Nanocomposite with chemiluminescence monitoring light-controlled drug release function and preparation method and application thereof

Abstract

The present invention provides a nanocomposite with a chemiluminescence-monitored photocontrolled drug release function, which is composed of a drug composition encapsulated by a drug-carrying molecule having a structure such as DTOR or DTNR, wherein R is a hydrophilic group; the drug composition includes a lipophilic therapeutic drug and a photosensitizer; in the nanocomposite, the molar ratio of the drug-carrying molecule to the photosensitizer is 2 to 5:1. The present invention also provides a method for preparing the nanocomposite, and the application of the nanocomposite in the preparation of a photocontrolled drug release system. In the nanocomposite of the present invention, the drug-carrying molecule not only has a self-assembly drug-carrying property, but also has a singlet oxygen response characteristic due to the presence of a specifically modified 9,10-dialkoxyanthracene (DN) group, so that the nanocomposite of the present invention has a photocontrolled rapid-release drug performance, and can perform drug release and efficient PDT treatment.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic materials, and specifically relates to a self-assembled nanocomposite based on 9,10-dialkoxyanthracene (DN) groups and having a chemiluminescence monitoring drug release function, as well as a preparation method thereof and its application as a photodynamic diagnosis and treatment platform and a multifunctional nano drug delivery platform. Background Art

[0002] Nanomaterials are often developed for the delivery of anticancer drugs due to their good modifiability, good biocompatibility, easy-to-control morphology, and high accumulation in tumors. In order to overcome the shortcomings of insufficient intracellular drug release and lack of visualization, more and more people are working hard to develop multifunctional stimuli-responsive nanocarriers.

[0003] Ideal nanocarriers have excellent drug loading, efficient tumor targeting and controllable drug release. Nanomaterials with special functional groups can be designed to have external stimulus-induced degradation properties by improving the chemical structure or through some physical methods, such as temperature response, pH response, light response, redox response, etc. Compared with other stimulus-responsive polymers, photoresponsive cleavage polymers have the characteristics of time and space control, which makes remote activation possible. Therefore, light-controlled cleavage groups that are not dependent on the physiological environment of cancer cells have attracted much attention.

[0004] In early work, polymers based on 9,10-dialkoxyanthracene (DN) groups have good photoresponsive cleavage properties. In the presence of photosensitizers, some of the singlet oxygen ( 1 O2) combines with the DN site to form a high-energy intermediate, and the unstable intermediate gradually changes to 9,10-anthraquinone (AQ), and the polymer is subsequently cleaved. At the same time, this type of polymer can encapsulate drugs through π-π stacking. Therefore, the DN group is a material suitable for synthesizing a photodegradable drug delivery platform.

[0005] The commonly used photosensitizer dihydrochlorin e6 (Ce6) has a high photodynamic effect (PDT) and can stimulate a large number of 1 O2, and there are reports that these porphyrin derivatives 1 O2 can produce sustained luminescence after interaction: Ce6 and 1O2 combines to first oxidize the C=C double bond at the α position to form an unstable dioxetane intermediate, and then continuously oxidizes the C=C double bond at the β or γ position. The intermediate gradually degrades and releases photons to produce chemiluminescence (CL). Chemiluminescence is the light produced by a substance after a chemical reaction. It is different from fluorescence and photoacoustic imaging, which require external light excitation to obtain light with higher sensitivity and deeper tissue penetration. Chemiluminescence has a fast detection speed, is easy to produce directly in situ, has no interference from autofluorescence, and has good photostability, making significant progress in medical imaging. Summary of the invention

[0006] In view of the above technical background, the primary purpose of the present invention is to provide a drug-carrying molecule with photoresponsive cleavage, the structure of which can respond to 1 O2 then breaks apart and is able to encapsulate the photosensitizer through self-assembly.

[0007] Another object of the present invention is to further provide a nanocomplex with chemiluminescence monitoring and light-controlled drug release functions based on the above-mentioned drug-carrying molecules.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned drug-carrying molecules and nanocomplexes.

[0009] Another object of the present invention is to provide application of the drug-carrying molecules and nanocomplexes in photodiagnosis and therapy.

[0010] The above-mentioned object of the present invention is achieved by the following technical solutions:

[0011] In the first aspect, the present invention first provides a precursor compound for synthesizing a drug-carrying molecule, which is a polymer having a structure as shown in formula (I):

[0012]

[0013] Here, m is a natural number less than or equal to 20, preferably a natural number of 1 to 15, more preferably a natural number of 5 to 10, and most preferably 9.

