Boron-rich polymer nano particle with organelle targeting property as well as preparation method and application of boron-rich polymer nano particle

Abstract

The invention discloses boron-rich polymer nanoparticles with organelle targeting as well as a preparation method and application of the boron-rich polymer nanoparticles. The naphthalimide and the dodecahydrododecaborate are subjected to azide-alkyne cycloaddition to form the boron-containing medicine. The boron-rich polymer nanoparticle is formed by electrostatic self-assembly of a boron-containing drug and a block polymer, has the particle size of 20-200nm, has a pomegranate-like structure, and has the functions of high boron content (greater than or equal to 10wt%), low dark toxicity (the cell survival rate is greater than or equal to 90%), good biocompatibility, specific tumor specific organelle targeting (the co-localization coefficient is greater than or equal to 0.82) and fluorescence imaging tracing. The method can be used for monitoring the treatment process in real time. According to the invention, the effect of boron neutron capture therapy (BNCT) is obviously improved, side effects on normal tissues are reduced, and the method has a wide application prospect in the field of tumor treatment.

Description

Technical Field

[0001] The present invention belongs to the fields of biomedicine technology and drug delivery, and particularly relates to a boron-rich polymer nanoparticle with organelle targeting property, and a preparation method and application thereof. Background Art

[0002] Boron neutron capture therapy (BNCT) is a precise radiotherapy mode based on nuclear capture and fission reactions, which has the advantages of short treatment cycle, small damage to adjacent healthy tissues, strong penetrability, no need for oxygen enhancement effect, and relatively low cost. During the BNCT process, the patient receives an appropriate dose of a boron compound rich in the stable isotope 10 B, which specifically targets tumor cells. Subsequently, the local tumor tissue is irradiated with a thermal neutron beam or an epithermal neutron beam. Due to 10 the significant affinity of 7 B for neutron capture, boron-containing cells will undergo a neutron capture reaction, releasing charged particles, generating alpha particles and 3+ Li

[0003] This reaction generates sufficient energy to effectively eradicate tumor cells. In addition, in water or tissue, the energy transfer path length is limited to the range of 4.5 - 10 μm, which is approximately equivalent to the diameter of a single cell. This property enables the selective elimination of tumor cells while minimizing damage to normal cells. In theory, BNCT can achieve precise targeted therapy by ensuring the sufficient and accurate delivery of boron compounds to tumor tissues.

[0004] CN119385954A discloses a drug-controlled release layer-by-layer self-assembled nano hydrogel boron carrier and its application. By loading boric acid in the layer-by-layer self-assembled nano hydrogel material, the intelligent controlled release of boric acid is achieved, and it has good biocompatibility. However, the nano hydrogel only targets tissues through local administration, and does not precisely target organelles to achieve efficient drug delivery.

[0005] CN116637191A discloses a carrier-free self-assembled nanoparticle based on boron neutron capture therapy, and a preparation method and application thereof, which is composed of a 10B drugs, polyphenol drugs and metal ions are self-assembled, and the interaction between drug molecules is used to form carrier-free self-assembled nanoparticles of various drugs without a carrier. It has the advantages of high boron content and good biocompatibility, but it also lacks tumor-specific targeting and fluorescence tracing capabilities.

[0006] CN115160181A discloses the application of a fluorescent probe in boron neutron capture therapy and its synthesis method. The probe can specifically bind to boron phenylalanine to trace and quantitatively detect boron, but its accumulation capacity and biocompatibility in tumor sites are relatively poor.

[0007] CN113318227 discloses a boron-doped tumor targeting drug and its preparation method and application, wherein the boron-doped tumor targeting drug comprises a polypeptide, a hydrophobic molecule located at the nitrogen end of the polypeptide, and a disodium thiododecaborane salt located on the lysine of the polypeptide, and has the advantages of achieving specific enrichment in tumor cells, good biocompatibility, and low toxicity. Most of the targeting groups reported in the patents are modified with polypeptides, and there are few reports on using fluorescent small molecule dyes for targeting and tracing.

[0008] Although many efforts have been made to improve the performance of boron delivery systems, existing technologies still face a series of problems that need to be solved: first, insufficient boron content limits the therapeutic effect; second, the selectivity and specificity of existing boron carriers are poor, making it difficult to achieve efficient and specific delivery of boron to tumor cells; in addition, the stability and biocompatibility of many boron delivery systems in vivo cannot meet clinical needs, which not only affects the effective delivery of boron, but also may cause unnecessary side effects. At the same time, the lack of real-time monitoring function also limits the accurate evaluation of the boron delivery process and therapeutic effect. The existence of these problems urgently requires the development of a new boron delivery system. Summary of the invention

[0009] The present invention is designed to solve the above problems and provides a boron-rich polymer nanoparticle with organelle targeting and a preparation method thereof, which aims to significantly improve the therapeutic effect of BNCT by optimizing the physicochemical properties and biological characteristics of boron compounds, while reducing the side effects on normal tissues, and opening up new avenues for cancer treatment. The present invention provides a boron-rich polymer nanoparticle with organelle targeting through electrostatic self-assembly of boron-containing naphthalimide derivatives and block polymers, which increases the boron accumulation in the tumor site by accurately delivering the boron delivery agent to the tumor site, thereby improving the killing effect of tumor cells while reducing damage to normal cells.

[0010] This innovative design concept will greatly promote the development of the BNCT field, overcome the limitations of existing technologies, and show broad prospects for clinical application.

[0011] In a first aspect, the present invention provides a boron-rich polymeric nanoparticle with organelle targeting property, which is formed by electrostatic self-assembly of a borane-containing naphthalimide derivative and a block polymer, has a particle size of 20 - 200 nm, and has a pomegranate-like structure; wherein,

[0012] The 4-position substituent of the borane-containing naphthalimide derivative is selected from one of methyl, ethyl, morpholine, pyrrolidine, piperazine, and methylpiperazine.

[0013] The borane is an azide-modified dodecahydrododecaborate.

[0014] The particle size of the nanoparticle is controlled by adjusting the length of the tetramethylguanidine block in the block polymer; the nanoparticle has mitochondrial targeting property (co-localization coefficient ≥ 82%), boron content ≥ 10 wt%, and low dark toxicity (cell survival rate ≥ 90%). Its applications include the preparation of the following preparations: boron neutron capture therapy (BNCT) preparation, fluorescence imaging preparation, organelle targeting preparation, and biocompatible preparation.

