Micromolecule self-assembled prodrug as well as preparation method and application thereof

Abstract

The invention provides a micromolecular self-assembled prodrug as well as a preparation method and application thereof, and belongs to the field of nano-drugs. According to the invention, a micromolecular self-assembled prodrug is synthesized through a drug-connexon conjugate, and the obtained micromolecular prodrug is spontaneously assembled into nanofibers in an aqueous solution. The design concept of the micromolecule self-assembly prodrug is adopted, SN38 is used as a structural unit, the hydrophilic and hydrophobic balanced micromolecule self-assembly prodrug is obtained by simply connecting hydrophilic micromolecules, and the structure of the micromolecule self-assembly prodrug is as shown in the formula I. The prodrug has high drug loading capacity and improved solubility, and can be used for preparing the micromolecule self-assembly prodrug. A one-dimensional nano-structure with a definite definition can be formed by simply dissolving in water, so that the compound has excellent repeatability and adjustability, and is of great significance to nano-drug production preparation and clinical conversion.

Description

Technical Field

[0001] This invention belongs to the field of nanomedicine, specifically relating to a small molecule self-assembled prodrug, its preparation method, and its uses. Background Technology

[0002] Currently, clinical drug use faces numerous physicochemical, biopharmaceutical, and pharmacokinetic obstacles. Prodrugs can address these issues by altering the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties of the parent drug. A prodrug involves reversibly modifying a drug to create a masked, inactive form with more desirable physicochemical properties. It then undergoes biotransformation in vivo to generate the active drug and exert its pharmacological effects.

[0003] In prodrug design, the chemical linking of hydrophilic adjuvants with hydrophobic drugs can endow prodrugs with amphiphilic properties. These self-assembled prodrugs (SAPDs) can form various nanostructures in aqueous solutions via nanoprecipitation or spontaneous assembly. Due to their nanoscale characteristics, the resulting drug nanostructures may exhibit reduced renal clearance, prolonged circulation time, and enhanced accumulation at disease sites. Furthermore, the assembly-disassembly equilibrium, drug release rate, surface modification, and physicochemical properties of the drug assembly can be tuned through rational prodrug design. Small-molecule SAPDs generated by chemically modifying parent drugs with low-molecular-weight fragments have attracted increasing interest in recent years. These prodrug assemblies are essentially single-component nanomedicines, possessing drug loading capacities comparable to individual prodrugs, and exhibiting negligible toxicity associated with the introduced component, thus achieving self-formulation and self-delivery. Moreover, their small-molecule nature enables large-scale production and simple chromatographic purification, ensuring the reproducibility of SAPDs. Most current strategies utilize nanoprecipitation to obtain spherical aggregates of small-molecule SAPDs, while examples of spontaneous self-assembly into various discrete nanostructures are often limited to peptide-drug conjugates, where hydrogen bonding interactions between peptides contribute more significantly to the self-assembly process. Unlike nanoprecipitation, self-assembly requires consideration of appropriate hydrophilic-hydrophobic balance and strong directional correlations of hydrophobic regions. Spontaneous self-assembly of small-molecule SAPDs driven solely by drug-drug interactions is rare. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of current self-assembled prodrug systems and provide a strategy and preparation method for small molecule self-assembled prodrugs that avoids complex synthesis and purification steps, has a simple molecular design, is easy to implement and repeat, and can be prepared in batches, which is more conducive to clinical translation.

[0005] This invention provides a small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer, the structure of which is shown in Formula I:

[0006]

[0007] Where L is selected from z is selected from integers between 0 and 20, and m is selected from integers between 0 and 20;

[0008] R is selected from amino, carboxyl, amino acid residues, and glycoside groups. R1 is an amino or carboxyl group, and R2 is a C group. 1-6 Alkyl group, x is selected from an integer between 0 and 20, and y is selected from an integer between 0 and 20.

[0009] Furthermore, the structure of the small molecule self-assembled prodrug is shown in Formula II, Formula III, or Formula IV:

[0010]

[0011] Further, z is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, and m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0012] The R is selected from amino, carboxyl, amino acid residues, glycosides, etc. or R1 is an amino or carboxyl group, and R2 is a C group. 1-3 Alkyl group, x is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, and y is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0013] Furthermore, the structure of the small molecule self-assembled prodrug is selected from one of the following structures:

[0014]

[0015] This invention also provides a method for preparing the above-mentioned small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer, wherein L is selected from... The preparation method includes the following steps: reacting RSH and SN38-SS-Pyr to obtain a small molecule self-assembled prodrug; SN38-SS-Pyr is...

[0016] Furthermore, the molar ratio of RSH to SN38-SS-Pyr is 1-2:1; the solvent for the reaction is an organic solvent; the reaction temperature is 10-40°C, and the reaction time is 5-20 hours.