[0014] In addition, the present invention also provides a drug-carrying molecule, which is synthesized based on the precursor compound shown in the above formula (I), and the structure is shown as DTOR or DTNR below:

[0015]

[0016] Wherein, m is a natural number less than or equal to 20, preferably a natural number of 1 to 15, more preferably a natural number of 5 to 10, and most preferably 9; R is a hydrophilic group, preferably a group containing a PEG segment or a group containing a glucosamine unit; more preferably, R is any of the following structures:

[0017]

[0018] The drug carrier molecules DTOR and DTNR described in the present invention are both linear polymers containing specifically modified 9,10-dialkoxyanthracene (DN) groups, which are obtained by the condensation reaction of DN and toluene diisocyanate and end-capping with hydrophilic molecules. In this structure, the middle DN group is lipophilic, while the two ends are end-capped with hydrophilic molecules, which allows the drug carrier molecules to self-assemble into micelles in aqueous solution, and thus have the ability to load drugs through self-assembly. Most of the fat-soluble drug molecules in the prior art can be encapsulated and delivered by the drug carrier molecules described in the present invention. At the same time, in the drug carrier molecule structure described in the present invention, the DN group used has 1 O2 response characteristics can be 1 The drug-carrying molecules are broken under the action of O2, so they are cleaved after being irradiated by a 660nm laser, releasing the contained drugs. Therefore, the drug-carrying molecules of the present invention have the performance of light-controlled rapid release of drugs.

[0019] In a second aspect, the present invention provides a nanocomplex with chemiluminescence monitoring and light-controlled drug release function, which is composed of a drug composition encapsulated by the drug carrier molecules provided in the first aspect of the present invention; the drug composition includes a fat-soluble therapeutic drug and a photosensitizer; in the nanocomplex, the molar ratio of the drug carrier molecules to the photosensitizer is 2 to 5:1; preferably 2:1.

[0020] In the preferred nanocomplex of the present invention, the photosensitizer may be pyropheophorbide A (Ppa), tetrakis(4-carboxyphenyl)porphine (TCPP) or chlorin e6 (Ce6), more preferably Ce6 photosensitizer.

[0021] The nanocomposite provided by the present invention is composed of 1 The O2-responsive polymer DTOR or DTNR is self-assembled with photosensitizers including Ce6. By combining the DN group with photosensitizers such as Ce6, the photosensitizer is stimulated by light to produce 1 In the case of O2, the nanocomposite of the present invention can release drugs and perform efficient PDT treatment. In addition, the ratio of the drug-carrying molecule and the photosensitizer can be regulated to control the effect of the two. 1 In summary, based on the phenomenon of chemiluminescence after the release of drugs from nanoparticles, the present invention designs a nanocarrier that can activate and visually release drugs, and constructs a self-assembled photodynamic diagnosis and treatment platform that can monitor drug release by chemiluminescence. The nanocomplex of the present invention helps to improve the precision treatment of tumors, and its application in the biomedical field is of great significance.

[0022] In a third aspect, the present invention also provides a method for preparing the drug-carrying molecule described in the first aspect of the present invention and the nanocomplex described in the second aspect of the present invention.

[0023] First, a method for preparing the drug-carrying molecule according to the first aspect of the present invention is provided, comprising:

[0024] ① reducing 9,10-anthraquinone to 9,10-dihydroxyanthraquinone salt in an alkaline solution in the presence of a catalyst and a reducing agent, and then reacting with iodopropanol to form a compound of formula (II);

[0025]

[0026] ② subjecting the compound of formula (II) obtained in ① to a condensation reaction with toluene diisocyanate to generate a linear polymer having a structure as shown in formula (I), i.e., the precursor compound described in the first aspect of the present invention;

[0027]

[0028] ③ The precursor compound obtained in ② is capped with a hydrophilic molecule, wherein the hydrophilic molecule is selected from various types of PEG containing hydroxyl or amino groups, chitosan quaternary ammonium salts, etc., to obtain the following drug delivery molecule:

[0029]

[0030]

[0031] Wherein, the definition of R is the same as that of the first aspect of the present invention.

[0032] The preferred method for preparing the drug-carrying molecule of the present invention comprises the following steps:

[0033] 1) Synthesis of iodopropanol: 3-chloro-1-propanol and sodium iodide are mixed in an acetone solution to react to generate iodopropanol, the structural formula of which is:

[0034]

[0035] 2) Synthesis of 9,10-dialkoxyanthracene (DN): 9,10-anthraquinone, catalyst Jizhi reagent 464, and reducing agent sodium dithionite were stirred and mixed to reduce 9,10-anthraquinone; sodium hydroxide aqueous solution was added and stirred for a period of time, and the iodopropanol prepared in 1) was added dropwise to react to generate an intermediate compound DN with a structure shown in formula (II):

[0036]

[0037] 3) Synthesis of DT: The intermediate compound DN of formula (II) obtained in 2) is mixed with toluene diisocyanate to undergo polymerization reaction to generate the corresponding linear polymer DT, the structure of which is shown in the following formula (I):

[0038]

[0039] 4) Synthesis of DTOR or DTON: The compound DT of formula (I) obtained in 3) is reacted with a hydrophilic molecule R-OH or R-NH2, wherein the definition of R is the same as that of the first aspect of the present invention, to obtain the corresponding polymer DTOR or DTNR, whose structural formulas are:

[0040]

[0041]

[0042] In a further preferred embodiment, the synthetic route of the method for preparing the drug-carrying molecule is as follows:

[0043]

[0044] The specific operations of each step are:

[0045] 1) dissolving 3-chloro-1-propanol and sodium iodide in an acetone solution, and repeatedly freezing and thawing with liquid nitrogen to remove oxygen, and reflux at 70-80° C. overnight to react. After the reaction is completed, the obtained product is washed and precipitated with ether and dichloromethane, and the solvent is removed to obtain iodopropanol;