[0015] In a second aspect, the present invention provides a preparation method of the naphthalimide derivative required for the boron-rich polymeric nanoparticle with organelle targeting property described above, including the following steps:

[0016] (1) Dissolve 4-bromo-1,8-naphthalimide and ethanolamine in organic solvent I, heat under reflux for 4 - 8 h, cool to room temperature, filter, concentrate by rotary evaporation, wash, and obtain product II; the heating temperature is 80 - 120 °C; the organic solvent I includes methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, ethylene glycol monomethyl ether, preferably ethanol; the molar ratio of 4-bromo-1,8-naphthalimide to ethanolamine is 1:(1 - 5); preferably, the molar ratio of 4-bromo-1,8-naphthalimide to ethanolamine is 1:(1 - 2);

[0017] (2) Dissolve product II and drug III in organic solvent IV, heat under reflux for 8 - 24 h, cool to room temperature, filter, dry, and purify to obtain product V; the drug III is selected from at least one of dimethylamine, diethylamine, morpholine, pyrrolidine, piperazine, and methylpiperazine; the organic solvent IV includes ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, ethanol, preferably ethylene glycol monomethyl ether; the molar ratio of product II to drug III is 1:(1 - 10);

[0018] (3) Under an anhydrous and anaerobic environment, dissolve the deprotonating reagent and product V in organic solvent VI, react at room temperature for 2 - 6 h, then add 1-halopropyne, react at room temperature overnight, quench and purify to obtain product VII; the molar ratio of product V, 1-halopropyne, and deprotonating reagent is 1:(1 - 3):(3 - 10); preferably, the molar ratio of product V to 1-halopropyne and deprotonating reagent is 1:(1.2 - 1.5):5; the organic solvent VI is selected from at least one of anhydrous dichloromethane, anhydrous N,N-dimethylformamide, and anhydrous 1,4-dioxane; the 1-halopropyne includes 1-bromopropyne, 1-chloropropyne, 1-iodopropyne, 1-fluoropropyne, preferably 1-bromopropyne; the deprotonating reagent is selected from one of sodium hydride, potassium hydride, lithium aluminum hydride, calcium hydride, lithium hydride, Grignard reagent, and alkyllithium.

[0019] In a third aspect, the present invention provides a method for preparing an organelle-targeted boron-containing preparation, comprising the following steps:

[0020] Dissolve the borane-containing naphthalimide derivative (product VII) prepared in the second aspect, azide-modified dodecahydrododecaborate (prepare the product according to the literature, the literature information is Closo-dodecaborate-based dianionicsurfactants with distorted classical morphology: Synthesis and atypicalmicellization in water), and copper sulfate pentahydrate in mixed solvent VIII, bubble for 30 - 60 min, then add drug VIIII, react at 40 - 60 °C for 48 - 72 h, filter, and purify; the mixed solvent VIII is composed of acetone, ethanol, and water in a volume ratio of (1 - 10):1:1; the drug VIIII includes sodium L-ascorbate, calcium ascorbate, sodium isoascorbate, glutathione, preferably sodium L-ascorbate; the molar ratio of product VII, azide-modified dodecahydrododecaborate, and copper sulfate pentahydrate is (0.5 - 3):1:1;

[0021] In a fourth aspect, the present invention provides a method for preparing a drug carrier, comprising the following steps

[0022] (1) Under an anhydrous and anaerobic environment, dissolve CTA in anhydrous reagent X, dropwise add drug XI under an ice-water bath, react at room temperature for 2 - 4 h, concentrate by rotary evaporation to obtain a yellow oily liquid, then add methoxypolyethylene glycol, react overnight at room temperature, concentrate by rotary evaporation, precipitate with cold diethyl ether, centrifuge, and dry to obtain a block polymer (product XII); the molar ratio of CTA, drug XI, and methoxypolyethylene glycol is 2:(4 - 10):1. The drug XI includes acetyl chloride, oxalyl chloride, phenylpropionyl chloride, chloroacetyl chloride, trichloroacetyl chloride, malonyl chloride, preferably oxalyl chloride; the anhydrous reagent X includes anhydrous dichloromethane, anhydrous 1,4-dioxane, anhydrous tetrahydrofuran, anhydrous N,N-dimethylformamide, preferably anhydrous dichloromethane, which is used as a solvent to dissolve CTA and methoxypolyethylene glycol; the molecular weight range of methoxypolyethylene glycol is 1000 - 4000 Da; in fact, the molecular weight can be selected according to design requirements, and in the examples of the present invention, methoxypolyethylene glycol 2000 is preferably used as the research object.

[0023] CTA was prepared with reference to the corresponding literature (Functional Polymers from Novel Carboxyl-Terminated Trithiocarbonates as Highly Efficient RAFT Agents).

[0024] (3) By using the Raft polymerization method, dissolve product XII, 2-bromoethyl acrylate, and an initiator in anhydrous reagent XIII, bubble for 30 - 60 min, react at 60 - 80 °C for 4 - 8 h, concentrate, precipitate, centrifuge, and dry to obtain product XIIII; the molar ratio of product XII, 2-bromoethyl acrylate, and the initiator is 1:(1 - 100):(0.2 - 1); the mass-volume ratio of the total mass of the three reactants to anhydrous reagent XIII is 0.15 - 0.17 g / mL; the anhydrous reagent XIII includes anhydrous dichloromethane, anhydrous 1,4-dioxane, anhydrous tetrahydrofuran, anhydrous N,N-dimethylformamide, preferably anhydrous dichloromethane; the initiator includes azobisisobutyronitrile, azobisisoheptonitrile, preferably azobisisobutyronitrile.

[0025] (4) Dissolve product XIIII and tetramethylguanidine in anhydrous reagent XV, react overnight at 80 - 120 °C, precipitate, centrifuge, and dry; the molar ratio of tetramethylguanidine to the 2-bromoethyl acrylate monomer in product XIV is 1.5 - 2.5:1. The anhydrous reagent XV includes anhydrous dichloromethane, anhydrous 1,4-dioxane, anhydrous tetrahydrofuran, anhydrous N,N-dimethylformamide, which is used as a solvent to dissolve tetramethylguanidine and product XIIII;

[0026] Fifth aspect, the present invention provides a method for preparing boron-rich polymer nanoparticles with organelle targeting properties, comprising the following steps: using the block polymer prepared by the method described in the fourth aspect, preparing a mother liquor of the block polymer with a concentration of 5-100 mg / mL (more preferably 40-60 mg / mL; most preferably 50 mg / mL); using the borane-containing naphthalimide derivative prepared by the method described in the second aspect, preparing a mother liquor of the borane-containing naphthalimide derivative with a concentration of 5-100 mM (more preferably 40-60 mg / mL; most preferably 50 mg / mL); mixing the mother liquor of the block polymer and the mother liquor of the borane-containing naphthalimide derivative in a charge ratio of 1:1, forming nanoparticles through electrostatic self-assembly, and dialyzing the obtained substance with ultrapure water for 24-48 h to obtain the product.