[0017] Furthermore, the molar ratio of RSH to SN38-SS-Pyr is 1.2:1; the solvent for the reaction is acetonitrile; the reaction temperature is 20–30°C, and the reaction time is 7–17 hours.

[0018] Furthermore, the preparation of the SN38-SS-Pyr includes the following steps:

[0019]

[0020] (1) Boc-SN38 reacts with Pyr-SS-NO2 to give Boc-SN38-SS-Pyr.

[0021] (2) Boc-SN38-SS-Pyr reacts with acid to obtain SN38-SS-Pyr.

[0022] Further, in step (1), the molar ratio of Boc-SN38, Pyr-SS-NO2 and catalyst is 1:1-2:0.1-1; the catalyst is 4-dimethylaminopyridine; the solvent for the reaction is an organic solvent; the reaction temperature is 50-60℃ and the time is 5-20 hours.

[0023] In step (2), the molar ratio of Boc-SN38-SS-Pyr to acid is 1:8-12; the acid is an organic acid; the solvent for the reaction is an organic solvent; the reaction temperature is 10-40℃ and the time is 5-20 hours.

[0024] Further, in step (1), the molar ratio of Boc-SN38, Pyr-SS-NO2 and catalyst is 1:1.5:0.5; the solvent for the reaction is dichloromethane; the reaction temperature is 55°C and the time is 7 to 17 hours.

[0025] In step (2), the molar ratio of Boc-SN38-SS-Pyr to acid is 1:10; the acid is trifluoroacetic acid; the solvent for the reaction is an organic solvent; the reaction temperature is 20-30°C and the reaction time is 7-17 hours.

[0026] Furthermore, the preparation of the Boc-SN38 includes the following steps:

[0027]

[0028] SN38, a hydroxyl protecting agent, and a base react to yield Boc-SN38;

[0029] The preparation of Pyr-SS-NO2 includes the following steps:

[0030]

[0031] (i) The reaction of mercaptoethanol and 2,2′-dithiopyridine yields Pyr-SS-OH;

[0032] (ii) Pyr-SS-OH, 4-nitrobenzoyl chloride and catalyst react to give Pyr-SS-NO2.

[0033] Further, the molar ratio of SN38, the hydroxyl protecting agent, and the base is 1:1-2:1-3; the hydroxyl protecting agent is di-tert-butyl dicarbonate; the base is an organic base; the solvent for the reaction is an organic solvent; the reaction temperature is 10-40°C, and the time is 45-50 hours.

[0034] In step (i), the molar ratio of mercaptoethanol to 2,2′-dithiopyridine is 1:1-3; the solvent for the reaction is an organic solvent; the reaction temperature is 10-40°C and the reaction time is 5-20 hours.

[0035] In step (ii), the molar ratio of Pyr-SS-OH, 4-nitrobenzoyl chloride, and catalyst is 1:1-3:0.5-2; the catalyst is 4-dimethylaminopyridine; the solvent for the reaction is an organic solvent; the reaction temperature is 10-40°C, and the reaction time is 5-20 hours.

[0036] Furthermore, the molar ratio of SN38, the hydroxyl protecting agent, and the base is 1:1.3:2; the base is triethylamine; the solvent for the reaction is dichloromethane; the reaction temperature is 20–30°C, and the reaction time is 48 hours.

[0037] Further, the molar ratio of mercaptoethanol to 2,2′-dithiodipyridine is 1:2; the solvent for the reaction is dichloromethane; the reaction temperature is 20–30°C, and the reaction time is 7–17 hours;

[0038] Furthermore, the molar ratio of Pyr-SS-OH, 4-nitrobenzoyl chloride, and catalyst is 1:1.5:1; the solvent for the reaction is dichloromethane; the reaction temperature is 20–30°C, and the reaction time is 7–17 hours.

[0039] The present invention also provides the use of the above-mentioned small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer in the preparation of medicaments for the prevention and / or treatment of cancer.

[0040] Furthermore, the cancer is selected from colon cancer, rectal cancer, small cell lung cancer, gastric cancer, and pancreatic cancer.

[0041] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0042] (1) This invention adopts the design concept of small molecule self-assembled prodrug. By pre-synthesizing the drug linker conjugate SN38-SS-Pyr, it can be obtained by simple reaction with hydrophilic small molecules with thiol groups and simple purification, which reduces the difficulty of synthesizing self-assembled prodrug.

[0043] (2) The small molecule self-assembled predrug prepared by the present invention has a low critical micelle concentration and a strong self-assembly ability, and can be obtained by directly dissolving it in water to obtain a well-defined fibrous nanodrug.

[0044] (3) The small molecule self-assembly prodrug prepared by the present invention can achieve the regulation of the morphology and surface properties of the assembled nanostructure by simply changing the type and surface properties of the hydrophilic fragment, thereby addressing different application scenarios.

[0045] (4) The small molecule self-assembled prodrug prepared in this invention can achieve controllable and efficient drug release in the presence of glutathione.