[0046] 2) Under nitrogen atmosphere, 9,10-anthraquinone, Jizhi reagent 464, and sodium dithionite were stirred evenly in a water-oil mixed solvent, and a quantitative sodium hydroxide solution was added, followed by dropwise addition of iodopropanol solution, and the mixture was refluxed at 40-60° C. overnight to generate product DN after multiple low-temperature recrystallizations;

[0047] 3) Under nitrogen atmosphere, DN and toluene diisocyanate (TDI) were mixed and dissolved in N,N-dimethylformamide (DMF) for polymerization reaction, and reacted at 45-85°C for 20-25h in the presence of 4-dimethylaminopyridine (DMAP). Ether was added for precipitation to obtain the corresponding linear polymer DT;

[0048] 4) Under nitrogen atmosphere, DT and a hydrophilic molecule R-OH or R-NH2 are dissolved in N,N-dimethylformamide (DMF), wherein the definition of R is the same as that of the first aspect of the present invention, and reacted at 45-85° C. for 20-25 h in the presence of DMAP, and ether is added for precipitation to obtain the corresponding polymer DTOR or DTNR.

[0049] Furthermore, the molar ratio of 3-chloro-1-propanol to sodium iodide used in step 1) is 1:3 to 1:5.

[0050] Furthermore, the molar ratio of 9,10-anthraquinone and Jizhi reagent 464 used in step 2) is 1:1 to 1:3; the molar ratio of 9,10-anthraquinone and sodium dithionite is 1:1 to 1:3; the molar ratio of 9,10-anthraquinone and sodium hydroxide is 1:1 to 1:3; the molar ratio of 9,10-anthraquinone and iodopropanol is 1:1 to 1:6.

[0051] Furthermore, in step 3), the molar ratio of 9,10-dialkoxyanthracene to toluene diisocyanate is 1:0.5 to 1:3, and the molar ratio of 9,10-dialkoxyanthracene to DMAP is 1:1 to 1:2.

[0052] Furthermore, in step 4), the molar ratio of DT to the hydrophilic molecule R-OH or R-NH2 is 1:1 to 1:3, and the molar ratio of DT to DMAP is 1:1 to 1:2.

[0053] Furthermore, the present invention provides a method for preparing the nanocomplex of the present invention, comprising: mixing the drug carrier molecule, the fat-soluble therapeutic drug and the photosensitizer of the first aspect of the present invention, controlling the molar ratio of the DN group in the drug carrier molecule to the photosensitizer to be 2:1 to 5:1, and ultrasonically dissolving the mixed material in an organic solvent, and then dropping the obtained solution into a mixed solution of the organic solvent and deionized water in a volume ratio of 1:8 to 10, stirring for 0.5 to 2 hours and then dialyzing for 3 days to obtain a solution containing the nanocomplex of the second aspect of the present invention.

[0054] In the preferred method for preparing the nanocomposite, the photosensitizer can be selected from pyropheophorbide A (Ppa), tetrakis(4-carboxyphenyl)porphine (TCPP) or dihydrochlorin e6 (Ce6), more preferably Ce6 photosensitizer.

[0055] In the preferred method for preparing the nanocomposite, the organic solvent may be any one of tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide solution, and dimethyl sulfoxide solution is most preferred.

[0056] In a preferred method for preparing the nanocomplex, during the 3-day dialysis, water is replaced every 3 hours on the first day, and every 6 hours on the second and third days.

[0057] In a fourth aspect, the present invention further provides use of the drug-carrying molecule described in the first aspect of the present invention or the nanocomplex provided in the second aspect of the present invention in the preparation of a light-controlled drug release system.

[0058] The light-controlled drug release system prepared by using the nanocomposite of the present invention can be used as a light diagnosis and treatment platform. When the light diagnosis and treatment platform is irradiated with a 660nm laser, the photosensitizer can be excited to produce singlet oxygen. 1 O2. Singlet oxygen1 O2 is preferentially absorbed by the polymer DTOR or DTNR in the nanocomposite, causing the nanocomposite platform to disintegrate, and then combine with the photosensitizer to produce chemiluminescence. Based on this principle, the optical diagnostic and therapeutic platform can be used for light-controlled drug release and efficient PDT treatment, and can be monitored in real time by chemiluminescence imaging.

[0059] Compared with traditional drug-carrying polymers, the present invention has the following beneficial effects:

[0060] 1. The invention can be 1 The synthetic route of O2-destroyed polymers DTOR or DTNR is simple and efficient.

[0061] 2. The invention can be 1 The O2-destroyed polymers DTOR or DTNR have stability and low toxicity.

[0062] 3. The self-assembled optical diagnostic and therapeutic nanoplatform obtained by the present invention has the characteristics of light-controlled rapid release, and can quickly release drugs after illumination, with advantages such as efficient treatment.

[0063] 4. The drug-carrying molecules of the self-assembled photo-diagnostic nano-platform obtained by the present invention can increase the encapsulation rate with many fat-soluble drugs through π-π stacking.