[0027] Sixth aspect, the present invention provides an application of boron-rich polymer nanoparticles with organelle targeting properties; including applications in the preparation of the following preparations: boron neutron capture therapy (BNCT) preparations, fluorescence imaging preparations, organelle targeting preparations, biocompatible preparations, etc.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The boron-rich polymer nanoparticles involved in the present invention are not only taken up by cells, but can also further target organelles. The boron-rich polymer nanoparticles involved in the present invention have a high boron content, good biocompatibility, and negligible dark toxicity. The boron-rich polymer nanoparticles involved in the present invention have the functions of in vivo fluorescence imaging tracing and quantification.

[0030] The boron-rich polymer nanoparticles involved in the present invention can not only be effectively taken up by cells, but can also further target specific organelles. The co-localization experiment in Example 13 shows that the co-localization coefficient of the nanoparticles with mitochondria is as high as 0.82, showing significant mitochondrial targeting properties. This targeting property enables the boron delivery agent to be precisely delivered to specific organelles of tumor cells, thereby significantly improving the effect of boron neutron capture therapy (BNCT).

[0031] In addition, the boron-rich polymer nanoparticles involved in the present invention have a high boron content and excellent biocompatibility, and their dark toxicity is negligible. The MTT experiment results in Example 12 show that the cell survival rate of BRPNs is higher than 90%, proving its low dark toxicity and good biocompatibility.

[0032] The boron-rich polymer nanoparticles of the present invention also have the functions of in vivo fluorescence imaging tracing and quantification. Example 13 can detect the cell uptake process and the optimal accumulation time in real time, further verifying the fluorescence tracing function of the nanoparticles in cells, and providing the possibility for real-time monitoring of the treatment process.

[0033] In terms of stability, the nanoparticles of the present invention exhibit excellent stability and a controllable particle size distribution. The dynamic light scattering (DLS) test results in Example 11 show that the average particle sizes of BRPNs 1-4 are 31.97 nm, 80.3 nm, 104.55 nm, and 137.53 nm, respectively, indicating that precise control of the nanoparticle size can be achieved by adjusting the chain length of the tetramethylguanidine block of the block polymer. In addition, the nanoparticles after dialysis purification show good stability in solution, providing a guarantee for their practical applications.

[0034] The preparation method of the present invention is simple, highly reproducible, and suitable for large-scale production. Examples 1-9 describe in detail the synthesis methods of borane-containing naphthalimide derivatives and block polymers, with clear steps, mild reaction conditions, and high yields (for example, the yield in Example 1 is 80%). The electrostatic self-assembly process requires no complex equipment and is easy to operate, making it suitable for industrial production.

[0035] Finally, the boron-rich polymer nanoparticles of the present invention show potential multifunctional application prospects in tumor treatment. The nanoparticles can not only be used for boron neutron capture therapy (BNCT), but also realize real-time monitoring of the treatment process through their fluorescence imaging function, and improve the accuracy of treatment through organelle targeting. This multifunctionality gives it broad application potential in the field of tumor treatment. Description of the Drawings

[0036] Figure 1 1H NMR spectrum of BN-DMA in Example 8; the chemical shifts, integral areas, and peak splittings of BN-DMA shown in the figure are correct, proving the successful preparation of BN-DMA;

[0037] Figure 2 1H NMR spectrum of BN-MOR in Example 8; the chemical shifts, integral areas, and peak splittings of BN-MOR shown in the figure are correct, proving the successful preparation of BN-DMA;

[0038] Figure 3 1H NMR spectrum of BN-THF in Example 8; the chemical shifts, integral areas, and peak splittings of BN-THF shown in the figure are correct, proving the successful preparation of BN-DMA;

[0039] Figure 4 Infrared spectra of dye NI-DMA and BN-DMA in Example 10; the figure shows that 3234.9 cm -1 corresponds to the stretching vibration of the alkyne C-H bond, and 2483.2 cm -1 corresponds to the stretching vibration of the B-H bond, proving the successful binding of NI-DMA to dodecahydrododecaborate.

[0040] Figure 5It is the nanoparticle size diagram of boron-rich polymer nanoparticles BRPNs in Example 11; the figure shows that the average particle sizes of BRPNs 1-4 are 31.97nm, 80.3nm, 104.55nm, and 137.53nm respectively. It proves that the nanoparticles have size controllability;

[0041] Figure 6 It is the cell dark toxicity diagram of dye BN-DMA, block polymer, and nanoparticles BRPNs in Example 12; the figure shows that the dark toxicities of the block polymer, BN-DMA, and BRPNs are relatively small, proving good biocompatibility;

[0042] Figure 7 It is the co-localization diagram of boron-rich polymer nanoparticles BRPNs in Example 13; the figure shows that the co-localization coefficients with commercial dyes of mitochondria, lysosomes, and Golgi apparatus are 0.82, 0.25, and 0.42 respectively, proving that the boron-rich polymer nanoparticles have mitochondrial targeting. Detailed implementation manners

[0043] The technical solution of the present invention will be further described below through specific implementation manners. The researchers should understand that the described embodiments are only for helping to understand the present invention and should not be a limitation to the present invention.

[0044] This embodiment provides a boron-containing naphthalimide derivative, and the boron-containing naphthalimide derivative is formed by a click reaction of a naphthalimide derivative with a triple bond and a dodecahydrododecaborate containing an azide group. Its molecular structure is shown as follows:

[0045]

[0046] Example 1

[0047] Synthesis of 6-(dimethylamino)-2-(2-(ethynyloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, and the synthesis route is as follows:

[0048]

[0049] 4-Bromo-1,8-naphthalic anhydride (4.006 g, 14.46 mmol), dimethylamine (6.4 mL, 48 mmol), and CuSO4·5H2O (524 mg, 3.28 mmol) were added to DMF (24 mL), and refluxed at 140 °C for 3 h. After quenching with water, the precipitate was collected and dried. The solid was dissolved in chloroform, and filtered to remove insoluble impurities. After removing the solvent, the crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether = 1 / 1) to obtain the desired product, which is a yellow solid (2.79 g, 80%). 11H NMR (500 MHz, Chloroform-d) δ 8.53 (dd, J = 8.4, 1.4 Hz, 1H), 8.40–8.34 (m, 2H), 7.67 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 2.86 (s, 5H).

