.14-3.10 (m, 348H), 2.94-2.88 (m, 180H), 2.68 (m, 180H), 2.01-1.30 (m, 792H), 0.91-0.78 (m, 522H).

##STR00048##

1.5.18 PPE90-TPrB-ALA10-ICG3

[0208] The synthesis of PPE90-TEPr-ALA10-ICG3 is shown in the following figure. The polymer PPE90-TPrB-Fmoc-ALA10 (150 mg, 0.0039 mmol) is dissolved in 2 ml DMF, and ICG-Osu (5.8 mg, 0.0069 mmol) and DIEA (25 mg, 0.2 mmol) were sequentially added. After stirring overnight at room temperature, DIEA was removed by rotary evaporation, 0.2 ml of piperidine was added, the system was stirred at room temperature for 0.5 hour, DMF was removed by concentration, the residue was dissolved in 100 ml of absolute ethanol, purified by ceramic membrane (5K) for 2 hours, and EtOH was removed by concentration. After vacuum drying, 112 mg of polymer was obtained, which was a dark green solid with a yield of 74.4%. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.17-7.53 (m, 45H), 6.72-6.45 (m, 12H), 4.32-4.20 (m, 570H), 4.04 (br, 20H), 3.82-3.55 (m, 488H), 3.34-3.31 (m, 154H), 3.13 (m, 308H), 2.87 (m, 2000H), 2.70-2.60 (m, 200H), 2.12 (t, J=7.2 Hz, 20H), 2.01-1.98 (m, 180H), 1.61-1.41 (m, 338H), 1.29-1.14 (m, 254H), 0.87-0.79 (m, 522H).

##STR00049##

EXAMPLE 2

pKa Test

[0209] 30 mg of the polymer prepared in Example 1 (1.4.3, 1.4.11-1.4.15) was accurately weighed and dissolved in 30 mL of 0.01 mol/L trifluoroacetic acid solution, titrated with 0.1 mol/L sodium hydroxide solution under the indication of a pH meter, and the volume of the consumed sodium hydroxide solution and the corresponding pH were recorded and plotted in terms of the volume versus the pH by Origin software for graphing, and the pKa value is one-half of the sum of the two intersection points of the two tangent lines and the platform tangent. The specific results are shown in FIG. 1. As can be seen from FIG. 1, the pKa of PPE with hydrophilic tertiary amine is greater than that with hydrophobic tertiary amine.

EXAMPLE 3

CMC Test of Typical PPE Nano-Fluorescent Probes

[0210] 2 ?L of 1?10.sup.?5 mol/L Nile Red in dichloromethane solution was added to PBS 8.0 solutions of the polymer (Examples 1.4.1 & 1.4.5) at a series of concentrations (1?10.sup.?6?1?10.sup.?1 mg/mL), and the mixture was mixed well using a vortex mixer, and then allowed to stabilize. The fluorescence intensity of the solution was tested. By plotting the fluorescence intensity ratio against the concentration, the critical micelle concentration is determined as the intersection of two tangent lines. The critical micelle concentration of all tested nanoprobes is less than 10 ng/m L. FIG. 2 shows the CMC test results of two typical polymers, the left part shows the test results of PPE90-TPrB, and the right part shows the test results of PPE200-TPrB.

EXAMPLE 4

4.1 Preparation and Characterization of Nanoparticle Solution

[0211] 5 mg of polymer was dissolved in 0.2 ml CH.sub.3CN, added to 5 ml of deionized water under ultrasonic conditions, concentrated to remove CH.sub.3CN on a rotary evaporator, and supplemented with deionized water until the volume was 5 ml, and the concentration of the obtained stock solution was 1 mg/ml.

4.2 DLS Test

[0212] The sample used in this example is the same as that in example 2. PPE90-TPrB was used to prepare the nanoparticle solution. The pH of the solution was about 8.0, the concentration was 1 mg/mL, and the sample was taken at room temperature (20? C.) for DLS (The instrument is: Brookhaven Omni Dynamic Light Scattering (DLS) Particle Sizer and zeta petential Analyzer, all other DLS tests are measured on Malvern Zetasizer Ultra, He-Ne laser, ?=633 nm). The data obtained is shown in FIG. 3a. The nanoparticles are 29.9 nm, and the particle sizes are uniformly distributed.

[0213] The nanoparticle solution of example 4.1 was dropped into PBS 6.0, the sample was shaken for 2 minutes and then the DLS test was performed. The data obtained is shown in FIG. 3b, and the polymer nanoparticles are all dissolved.

4.3 TEM Test

[0214] PPE90-TPrB-ICG was used to prepare the nanoparticle solution. The concentration of this solution is 1 mg/mL, the pH is about 8.0, and the sample is taken for TEM test (ThermoFisher Scientific (formerly FEI), model: Tabs F200S, origin: Netherlands). The data is shown in FIG. 3c. The nanoparticles are about 20-50 nm, and the particle sizes are uniform and are evenly distributed.

[0215] The above-mentioned nanoparticle solution was dropped into the PBS6.0 solution for TEM test, and the obtained data is shown in FIG. 3d. Compared with FIG. 3c, the polymer nanoparticles are all dissolved

EXAMPLE 5

5.1 Fluorescence Test

[0216] 100 uL nanoparticle stock solution (1 mg/mL, refer to example 4.1 for preparation method) was diluted into 2.0 mL of PBS buffer (pH 5.5-8.0), mixed well and emission fluorescence was measured. The excitation light wavelength is 730 nm, and the emission light wavelength detection range is 785-900 nm. The properties of PPE series fluorescent probes are shown in Table 1, where:

[0217] pKa and CMC measurement methods refer to Examples 2 and 3.