[0064] In summary, the self-assembled phototherapy nanoplatform obtained by the present invention can encapsulate fat-soluble photosensitizers (such as dihydrochlorin e6 (Ce6)) and therapeutic drugs, and produce 1 O2, forming an optical diagnosis and treatment platform with light-controlled rate release, chemiluminescence monitoring, and photodynamic therapy effect, which improves the disadvantages of traditional drug delivery platforms that cannot release drugs visually and controllably, and has great application prospects in the integration of biological diagnosis and treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 The iodopropanol prepared in step A1 of Example 1 1 H NMR spectrum.

[0066] Figure 2 The DN prepared in step A2 of Example 1 1 H NMR spectrum.

[0067] Figure 3 is the DT prepared in step A3 of Example 1 1 H NMR spectrum.

[0068] Figure 4 is the DTOP prepared in step A4 of Example 1 1 H NMR spectrum.

[0069] Figure 5is the CT prepared in step B1 of comparative example 1 1 H NMR spectrum.

[0070] Figure 6 is the CTOP prepared in step B2 of Comparative Example 1 1 H NMR spectrum.

[0071] Figure 7 It reflects the change in the nanoparticle size of the drug-loaded molecules prepared in Example 2 after encapsulating Ce6, whether or not it is irradiated with light.

[0072] Figure 8 The results show that the nanoparticle size of the Ce6 nanoparticles prepared in Example 3 changes with or without light exposure.

[0073] Fig. 9 It reflects the change in nanoparticle size of the drug-loaded molecules prepared in Comparative Example 2 after encapsulating Ce6, whether or not they are irradiated with light.

[0074] Fig.10 It reflects the change in the nanoparticle size of the drug-loaded molecules prepared in Comparative Example 3 after encapsulating Ce6, whether it is irradiated with light or not.

[0075] Fig.11 It reflects the change in the nanoparticle size of the drug-loaded molecules prepared in Comparative Example 4 after encapsulating Ce6, whether it is irradiated with light or not.

[0076] Fig.12 The Zeta potential of the nanoparticles prepared in Example 2, Comparative Example 3, Example 3, and Comparative Example 4 after encapsulating Ce6 with drug molecules in different proportions is reflected.

[0077] Fig.13 These are the chemiluminescence images of the nanoparticles after Ce6 was wrapped with drug-loaded molecules in corresponding proportions prepared in Comparative Example 3, Example 2 and Example 3 under illumination.

[0078] Fig.14 The chemiluminescence quantitative graphs of the nanoparticles after Ce6 was wrapped with drug-loaded molecules in corresponding proportions prepared in Comparative Example 3, Example 2 and Example 3 under illumination.

[0079] Fig.15 This is a graph showing the fluorescence emission ratio of Ce6 of the nanoparticles prepared in Example 2 and Comparative Example 3 after being irradiated for different periods of time.

[0080] Fig.16 The SOSG fluorescence spectra of the Ce6 nanoparticles encapsulated by DTOP prepared in Example 2 after being irradiated for different time periods.

[0081] Fig.17 This is the SOSG fluorescence spectrum of the Ce6 nanoparticles encapsulated by CTOP prepared in Comparative Example 3 after being irradiated for different times.

[0082] Fig.18 The fluorescence spectra of SOSG without any nanoparticles after exposure to light for different time periods.

[0083] Fig.19 The graph shows the fluorescence emission ratio of SOSG of the nanoparticles prepared in Example 2 and Comparative Example 3 and SOSG alone after being irradiated for different time periods.

[0084] Fig. 20 The UV absorption spectra of the Ce6 nanoparticles encapsulated by DTOP prepared in Example 2 after being irradiated for different time periods.

[0085] Fig.21 The UV absorption spectra of the Ce6 nanoparticles encapsulated by CTOP prepared in Comparative Example 3 after being irradiated for different times.

[0086] Fig. 22 The graph is a graph showing the change ratio of ultraviolet absorption of the nanoparticles prepared in Example 2 and Comparative Example 3 after being irradiated for different periods of time.

[0087] Fig.23 It reflects the release rate of the drug-loaded nanocomplex prepared in Example 4 under light conditions. DETAILED DESCRIPTION

[0088] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0089] Example 1. Preparation of polymer drug carrier molecules containing specifically modified 9,10-dialkoxyanthracene (DN) groups A1. Synthesis of iodopropanol

[0090]

[0091] 3-Chloro-1-propanol (945.4 mg, 10 mmol) and acetone (200 mL) were mixed and frozen and thawed three times with liquid nitrogen to remove oxygen. Under a nitrogen atmosphere, the above mixture was added with NaI (3 g, 20 mmol) and refluxed at 80°C overnight. After the reaction was cooled, the solution was filtered and evaporated to remove the solvent to obtain a yellow paste precipitate, and ether solution was added. The precipitate was removed and the solvent was evaporated to obtain a reddish brown oily product. The product was ultrasonically dissolved with dichloromethane and water and then separated. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed to obtain iodopropanol, which could be further purified by column chromatography (dichloromethane: ethyl acetate = 4:1) to obtain 1.69 g of a yellow viscous product iodopropanol (yield 91%). 1H NMR (600MHz, CHLOROFORM-D) δ3.73 (td, J = 5.9, 2.2 Hz, 2H), 3.29 (td, J = 6.8, 2.2 Hz, 2H), 2.09–1.95 (m, 2H). 1 H NMR spectrum is shown in Figure 1 .