[0050] Under a N2 atmosphere, 4-(dimethylamino)-1,8-naphthalic anhydride (1.004 g, 4.163 mmol) was placed in a round-bottom flask. Anhydrous ethanol (27 mL) was added to the flask to form a clear orange solution. After heating to 80 °C, ethanolamine (0.32 mL, 5.3 mmol) was added. The mixture was refluxed for 2 h and the solution was cooled to room temperature. After removing the solvent, the desired product was obtained as an orange solid (1.02 g, 85%). 1 1H NMR (500 MHz, Chloroform-d) δ 8.51 (dd, J = 8.1, 1.2 Hz, 1H), 8.40–8.35 (m, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.72 (s, 0H), 7.19 (d, J = 8.2 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.88 (q, J = 6.1 Hz, 2H), 3.55 (t, J = 6.3 Hz, 1H), 2.86 (s, 5H).

[0051] The Schlenk flask was subjected to anhydrous oxygen-free operation using a double-tube. Sodium hydride (212 mg, 8.79 mmol) was dissolved in anhydrous dichloromethane (20 mL). After complete dissolution, 6-(dimethylamino)-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (500 mg, 1.76 mmol) was added. The reaction was carried out at room temperature for 2 h. Propargyl bromide (314 mg, 2.64 mmol) was added and the reaction was carried out overnight at room temperature. Methanol was added to quench the excess sodium hydride. After removing the solvent, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 30) to obtain the desired product as a yellow solid (294 mg, 54%). 1 1H NMR (500 MHz, Chloroform-d) δ 8.51 (dd, J = 8.1, 1.2 Hz, 1H), 8.40–8.35 (m, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.72 (s, 0H), 7.19 (d, J = 8.2 Hz, 1H), 4.28 (t, J = 5.1 Hz, 2H), 4.13 (t, J = 5.0 Hz, 2H), 3.33 (s, 1H), 2.86 (s, 5H).

[0052] Example 2

[0053] Synthesis of 6-morpholino-2-(2-(prop-2-yn-1-yloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione. The synthetic route is as follows:

[0054]

[0055] Dissolve 2.77 g (10.0 mmol) of 4-bromo-1,8-naphthalic anhydride in 20 mL of ethylene glycol monomethyl ether, and stir at 25 °C until dissolved. Add 0.96 mL (11.0 mmol) of morpholine to the reaction system, and heat the oil bath to reflux. Monitor by TLC, stop after 4 h, cool to room temperature, transfer the reaction solution to a water beaker, filter and dry after complete precipitation of the yellow solid to obtain the desired product as a yellow solid (2.63 g, 93%).

[0056] 1 H NMR (500 MHz, Chloroform-d) δ 8.45–8.40 (m, 1H), 8.39–8.30 (m, 2H), 7.69 (s, 0H), 7.26 (d, J = 8.1 Hz, 1H), 3.81 (ddd, J = 9.2, 6.1, 3.4 Hz, 4H), 3.13 (ddd, J = 6.0, 3.3, 2.0 Hz, 4H).

[0057] Under a N2 atmosphere, place 6-morpholino-1H,3H-benzo[de]isoquinoline-1,3-dione (1 g, 3.53 mmol) in a round-bottom flask. Add anhydrous ethanol (15 mL) to the flask to form a clear yellow solution. After heating to 80 °C, add ethanolamine (238 mg, 3.88 mmol). Reflux the mixture for 3 h, and cool the solution to room temperature. Pour the reaction solution into a beaker containing cold water, filter with suction, and dry to obtain the desired product as a yellow solid (800 mg, 70%). 1 H NMR (500 MHz, Chloroform-d) δ 8.51 (dd, J = 8.2, 1.2 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.31–8.26 (m, 1H), 7.71 (s, 0H), 7.14 (d, J = 8.1 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.88 (q, J = 6.1 Hz, 2H), 3.81 (ddd, J = 9.2, 6.1, 3.4 Hz, 4H), 3.55 (t, J = 6.3 Hz, 1H), 3.13 (ddd, J = 6.0, 3.3, 2.0 Hz, 4H).

[0058] The Shrek bottle was subjected to anhydrous pentaoxygen operation using a double-tube. Sodium hydride (184 mg, 7.66 mmol) was added and dissolved in anhydrous dichloromethane (20 mL). After complete dissolution, 2-(2-hydroxyethyl)-6-morpholino-1H-benzo[de]isoquinoline-1,3(2H)-dione (500 mg, 1.53 mmol) was added. The reaction was carried out at room temperature for 2 h. Then propargyl bromide (183 mg, 1.53 mmol) was added, and the reaction was continued overnight at room temperature. Methanol was added to quench the excess sodium hydride. After removing the solvent, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 200) to obtain the desired product as an orange-yellow solid (336 mg, 60%). 1 HNMR(500MHz,DMSO-d6)δ8.48(dd,J=8.1,1.2Hz,2H),8.35(d,J=8.0Hz,2H),8.29(dt,J=8.3,0.8Hz,2H),7.73(d,J=16.3Hz,1H),7.73(s,1H),7.14(d,J=8.1Hz,2H),4.23(dt,J=12.7,6.2Hz,2H),4.17–4.09(m,6H),3.83(t,J=6.3Hz,4H),3.77(ddd,J=6.0,4.9,3.4Hz,8H),3.12(ddd,J=6.2,4.6,3.4Hz,8H),2.48(s,1H),2.48(d,J=6.0Hz,1H).

[0059] Example 3

[0060] 2-(2-(Prop-2-yn-1-yloxy)ethyl)-6-(pyrrolidin-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, the synthetic route is as follows:

[0061]

[0062] Under a N2 atmosphere, 4-bromo-1,8-naphthalic anhydride (15 g, 54.14 mmol) and ethanolamine (4 mL) were added to ethanol (150 mL). The mixture was heated under reflux for 4 h, cooled to room temperature, filtered, the filtrate was removed, the filter cake was collected, washed with methanol three times, and dried under vacuum to obtain the desired product as a gray solid (15.7 g, 90%).

[0063] 11H NMR (500 MHz, DMSO-d6) δ 8.57–8.52 (m, 1H), 8.48 (dd, J = 8.2, 1.1 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 4.60 (t, J = 6.3 Hz, 1H), 3.95 (d, J = 12.3 Hz, 1H), 3.75 (q, J = 6.1 Hz, 2H).