[0218] The calculation of the fluorescence intensity ratio (FIR) is the ratio of the fluorescence intensity at 821 nm in the pH 6.0 buffer solution of the nano fluorescent probe to the fluorescence intensity at 821 nm in the pH 8.0 buffer solution. The calculation method is as follows:

FIR=1821(pH 6.0)/1821(pH 8.0)

[0219] Calculation of pH transition point (pHt): Take the fluorescence intensity at 821 nm of different pH values, perform mathematical normalization, and plot the pH versus fluorescence intensity. Then the obtained scatter plot is fitted with boltzmann function. The pH value at 50% fluorescence intensity of the highest fluorescence value is pHt.

[0220] pH50%. The calculation method of pH mutation range is as follows:

?pH.sub.10%?90%=pH.sub.10%?pH.sub.90%

TABLE-US-00001 TABLE 1 Screening of PPE nano fluorescent probes Tertiary amine Hydrophobic Example side side ICG/ CMC number DP chain chains/number Chain pKa (ng/mL) FIR pHt ?pH.sub.10?90% 1.5.1 70 TPrB None 3 6.45 9.71 5.5 7.21 0.46 1.5.2 90 TPrB None 3 6.55 8.64 19.0 7.14 0.51 1.5.3 120 TPrB None 3 6.53 8.85 4.3 7.05 0.44 1.5.4 150 TPrB None 3 6.27 4.40 7.3 7.03 0.40 1.5.5 200 TPrB None 3 6.48 4.37 10.8 7.09 0.38 1.5.8 200 TPrB C5/40 3 6.34 7.17 4.9 6.91 0.26 1.5.9 200 TPrB C9/40 3 6.24 3.56 15.2 6.75 0.22 1.5.10 200 TPrB C9/80 3 6.00 1.27 9.0 6.35 0.51 1.5.6 250 TPrB None 3 6.42 4.42 3.8 7.22 0.49 1.5.7 300 TPrB None 3 6.35 4.11 3.5 7.16 0.23 1.5.13 90 TBB None 3 6.47 4.23 4.5 6.84 0.52 1.5.14 90 TPePe None 3 5.36 3.48 7.4 5.67 0.36 1.5.15 90 THH None 3 5.19 2.09 N/A N/A N/A

5.2 The Effect of the Degree of Polymerization of the Hydrophobic Block (PPE) on FIR, pHt and ?pH

[0221] The fluorescence test of the nanoparticle stock solution (1 mg/mL, the preparation method refers to example 4.1) was implemented with reference to example 5.1. The relationship between the fluorescence emission intensity (at 821 nm) of PPE-TPrB-ICG3 with different degree of polymerization (DP) and pH is summarized in Table 1 and FIG. 4a. The fluorescence emission spectra of PPE-TPrB-ICG3 with different DP in different PBS buffers are shown in FIGS. 4b-4h.

5.3 The Effect of Hydrophobic Side Chains on FIR, pHt and ?pH of PPE200-TPrB

[0222] The fluorescence test of the nanoparticle stock solution (1 mg/mL, the preparation method refers to example 4.1) was implemented with reference to example 5.1. The relationship between fluorescence emission spectra and pH of PPE200-TPrB-ICG3 fluorescent probe with 20% C.sub.5H.sub.11, 20% C.sub.9H.sub.19 or 40% C.sub.9H.sub.19 hydrophobic side chain is summarized in Table 1 and FIGS. 5a-5d. When the PPE200 probe is connected with 20% C.sub.5H.sub.11 side chain, its pHt and FIR are slightly reduced. When the PPE200 probe is connected with 20% C.sub.9H.sub.19 or 40% C.sub.9H.sub.19 side chain, its pHt is significantly reduced, and the 20% C.sub.9H.sub.19 side chain can improve the FIR. 20% C.sub.5H.sub.11 and 20% C9H19 significantly reduced the ?pH.

5.4 The Effect of Side Chain Tertiary Amine on FIR, pHt and ?pH of PPE200-ICG3

[0223] The fluorescence test of the nanoparticle stock solution (1 mg/mL, the preparation method refers to example 4.1) was implemented with reference to example 5.1. The relationship between fluorescence emission spectrum and pH of PPE200-TPrB-ICG3 fluorescent probe with TPrPr, TPrB, TBB, TBPe, TPePe or THH side chain is summarized in Table 1 and FIGS. 6a-6e. With the increase of hydrophobicity of side chain tertiary amine, the pHt of the probe decreased, and the FIR and ?pH did not change regularly.

[0224] As mentioned above, the present disclosure effectively overcomes various shortcomings in the traditional technology and has high industrial utilization value.

[0225] The above-mentioned embodiments are merely illustrative of the principle and effects of the present disclosure instead of limiting the present disclosure. Modifications or variations of the above-described embodiments may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Therefore, all equivalent modifications or changes made by those who have common knowledge in the art without departing from the spirit and technical concept disclosed by the present disclosure shall be still covered by the claims of the present disclosure.