[0092] Synthesis of A2 and DN

[0093]

[0094] 120 mL of water and 120 mL of dichloromethane were mixed and then frozen and thawed three times with liquid ammonia to remove oxygen. The mixture was added to a 500 mL round-bottom flask containing 9,10-anthraquinone (2.57 g, 0.012 mol), Jizhi reagent 464 (14.55 g, 0.036 mol), and sodium dithionite (2.09 g, 0.012 mol) under a nitrogen atmosphere and refluxed. Then, sodium hydroxide (0.48 g, 0.012 mol) solution was added. After stirring for a period of time, 3-iodo-1-propanol (4.46 g, 0.024 mol) was added and refluxed at 50°C overnight. After the reaction was completed, the two phases were separated, and the aqueous phase was extracted with dichloromethane solution 2-3 times and mixed. Then, the mixture was washed with deionized water 1-2 times, and the organic phases were combined and dried with anhydrous sodium sulfate. After removing the solvent and allowing precipitation to proceed overnight, the obtained yellow solid was further purified by multiple recrystallizations to finally obtain 978 mg of a light yellow product, iodopropanol (yield 24.6%). 1 H NMR (600MHz, DMSO-D6) δ8.32–8.17 (m, 4H), 7.52 (dd, J=6.8, 3.4 Hz, 4H), 4.63 (t, J=4.9 Hz, 2H), 4.16 (t, J=6.2 Hz, 4H), 3.76 (q, J=5.7 Hz, 4H), 2.10 (p, J=6.1 Hz, 4H). 1 H NMR spectrum is shown in Figure 2 .

[0095] A3. Synthesis of DT

[0096]

[0097] Under a nitrogen atmosphere, DN (100 mg, 0.3 mmol) and DMAP (73.3 mg, 0.6 mmol) were dissolved in 5 mL of anhydrous N,N-dimethylformamide (DMF) solution, and toluene diisocyanate (TDI) (52.26 mg, 0.3 mmol) was added dropwise. After stirring at 50 °C for 24 h, the mixture was precipitated with ether three times to obtain 133 mg of a light yellow product (yield 87.4%). 1H NMR (600MHz, DMSO-D6) δ8.20 (s, 1H), 7.48 (s, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 2.11 (d, J = 42.7 Hz, 1H). 1 H NMR spectrum is shown in Figure 3 .

[0098] Synthesis of A4 and DTOP

[0099]

[0100] Under a nitrogen atmosphere, DT (100 mg, 0.021 mmol), hydrophilic molecule polyethylene glycol monomethyl ether (210 mg, 0.042 mmol), and DMAP (5.13 mg, 0.042 mmol) were mixed and dissolved in 5 mL of anhydrous N,N-dimethylformamide (DMF) solution for polymerization reaction. After stirring at 45 ° C for 20 h, the mixture was precipitated with ether three times to obtain 139.5 mg of a light yellow product (yield 45%). 1 HNMR (600MHz, DMSO-D6) δ8.20 (s, 4H), 7.48 (s, 4H), 4.41 (s, 4H), 4.17 (s, 4H), 3.99 (s, 1H), 2.07 (s, 4H). 1 H NMR spectrum is shown in Figure 4 .

[0101] Comparative Example 1: Preparation of a polymer drug-carrying molecule not containing a 9,10-dialkoxyanthracene (DN) group

[0102] B1. Synthesis of CT

[0103]

[0104] Under a nitrogen atmosphere, 1,10-decanediol (100 mg, 0.57 mmol) and DMAP (140.19 mg, 1.15 mmol) were dissolved in 5 mL of anhydrous N,N-dimethylformamide (DMF) solution, and toluene diisocyanate (TDI) (99.27 mg, 0.6 mmol) was added dropwise. After stirring at 50 °C for 24 h, the mixture was precipitated three times with ether to obtain 117 mg of a white product (yield 58.7%). 1 H NMR (600 MHz, DMSO-D6) δ 4.00 (s, 4H), 1.56 (s, 4H), 1.28 (d, J = 81.5 Hz, 21H). 1 H NMR spectrum is shown in Figure 5 .

[0105] Synthesis of B2 and CTOP

[0106]

[0107] Under a nitrogen atmosphere, CT (100 mg, 0.023 mmol), hydrophilic molecule polyethylene glycol monomethyl ether (229.86 mg, 0.046 mmol), and DMAP (5.62 mg, 0.046 mmol) were mixed and dissolved in 5 mL of anhydrous N,N-dimethylformamide (DMF) solution for polymerization reaction. After stirring at 45 ° C for 20 h, the mixture was precipitated with ether three times to obtain 170 mg of a light yellow product (yield 51.54%). 1 H NMR (600MHz, DMSO-D6) δ3.99 (s, 4H), 3.20 (d, J=2.2Hz, 3H), 1.55 (s, 4H), 1.35–1.21 (m, 21H). 1 H NMR spectrum is shown in Figure 6 .