[0064] 6-Bromo-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (1 g, 3.12 mmol) and pyrrolidine (0.55 mL) were dissolved in ethylene glycol monomethyl ether (30 mL), and the mixture was heated under reflux for 12 h. After cooling to room temperature, the reaction solution was dropped into water, filtered, washed with water, and dried to obtain the desired product as an orange solid (810 mg, 83%). 1 1H NMR (500 MHz, Chloroform-d) δ 8.51 (dd, J = 8.1, 1.2 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.28 (dd, J = 8.4, 1.2 Hz, 1H), 7.72 (t, J = 8.2 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.88 (q, J = 6.1 Hz, 2H), 3.58–3.49 (m, 5H), 1.97 (q, J = 2.1 Hz, 4H).

[0065] The Schlenk flask was subjected to anhydrous oxygen-free operation using a double-tube. Sodium hydride (194 mg, 8.06 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). After complete dissolution, 2-(2-hydroxyethyl)-6-(pyrrolidin-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (500 mg, 1.61 mmol) was added, and the reaction was carried out at room temperature for 2 h. Propargyl bromide (288 mg, 2.42 mmol) was added, and the reaction was carried out overnight at room temperature. Methanol was added to quench the excess sodium hydride. After removing the solvent, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain the desired product as an orange-yellow solid (350 mg, 62%). 11H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 6.6 Hz, 1H), 6.53–6.47 (m, 1H), 5.59–5.53 (m, 1H), 4.14 (d, J = 2.9 Hz, 1H), 3.94 (t, J = 6.0 Hz, 1H), 3.79 (t, J = 6.0 Hz, 1H), 3.59–3.52 (m, 2H), 1.93–1.86 (m, 2H).

[0066] Example 4

[0067] 6-(Diethylamino)-2-(2-(prop-2-yn-1-yloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, the synthetic route is as follows:

[0068]

[0069] Under a N2 atmosphere, 6-bromo-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (1 g, 3.12 mmol), diethylamine (3.22 mL), and triethylamine (4.33 mL) were added to a round-bottom flask containing ethylene glycol monomethyl ether (20 mL). The mixture was heated under reflux for 24 h, cooled to room temperature, and the reaction solution was added dropwise to cold water. The precipitate was filtered, dried, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20 / 1) to obtain the desired product as a yellow solid (410 mg, 42%). 1 1H NMR (500 MHz, Chloroform-d) δ 8.51 (dd, J = 8.1, 1.2 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.31–8.26 (m, 1H), 7.72 (s, 0H), 7.16 (d, J = 8.1 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.88 (q, J = 6.1 Hz, 2H), 3.55 (t, J = 6.3 Hz, 1H), 3.45 (q, J = 7.0 Hz, 4H), 1.12 (t, J = 7.0 Hz, 6H).

[0070] The Shrek bottle was subjected to anhydrous pentaoxygen operation using a double-row tube. Sodium hydride (135 mg, 5.60 mmol) was added and dissolved in anhydrous dichloromethane (15 mL). After complete dissolution, 6-(diethylamino)-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (350 mg, 1.12 mmol) was added, and the reaction was carried out at room temperature for 2 h. Propargyl bromide (200 mg, 1.68 mmol) was added, and the reaction was carried out overnight at room temperature. Methanol was added to quench the excess sodium hydride. After removing the solvent, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the desired product as an orange-yellow solid (100 mg, 25%). 1 HNMR(500MHz,Chloroform-d)δ8.51(dd,J=8.1,1.2Hz,1H),8.36(d,J=8.2Hz,1H),8.31–8.26(m,1H),7.72(s,0H),7.16(d,J=8.1Hz,1H),4.22(t,J=6.3Hz,2H),4.14(d,J=2.9Hz,2H),3.84(t,J=6.3Hz,2H),3.45(q,J=7.0Hz,4H),2.45(d,J=6.0Hz,0H),1.12(t,J=7.0Hz,5H).

[0071] Example 5

[0072] Synthesis of 6-(piperazin-1-yl)-2-(2-(prop-2-yn-1-yloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione. The synthetic route is as follows:

[0073]

[0074] Under a N2 atmosphere, 6-bromo-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (1 g, 3.12 mmol) and piperazine (320 mg, 3.75 mmol) were added to a round-bottom flask containing ethylene glycol monomethyl ether (30 mL). The mixture was heated under reflux for 5 h. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain the desired product as a yellow solid (530 mg, 52%). 11H NMR (500 MHz, DMSO) δ 13.25 (d, J = 8.5 Hz, 1H), 13.21 (d, J = 7.3 Hz, 1H), 13.14 (d, J = 8.0 Hz, 1H), 12.57 (t, J = 7.8 Hz, 1H), 12.16 (d, J = 8.1 Hz, 1H), 8.87 (t, J = 6.3 Hz, 2H), 8.35 (t, J = 6.2 Hz, 2H), 8.18 (d, J = 15.3 Hz, 8H), 7.26 (d, J = 1.6 Hz, 2H).

[0075] The Schlenk flask was subjected to anhydrous pentoxide operation using a double-tube. Sodium hydride (185 mg, 7.68 mmol) was added and dissolved in anhydrous dichloromethane (30 mL). After complete dissolution, 2-(2-hydroxyethyl)-6-(piperazin-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (500 mg, 1.54 mmol) was added, and the reaction was carried out at room temperature for 2 h. Propargyl bromide (275 mg, 2.31 mmol) was added, and the reaction was carried out overnight at room temperature. Methanol was added to quench the excess sodium hydride. After removing the solvent, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the desired product as an orange-yellow solid (180 mg, 32%).

[0076] Example 6

[0077]

[0078] Synthesis of 6-(4-methylpiperazin-1-yl)-2-(2-(prop-2-yn-1-yloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione. The synthetic route is as follows:

[0079] Under a N2 atmosphere, 6-bromo-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (1 g, 3.12 mmol) and 1-methylpiperazine (372 mg, 3.75 mmol) were added to a round-bottom flask containing ethylene glycol monomethyl ether (30 mL). The mixture was heated under reflux for 5 h. The solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the desired product as a yellow solid (647 mg, 61%). 11H NMR (300 MHz, DMSO-d6) δ 8.43 (dd, J = 11.9, 8.1 Hz, 2H), 8.37 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.81 (t, J = 5.7 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 3.59 (d, J = 6.2 Hz, 2H), 3.22 (s, 4H), 2.63 (s, 4H), 2.30 (s, 3H).