[0108] Example 2, Preparation of Nanoparticle-I

[0109] The DTOP drug carrier molecule prepared by A4 in Example 1 and commercially available Ce6 were weighed separately, the drug carrier molecule and Ce6 were mixed so that the molar ratio of the DN group in DTOP to Ce6 was 2:1, and the mixed material was ultrasonically dissolved in a dimethyl sulfoxide solution, and then added dropwise into a mixed solution of dimethyl sulfoxide and deionized water in a volume ratio of 1:9, stirred for half an hour, and dialyzed. The water was replaced every 3 hours on the first day, and every 6 hours on the second and third days. The resulting solution was a solution containing nanoparticles-I.

[0110] Example 3. Preparation of Nanoparticles-II

[0111] The DTOP drug carrier molecule prepared by A4 in Example 1 and commercially available Ce6 were weighed separately, the drug carrier molecule and Ce6 were mixed so that the molar ratio of the DN group in DTOP to Ce6 was 5:1, and the mixed material was ultrasonically dissolved in a dimethyl sulfoxide solution, and then added dropwise into a mixed solution of dimethyl sulfoxide and deionized water in a volume ratio of 1:9, stirred for half an hour, and dialyzed. The water was replaced every 3 hours on the first day, and every 6 hours on the second and third days. The resulting solution is a solution containing nanoparticles-II.

[0112] Comparative Example 2: Preparation of Control Nanoparticles-III

[0113] The DTOP drug-carrying molecule prepared by A4 in Example 1 and commercially available Ce6 were weighed separately, the drug-carrying molecule and Ce6 were mixed so that the molar ratio of the DN group in DTOP to Ce6 was 10:1, and the mixed material was ultrasonically dissolved in a dimethyl sulfoxide solution, and then added dropwise into a mixed solution of dimethyl sulfoxide and deionized water in a volume ratio of 1:9, stirred for half an hour, and dialyzed. The water was replaced every 3 hours on the first day, and every 6 hours on the second and third days. The resulting solution is a solution containing nanoparticles-III.

[0114] Comparative Example 3: Preparation of Control Nanoparticles-IV

[0115] The drug-carrying molecule CTOP prepared by B2 in Comparative Example 1 and commercially available Ce6 were weighed separately, mixed, and the drug-carrying molecule and Ce6 were mixed so that the molar ratio of 1,10-cetodiol group in CTOP to Ce6 was 2:1, and the mixed material was ultrasonically dissolved in a dimethyl sulfoxide solution, and then added dropwise into a mixed solution of dimethyl sulfoxide and deionized water in a volume ratio of 1:9, stirred for half an hour, and dialyzed. The water was replaced every 3 hours on the first day, and every 6 hours on the second and third days. The resulting solution is a solution containing control nanoparticles-IV.

[0116] Comparative Example 4: Preparation of Control Nanoparticles-V

[0117] The drug carrier molecule CTOP prepared by B2 in Comparative Example 1 and commercially available Ce6 were weighed separately, mixed, and the drug carrier molecule and Ce6 were mixed so that the molar ratio of 1,10-cetodiol group in CTOP to Ce6 was 5:1, and the mixed material was ultrasonically dissolved in a dimethyl sulfoxide solution, and then added dropwise into a mixed solution of dimethyl sulfoxide and deionized water in a volume ratio of 1:9, stirred for half an hour, and dialyzed. The water was replaced every 3 hours on the first day, and every 6 hours on the second and third days. The resulting solution is a solution containing control nanoparticles-V.

[0118] Nanoparticle size and potential testing

[0119] The nanoparticle sizes of the series of nanoparticles prepared above (nanoparticle-I, nanoparticle-II, control nanoparticle-III, control nanoparticle-IV and control nanoparticle-V) were measured by nanoparticle size and Zeta potential analyzer, and each nanoparticle was illuminated under the same illumination conditions to observe the changes in the particle size of each nanoparticle before and after illumination. The measurement results are shown in Figure 7 to Figure 11 , it was found that under DN:Ce6=10:1 ( Fig. 9 ), the nanoparticle size remained basically unchanged after illumination, indicating that under the condition of DN:Ce6=10:1, the quantitative 1O2 is not enough to cleave a large amount of DN. The Zeta potential analysis results of the nanoparticles prepared in Example 2, Example 3, Comparative Example 3 and Comparative Example 4 are as follows: Fig.12 As shown in Figure 2, the smaller the molecules or dispersed particles are, the higher the absolute value of the Zeta potential (positive or negative) is, and the more stable the system is, that is, the dissolution or dispersion can resist aggregation. Fig.12 The results show that the nanoparticles prepared in Examples 2 and 3 of the present invention are more stable than the nanoparticles prepared in Comparative Examples 3 and 4, and the nanoparticles prepared in Example 2 of the present invention have the best stability.