[0080] The Schlenk flask was subjected to anhydrous pentoxygen operation using a double-tube. Sodium hydride (177 mg, 7.37 mmol) was added and dissolved in anhydrous dichloromethane (30 mL). After complete dissolution, 6-(4-methylpiperazin-1-yl)-2-(2-(prop-2-yn-1-yloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (500 mg, 1.47 mmol) was added. The reaction was carried out at room temperature for 2 h. Propargyl bromide (263 mg, 2.21 mmol) was added and the reaction was carried out overnight at room temperature. Methanol was added to quench the excess sodium hydride. After removing the solvent, the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the desired product as a yellow solid (184 mg, 32%). 1 1H NMR (500 MHz, DMSO-d6) δ 8.48 (dd, J = 8.2, 1.2 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.29 (ddd, J = 8.2, 1.1, 0.5 Hz, 1H), 7.73 (t, J = 8.2 Hz, 1H), 7.14 (dd, J = 8.1, 0.5 Hz, 1H), 4.23 (dt, J = 13.0, 6.3 Hz, 1H), 4.17–4.08 (m, 3H), 3.83 (d, J = 12.6 Hz, 1H), 3.23–3.09 (m, 4H), 2.78–2.67 (m, 4H), 2.48 (t, J = 3.0 Hz, 1H).

[0081] Example 7

[0082] Synthesis of azide-modified dodecahydrododecaborate, and the synthetic route is as follows:

[0083]

[0084] Under a N2 atmosphere, tetrabutylammonium bromide (1.66 g, 5.15 mmol) was dissolved in water and added dropwise to a round-bottom flask containing cesium dodecahydrododecaborate (1 g, 2.45 mmol). The mixture was stirred at room temperature for 12 h, changing from crystal particles to fine powder. It was filtered by suction and washed with water three times to remove the excess tetrabutylammonium bromide. The obtained product B-1 was a white solid (1.39 g, 80%).

[0085] Under a N2 atmosphere, B-1 (1.25 g, 1.77 mmol) and sodium tetrafluoroborate (1.10 g, 10.01 mmol) were dissolved in anhydrous 1,4-dioxane (70 mL). The reaction was carried out at 100 °C for 2 h and then cooled to room temperature. The mixture was concentrated by rotary evaporation, and a mixed solution of acetone (20 mL), ethanol (30 mL), and water (10 mL) was added. After standing for a while, a white solid precipitated and was collected by centrifugation. The obtained product B-2 was a white solid (780 mg, 83%). 1 HNMR(400MHz,Chloroform-d)δ4.64–4.53(m,4H),3.99–3.85(m,4H),3.25–3.13(m,8H),1.62(t,J=8.3Hz,8H),1.44(h,J=7.4Hz,8H),1.00(t,J=7.2Hz,12H).

[0086] B-2 (500 mg, 1.06 mmol), sodium azide (280 mg, 4.31 mmol), and tetrabutylammonium bromide (35 mg, 1.06 mmol) were dissolved in anhydrous ethanol (40 mL). The mixture was refluxed by heating for 16 h, cooled to room temperature, concentrated by rotary evaporation, water was added, and a white solid precipitated. It was centrifuged and dried under vacuum. The obtained product was a white solid (604 mg, 76%). 1 H NMR(400MHz,Chloroform-d)δ3.84(t,J=5.7Hz,2H),3.71(t,J=5.2Hz,4H),3.35(t,J=5.1Hz,2H),3.32–3.12(m,16H),1.73–1.54(m,16H),1.45(h,J=7.4Hz,16H),1.36–1.12(m,12H),0.99(t,J=7.3Hz,24H). Example 8

[0087] Synthesis of boron-containing naphthalimide derivatives, and the synthesis route is as follows:

[0088]

[0089] Taking R = dimethylamine as an example, 6-(dimethylamino)-2-(2-(ethynyloxy)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (500 mg, 1.55 mmol), B-3 (600 mg, 0.78 mmol), and copper(II) sulfate pentahydrate (400 mg, 1.55 mmol) were dissolved in a mixed solvent (acetone:ethanol:water = 10:1:1). After bubbling for 40 min, sodium ascorbate (95 mg, 4.80 mmol) was added, and the reaction was carried out at 55 °C for 48 h. The mixture was concentrated by rotary evaporation, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the desired product as a yellow solid (395 mg, 47%). 1 H NMR (400 MHz, Chloroform-d) δ 8.52 (dd, J = 7.3, 1.2 Hz, 1H), 8.42 (d, J = 8.3 Hz, 2H), 7.90 (s, 1H), 7.65 (dd, J = 8.5, 7.3 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 4.65 (s, 2H), 4.52 (t, J = 5.2 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 3.88 (t, J = 5.2 Hz, 2H), 3.80 (dt, J = 20.9, 5.5 Hz, 4H), 3.65 (t, J = 4.9 Hz, 2H), 3.33–3.14 (m, 16H), 3.10 (s, 6H), 1.66–1.55 (m, 16H), 1.42 (p, J = 7.3 Hz, 16H), 0.94 (t, J = 7.3 Hz, 24H).

[0090] BN-DMA-1 (300 mg, 0.28 mmol) was dissolved in methanol (10 mL), and a solution of CsF (106 mmol, 0.70 mmol) dissolved in methanol (10 mL) was added dropwise. The mixture was stirred at room temperature for 6 h, and the precipitate was collected by centrifugation. The filter cake was washed with methanol three times, and the resulting product was a yellow solid (164 mg, 80%).

[0091] The naphthalimide-containing cesium borate salt (100 mg, 0.14 mmol) was added to 5 mL of water, and 0.13 mL of hydrochloric acid (35%) and Et3N (0.21 mL, 1.44 mmol) were added. The mixture was stirred at room temperature for 1 h to obtain a yellow precipitate. The solid was filtered and washed with water (72 mg, 65%).

[0092] The naphthalimide-containing triethylamine borate salt (72 mg, 0.92 mmol) was dissolved in an aqueous sodium hydroxide solution, and the suspension was heated until it became a clear solution. The solution was evaporated to dryness to obtain the final product BN-DMA as a white powder (50 mg, 87%). 1HNMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 16.8, 7.8 Hz, 2H), 8.36 (d, J = 8.3 Hz, 1H), 8.08 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.54 (s, 2H), 4.46 (t, J = 5.2 Hz, 2H), 4.25 (t, J = 6.3 Hz, 2H), 3.71 (dt, J = 17.4, 5.8 Hz, 4H), 3.38 (s, 4H), 3.10 (s, 6H).

[0093] The synthesis methods of R = dimethylamine, morpholine, pyrrolidine, piperazine, and 1 - piperazine are similar to the above.

[0094] Example 9

[0095] Synthesis of block polymers, and its synthetic route is as follows:

[0096]

[0097] Dissolve CTA (420 mg, 1.15 mmol) in anhydrous dichloromethane (10 mL), and slowly add oxalyl chloride (0.2 mL, 2.29 mmol) dropwise under an ice - water bath. React at 30 °C for 2 h (CO2 is generated), rotary evaporate to remove the solvent and the remaining oxalyl chloride, add 5 mL of anhydrous dichloromethane to dissolve, then add methoxypolyethylene glycol 2000 (1.26 g, 0.573 mmol) dissolved in anhydrous dichloromethane (10 mL), and react overnight at 30 °C. The crude product is precipitated in cold ether, and then collected by centrifuge, repeating 3 times.

[0098] Taking n = 25 as an example, using the Raft polymerization method, PEO 50 -CTA (281 mg, 0.12 mmol), 2 - bromoethyl acrylate (1.074 g, 6 mmol) and AIBN (3.68 mg, 0.023 mmol) dissolved in anhydrous 1,4 - dioxane (1 mL) are added to a Schlenk flask, add 4 mL of anhydrous 1,4 - dioxane, purge with nitrogen for 40 min, heat up to 80 °C and react for 4 h. The product is precipitated in cold ether, and the degree of polymerization of the polymer is determined by 1 HNMR. 1 H NMR (400 MHz, Chloroform - d) δ 4.39 (s, 40H), 3.64 (s, 204H), 3.60–3.43 (m, 41H), 3.37 (s, 3H).

[0099] Taking n = 25 as an example, 200 mg of PEO 50-CTA was dissolved in 5 mL of anhydrous DMF, 642 mg of tetramethylguanidine was added, and the mixture was stirred overnight at 80 °C. The crude product was precipitated in cold diethyl ether and then collected by centrifuge. 1 H NMR (400 MHz, Chloroform-d) δ 3.63 (s, 200H), 3.36 (s, 3H), 3.06 (s, 234H).

[0100] The synthetic method of the block polymer with n = 1 - 100 and m = 20 was similar to the above.

[0101] The self-assembly process of boron-rich polymer nanoparticles included: preparing a stock solution of 50 mM block polymer and 50 mg / mL naphthalimide derivative containing borane, performing electrostatic self-assembly according to a charge ratio of 1:1, and dialyzing the resulting substance in ultrapure water for 48 h for subsequent use.

[0102] Example 10

[0103] Infrared spectroscopy test

[0104] An appropriate amount of the powders of dyes NI-DMA and BN-DMA was placed in a mortar, and an appropriate amount of potassium bromide was added and ground thoroughly and then pressed into a tablet. The Fourier transform microscopic infrared spectrometer was used to test its infrared spectrum.

[0105] From Figure 4 the infrared spectrum, it could be clearly observed that 3234.9 cm -1 corresponded to the stretching vibration of the alkyne C-H bond, and 2483.2 cm -1 corresponded to the stretching vibration of the B-H bond, indicating that NI-DMA was successfully combined with dodecahydrododecaborate.

[0106] Example 11

[0107] Average particle size test

[0108] BD-DME and PEO 50 -b-PBEA 20 、PEO 50 -b-PBEA 50 、PEO 50 -b-PBEA 75 、PEO 50 -b-PBEA 100 were self-assembled into boron-rich polymer nanoparticles BRPNs-1, BRPNs-2, BRPNs-3, and BRPNs-4 according to a charge ratio of 1:1. After diluting the stock solution, it was added to a plastic cuvette (bottom: 1 cm × 1 cm), and then placed on a nanoparticle size analyzer to test the average particle size of the boron-rich nanoparticles in aqueous solution respectively.

[0109] AsFigure 5 As shown, the average particle sizes of BRPNs 1-4 are 31.97 nm, 80.3 nm, 104.55 nm, and 137.53 nm, respectively.

[0110] Example 12

[0111] First, a 4T1 cell suspension at approximately 1×10 5 cells / mL was inoculated into each well of a 96-well plate. 100 μL of DMEM medium containing 10% FBS was added to each well and incubated for 24 h. The cell density was approximately 60%. The medium was removed using a pipette. Second, DMEM media containing BN-DMA, block polymers, and nanoparticles BRPNs at different concentrations were added to the 96-well plate respectively and incubated for another 12 h in the dark. After removing the medium again, 100 μL of DMEM medium solution containing MTT (0.5 mg / mL) was added to each well of the 96-well plate and continuously cultured in an incubator for 4 h. Finally, the solution in each well was carefully removed using a pipette, leaving purple formazan crystals. Then, 100 μL of DMSO solvent was added to each well. The plate was placed on a multi-functional microplate reader and shaken for 30 s, and the absorbance value of the formazan solution at 490 nm was measured. The cell viability was calculated according to the following formula.

[0112]

[0113] Where OD is the absorbance value at 490 nm, sample represents the treatment group, control represents the control group, and black represents the blank group. Each experimental group was repeated 6 times.

[0114] From Figure 6 the MTT experiment, it can be clearly observed that the dark toxicity of block polymers, BN-DMA, and BRPNs is relatively low, and they have good biocompatibility.

[0115] Example 13

[0116] A suspension of 4T1 cells at a concentration of approximately 1×10 5 cells / mL was inoculated into confocal cell culture dishes containing 1 mL of medium respectively. After dispersion and mixing, it was incubated in an incubator for 24 h (5% CO2 / 95% air, 37 °C). The medium was removed and the cells were washed three times with PBS. Commercial dyes and BRPNs were added to the culture dishes containing 4T1 cells and incubated for 30 min. Then the DMEM medium was removed, and the cells were washed three times with PBS to remove free nanoparticles and cell debris. After adding fresh DMEM medium, it was placed under a confocal fluorescence microscope to observe the staining situation and calculate the colocalization coefficient.

[0117] From Figure 7As shown, the co-localization coefficients with commercial dyes of mitochondria, lysosomes, and Golgi apparatus are 0.82, 0.25, and 0.42 respectively, indicating that the boron-rich polymer nanoparticles have mitochondrial targeting, thus enriching more boron at the tumor site and improving the therapeutic effect of boron neutron capture therapy.

[0118] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, various modifications and changes can be made to the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A boron-rich polymer nanoparticle with organelle targeting property, characterized in that: Formed by electrostatic self-assembly of a borane-containing naphthalimide derivative and a block polymer, with a particle size of 20-200 nm and a pomegranate-like structure; wherein, The 4-position substituent of the borane-containing naphthalimide derivative is selected from one of methyl, ethyl, morpholine, pyrrolidine, piperazine, and methylpiperazine; The borane is an azide-modified dodecahydrododecaborate; The particle size of the nanoparticles is controlled by regulating the length of the tetramethylguanidine block in the block polymer.