[0120] Lighting experiment

[0121] The chemiluminescence phenomenon of the solution containing nanoparticles-IV (A) prepared in the above comparative example 3, the solution containing nanoparticles-I (B) prepared in Example 2, and the solution containing nanoparticles-II (C) prepared in Example 3 under 660nm laser light irradiation was tested. Each solution was irradiated for different time periods, and the corresponding chemiluminescence images were taken using a small animal imaging device (see Fig.13 , Fig.13 The three rows of test tubes from top to bottom correspond to solution (A), solution (B), and solution (C), and the average ROI is read and plotted (see Fig.14 , Fig.14 The three curves A, B and C in the figure correspond to solution (A), solution (B) and solution (C) respectively. Figure 13-14 The results show that when the amount of Ce6 encapsulated in each nanoparticle remains unchanged, as the amount of drug-loaded molecules increases, the chemiluminescence phenomenon is delayed and the intensity decreases. Fig.15 It was concluded that the presence of DN groups delayed the decomposition of photosensitizer Ce6 and weakened the decrease in its fluorescence intensity. This proves that materials containing DN groups can compete with Ce6 for the fluorescence produced by light. 1 O2, that is, the drug-carrying molecules in the nanocomplex provided by the present invention can first absorb 1 O2 cleavage produces 9,10-anthraquinone, followed by nanoparticle cleavage to release the internal drug. 1 O2 then combines with Ce6, and Ce6 cleaves and produces chemiluminescence, achieving a visual effect of drug release. In order not to lose too much luminescence intensity, the molar ratio of DN group and Ce6 in the nanoparticles prepared in Example 2 of the present invention is finally determined to be 2:1 as the optimal ratio.

[0122] Fluorescence, UV test

[0123] The nanoparticles prepared in Example 2 (the molar ratio of DN group to Ce6 is 2:1) and the nanoparticles prepared in Comparative Example 3 (the molar ratio of 1,10-decanediol group to Ce6 is 2:1) were tested respectively. 1The O2 release capacity of the two materials was tested by fluorescence spectrophotometer under 660nm laser irradiation. 1 O2 release capacity is determined by the increase in SOSG fluorescence. 1 O2 generation, test results see Figure 16-Figure 19 As can be seen from the figure, the fluorescence value of SOSG of the nanoparticles prepared by the two methods increases continuously under light, while the fluorescence peak of SOSG alone does not change significantly under light, thus proving that the nanoparticles have the ability to produce 1 O2 capabilities.

[0124] The ultraviolet absorption changes of the nanoparticles prepared in Example 2 (the molar ratio of DN group to Ce6 is 2:1) and the nanoparticles prepared in Comparative Example 3 (the molar ratio of 1,10-decanediol group to Ce6 is 2:1) were tested respectively, and the different absorption of the two materials under 660nm laser irradiation was tested by ultraviolet spectrophotometer to verify the DTOR 1 O2's responsiveness, test results see Figure 20-22 As can be seen from the figure, the peak value of the ultraviolet characteristic absorption peak of the nanoparticles prepared in Example 2 decreases continuously with light exposure, while the change of the nanoparticles prepared in Comparative Example 3 is not obvious (because Ce6 itself has absorption at around 405nm, and Ce6 will have a slight decomposition phenomenon under light exposure, so the ultraviolet absorption peak of the nanoparticles prepared in Comparative Example 3 will also have a slight decrease phenomenon). Therefore, the nanoparticles prepared in Example 2 (the molar ratio of DN group to Ce6 is 2:1) have a certain 1 O2's responsiveness.

[0125] Example 4: Preparation of a nanocomposite with chemiluminescence monitoring and light-controlled drug release function

[0126] The commercially available photosensitizer Ce6, the drug-carrying molecule DTOP prepared in Example 1, and the drug to be encapsulated were prepared into nanoparticles according to the method of Example 2, that is, the drug-carrying molecule DTOP and Ce6 were mixed so that the molar ratio of the DN group in DTOP to Ce6 was 2:1, and a certain amount of the drug to be encapsulated was added at the same time, and the mixed materials were ultrasonically dissolved in a dimethyl sulfoxide solution, and then treated by the dropping, stirring and dialysis method described in Example 2 to obtain a solution containing a nanocomposite having the function of chemiluminescence monitoring and light-controlled drug release. The encapsulation rate of the nanocomposite was calculated to be about 45% by an ultraviolet spectrophotometer.

[0127] Take out two portions of the nanocomposite prepared in this example, with 500 μL as one portion, one portion is irradiated with 660 nm laser for 10 min, and the other portion is not treated. The two portions are placed in a dialysis bag with a molecular weight of 3500 KDA, and then placed in a 50 mL centrifuge tube containing 30-40 mL of release medium (wherein the release medium is a mixture of deionized water and 2% Tween 20). The centrifuge tube is placed on a shaker and shaken at 200 rpm. 50 μL of samples are taken at 0 h, 2 h, 4 h, 8 h, 12 h and 36 h, respectively, and 50 μL of new release medium is added. After summing up, the drug concentration is tested using an ultraviolet spectrophotometer and the release amount is calculated. The test results are shown in Fig.23 ,It can be clearly seen that under light ,the drug release rate of the nanocomplex will be higher, which has the expected effect.

Claims

1. A precursor compound for synthesizing a drug-carrying molecule, which is a polymer having a structure as shown in formula (I): in, m is a natural number less than or equal to 20.

2. The precursor compound according to claim 1, characterized in that: In the formula (I), m is a natural number of 1-15.

3. The precursor compound according to claim 1, characterized in that: In the formula (I), m is a natural number of 5 to 10.