2. The preparation method of the naphthalimide derivative required for the nanoparticles as claimed in claim 1, characterized in that: It includes the following steps: (1) Dissolve 4-bromo-1,8-naphthalimide and ethanolamine in organic solvent I, heat under reflux for 4-8 h, cool to room temperature, filter, concentrate by rotary evaporation, and wash to obtain product II; the molar ratio of 4-bromo-1,8-naphthalimide to ethanolamine is 1:(1-5); (2) Dissolve product II and drug III in organic solvent IV, heat under reflux for 8-24 h, cool to room temperature, filter, dry, and purify to obtain product V; drug III is selected from one of dimethylamine, diethylamine, morpholine, pyrrolidine, piperazine, and methylpiperazine; the molar ratio of product II to drug III is 1:(1-10); (3) Under an anhydrous and anaerobic environment, dissolve the deprotonating agent and product V in organic solvent VI, react at room temperature for 2-6 h, then add 1-halopropyne, react overnight at room temperature, quench and purify to obtain product VII; the molar ratio of product V, 1-halopropyne, and deprotonating agent is 1:(1-3):(3-10); the 1-halopropyne includes 1-bromopropyne, 1-chloropropyne, 1-iodopropyne, and 1-fluoropropyne, preferably 1-bromopropyne; the deprotonating agent is selected from one of sodium hydride, potassium hydride, lithium aluminum hydride, calcium hydride, lithium hydride, Grignard reagent, and alkyllithium.

3. The preparation method according to claim 2, wherein: The heating temperature in step (1) is 80-120 °C; the organic solvent I is selected from one of methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, and ethylene glycol monomethyl ether; The organic solvent IV in step (2) is selected from one of ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, and ethanol; The organic solvent VI in step (3) is selected from one of anhydrous dichloromethane, anhydrous N,N-dimethylformamide, and anhydrous 1,4-dioxane.

4. A preparation method of an organelle-targeted boron-containing preparation, characterized in that: It includes the following steps: Dissolve product VII prepared by the method of claim 2, azide-modified dodecahydrododecaborate, and copper sulfate pentahydrate in mixed solvent VIII, bubble for 30-60 min, then add drug VIIII, react at 40-60 °C for 48-72 h, filter, and purify; The mixed solvent VIII is composed of acetone, ethanol, and water in a volume ratio of (1-10):1:1; The drug VIIII is selected from one of sodium L-ascorbate, calcium ascorbate, sodium erythorbate, and glutathione; The molar ratio of product VII, azide-modified dodecahydrododecaborate, and anhydrous copper sulfate is (0.5-3):1:

1.

5. A preparation method of a drug carrier, characterized in that, It includes the following steps: (1) Under an anhydrous and anaerobic environment, dissolve CTA in anhydrous reagent X, add drug XI dropwise under an ice-water bath, react at room temperature for 2 - 4 h, concentrate by rotary evaporation to obtain a yellow oily liquid, then add methoxypolyethylene glycol, react overnight at room temperature, concentrate by rotary evaporation, precipitate with cold diethyl ether, centrifuge, and dry to obtain a block polymer (product XII); The molar ratio of CTA, drug XI, and methoxypolyethylene glycol is 2:(4 - 10):

1. The drug XI is selected from one of acetyl chloride, oxalyl chloride, phenylpropionyl chloride, chloroacetyl chloride, trichloroacetyl chloride, and malonyl chloride; The molecular weight range of the methoxypolyethylene glycol is 1000 - 4000 Da; (2) Using the Raft polymerization method, dissolve product XII, 2-bromoethyl acrylate, and an initiator in anhydrous reagent XIII, bubble for 30 - 60 min, react at 60 - 80 °C for 4 - 8 h, concentrate, precipitate, centrifuge, and dry to obtain product XIIII; The molar ratio of product XII, 2-bromoethyl acrylate, and the initiator is 1:(1 - 100):(0.2 - 1); The initiator is azobisisobutyronitrile or azobisisoheptonitrile; (3) Dissolve product XIIII and tetramethylguanidine in anhydrous reagent XV, react overnight at 80 - 120 °C, precipitate, centrifuge, and dry; The molar ratio of tetramethylguanidine to the 2-bromoethyl acrylate monomer in product XIV is 1.5 - 2.5:

1.

6. According to the preparation method described in claim 5, it is characterized in that: The anhydrous reagent X is selected from one of anhydrous dichloromethane, anhydrous 1,4-dioxane, anhydrous tetrahydrofuran, and anhydrous N,N-dimethylformamide; The usage amount of the anhydrous reagent X is such that CTA and methoxypolyethylene glycol can be dissolved as a solvent; The anhydrous reagent XIII is selected from one of anhydrous dichloromethane, anhydrous 1,4-dioxane, anhydrous tetrahydrofuran, and anhydrous N,N-dimethylformamide; The mass-volume ratio of the total mass of the three reactants to the anhydrous reagent XIII is 0.15 - 0.17 g / mL; The anhydrous reagent XV is selected from one of anhydrous dichloromethane, anhydrous 1,4-dioxane, anhydrous tetrahydrofuran, and anhydrous N,N-dimethylformamide; The usage amount of the anhydrous reagent XV as a solvent is such that tetramethylguanidine and product XIIII can be dissolved.

7. A method for preparing boron-rich polymer nanoparticles with organelle targeting properties, characterized in that: It includes the following steps: using the block polymer prepared by the method described in claim 5 to prepare a block polymer mother liquor with a concentration of 5 - 100 mg / mL; using the boron-containing naphthalimide derivative prepared by the method described in claim 3 to prepare a mother liquor of the boron-containing naphthalimide derivative with a concentration of 5 - 100 mM; mixing the block polymer mother liquor and the mother liquor of the boron-containing naphthalimide derivative according to a charge ratio of 1:1, forming nanoparticles by electrostatic self-assembly, and dialyzing the obtained substance with ultrapure water.

8. The preparation method according to claim 7, wherein The concentration of the block polymer mother liquor is 40 - 60 mg / mL.

9. The preparation method according to claim 7, characterized in that, The concentration of the mother liquor of the boron-containing naphthalimide derivative is 40 - 60 mM.

10. Use of the boron-rich polymer nanoparticles with organelle targeting property as described in claim 1; including use in the preparation of the following preparations: boron neutron capture therapy (BNCT) preparation, fluorescence imaging preparation, organelle targeting preparation, biocompatible preparation.

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