4. The precursor compound according to claim 1, characterized in that: In the formula (I), m is 9.

5. A drug-carrying molecule, characterized in that: The structure is shown in the following DTOR: Wherein, m is a natural number less than or equal to 20; R is the following structure: Where n is 113.

6. The drug carrier molecule according to claim 5, characterized in that In the DTOR structure, m is a natural number ranging from 1 to 15.

7. The drug carrier molecule according to claim 5, characterized in that In the DTOR structure, m is a natural number ranging from 5 to 10.

8. The drug carrier molecule according to claim 5, characterized in that The m in the DTOR structure is 9.

9. A method for preparing the precursor compound of claim 1, comprising: ① reducing 9,10-anthraquinone to 9,10-dihydroxyanthraquinone salt in an alkaline solution in the presence of a catalyst and a reducing agent, and then reacting with iodopropanol to form a compound of formula (II); ② subjecting the compound of formula (II) obtained in ① to a condensation reaction with toluene diisocyanate to generate a linear polymer having a structure as shown in formula (I), i.e., the precursor compound as described in claim 1; 10. A method for preparing the drug carrier molecule according to any one of claims 5 to 8, comprising: The precursor compound obtained in claim 9 is capped with a hydrophilic molecule, wherein the hydrophilic molecule contains a PEG segment, to obtain the following drug-carrying molecule: Wherein, the R is the following structure: Where n is 113.

11. A method for preparing the drug carrier molecule according to any one of claims 5 to 8, comprising the following steps: 1) Synthesis of iodopropanol: 3-chloro-1-propanol and sodium iodide are mixed in an acetone solution to react to generate iodopropanol, the structural formula of which is: 2) Synthesis of 9,10-dialkoxyanthracene (DN): 9,10-anthraquinone, phase transfer catalyst Jizhi reagent 464, and reducing agent sodium dithionite are stirred in a water-oil mixed solvent to reduce 9,10-anthraquinone; sodium hydroxide aqueous solution is added and stirred for a period of time, and the iodopropanol prepared in 1) is added dropwise to react to generate an intermediate compound DN with a structure shown in formula (II): 3) Synthesis of DT: The intermediate compound DN of formula (II) obtained in 2) is mixed with toluene diisocyanate to undergo polymerization reaction to generate the corresponding linear polymer DT, the structure of which is shown in the following formula (I): Wherein, m is a natural number less than or equal to 20; 4) Synthesis of DTOR: The compound DT of formula (I) obtained in 3) is reacted with a hydrophilic molecule R-OH to obtain the corresponding polymer DTOR, whose structural formulas are: Where R is the following structure: Where n is 113.

12. A method for preparing the drug-carrying molecule according to any one of claims 5 to 8, characterized in that: The specific operations of each step are: 1) dissolving 3-chloro-1-propanol and sodium iodide in an acetone solution, wherein the molar ratio of 3-chloro-1-propanol to sodium iodide is 1:3 to 1:5, and repeatedly freezing and thawing with liquid nitrogen to remove oxygen, and reflux at 70-80° C. overnight to react. After the reaction is completed, the obtained product is precipitated by washing with ether and dichloromethane, and the solvent is removed to obtain iodopropanol; 2) Under nitrogen atmosphere, 9,10-anthraquinone, Jizhi reagent 464 and sodium dithionite are stirred evenly in a water-oil mixed solvent, a quantitative sodium hydroxide solution is added, and then the iodopropanol solution obtained in 1) is added dropwise, and the mixture is refluxed at 40-60° C. overnight to react, and product DN is generated after multiple low-temperature recrystallizations; the molar ratio of 9,10-anthraquinone to Jizhi reagent 464 is 1:1 to 1:3; the molar ratio of 9,10-anthraquinone to sodium dithionite is 1:1 to 1:3; the molar ratio of 9,10-anthraquinone to sodium hydroxide is 1:1 to 1:3; the molar ratio of 9,10-anthraquinone to iodopropanol is 1:1 to 1:6; 3) Under a nitrogen atmosphere, the DN obtained in 2) is mixed with toluene diisocyanate (TDI), dissolved in N,N-dimethylformamide (DMF) for polymerization reaction, reacted at 45-85° C. for 20-25 hours in the presence of 4-dimethylaminopyridine (DMAP), and ether is added for precipitation to obtain the corresponding linear polymer DT; the molar ratio of 9,10-dialkoxyanthracene to toluene diisocyanate is 1:0.5-1:3, and the molar ratio of 9,10-dialkoxyanthracene to DMAP is 1:1-1:2; 4) Under a nitrogen atmosphere, dissolving the DT obtained in 3) and the hydrophilic molecule R-OH in N,N-dimethylformamide (DMF), wherein R is a hydrophilic group containing a PEG segment, reacting at 45-85° C. for 20-25 h in the presence of DMAP, and adding ether for precipitation to obtain the corresponding polymer DTOR; the molar ratio of DT to the hydrophilic molecule R-OH is 1:1-1:3, and the molar ratio of DT to DMAP is 1:1-1:

2.

13. Use of the drug-carrying molecule according to any one of claims 5 to 8 in the preparation of a light-controlled drug release system.

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