[0046] (5) The small molecule self-assembly prepared by the present invention has high cytotoxicity to colorectal cancer cell lines, which is significantly better than the small molecule prodrug irinotecan used in clinical practice.

[0047] Experimental results show that this invention synthesizes small-molecule self-assembling prodrugs via drug-linker conjugates, and the resulting small-molecule prodrugs spontaneously assemble into nanofibers in aqueous solution. The method disclosed in this invention provides a novel strategy for preparing self-assembling prodrugs. This strategy features simple molecular design, significantly reducing the difficulty of preparation while ensuring high overall drug loading of the prodrug molecule. Furthermore, the method utilizes a wide range of hydrophilic small molecule forms, exhibiting excellent tunability to address various application scenarios.

[0048] The method of this invention uses SN38 as a structural unit, and can obtain a small molecule self-assembled prodrug with hydrophilic-hydrophobic balance by simply connecting hydrophilic small molecules. The prodrug has high drug loading and improved solubility. It can form a well-defined one-dimensional nanostructure by simply dissolving in water. It has excellent reproducibility and adjustability, which is of great significance for the production and clinical translation of nanomedicines.

[0049] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0050] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C1～6 Alkyl groups are straight-chain or branched alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms; and so on.

[0051] Amino acid residues refer to the portion of an amino acid molecule that remains after removing the amino and / or carboxyl groups.

[0052] A carbohydrate group refers to the portion of a carbohydrate compound remaining after the leaving group is removed.

[0053] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0054] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0055] Figure 1 Schematic diagrams of synthetic routes for drug-linker conjugates: (A) Schematic diagram of synthetic route for Pyr-SS-NO2; (B) Schematic diagram of synthetic route for Boc-SN38; (C) Schematic diagram of synthetic route for SN38-SS-Pyr.

[0056] Figure 2 This is a schematic diagram of the synthetic route for a small molecule self-assembled prodrug.

[0057] Figure 3 (A) is a drug linker conjugate. 1 (A) H NMR, (B) HPLC and (C) LCMS spectra.

[0058] Figure 4 The images show the (A) HPLC and (B) LCMS spectra of SAPD1.

[0059] Figure 5 The HPLC and LCMS spectra of SAPD2 are shown in (A) and (B) respectively.

[0060] Figure 6 The images show the (A) HPLC and (B) LCMS spectra of SAPD3.

[0061] Figure 7 The images show the (A) HPLC and (B) LCMS spectra of SAPD4.

[0062] Figure 8 The images show the (A) HPLC and (B) LCMS spectra of SAPD5.

[0063] Figure 9 The images show the (A) HPLC and (B) LCMS spectra of SAPD6.

[0064] Figure 10 The images show the (A) HPLC and (B) LCMS spectra of SAPD7.

[0065] Figure 11 Transmission electron microscopy images of small molecule self-assembled prodrugs: (A) SAPD1; (B) SAPD2; (C) SAPD3; (D) SAPD4.

[0066] Figure 12 Critical micelle concentration analysis diagrams for small molecule self-assembled prodrugs: (A) SAPD1; (B) SAPD2; (C) SAPD3; (D) SAPD4.

[0067] Figure 13 This is a Zeta potential analysis diagram of a small molecule self-assembled prodrug.

[0068] Figure 14 The following are chromatograms showing the drug release capacity analysis of small molecule self-assembled pre-drugs: (A) Drug release rate of SAPD1; (B) HPLC chromatogram of SAPD1 degradation process; (C) Drug release rate of SAPD2; (D) HPLC chromatogram of SAPD2 degradation process.

[0069] Figure 15 Cytotoxicity analysis of small molecule self-assembly prodrugs (SAPD1, SAPD2, SAPD3, SAPD4): (A) CT26 cell line; (B) HT29 cell line.

[0070] Figure 16 This is a cytotoxicity analysis diagram of small molecule self-assembly prodrugs (SAPD5, SAPD6, SAPD7) in the HT29 cell line. Detailed Implementation

[0071] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0072] In this invention, "room temperature" means 25±5℃.

[0073] In this invention, "overnight" means a reaction time of 12 ± 5 hours.

[0074] Example 1: Preparation of drug-linker conjugates

[0075] like Figure 1 As shown, the method for preparing drug-linker conjugates according to the present invention includes the following steps:

[0076] 1) Preparation of Pyr-SS-OH: Mercaptoethanol (1 eq.) was dissolved in methanol and slowly added dropwise to a methanol solution of 2,2′-dithiodipyridine (2 eq.). The reaction mixture was stirred overnight at room temperature. After removing the solvent, the crude product (petroleum ether / ethyl acetate = 1 / 1) was purified by column chromatography to obtain Pyr-SS-OH (pale yellow oil). MS (ESI-MS) m / z: [M+H] + The theoretical value is C7H9NOS2, 187.0; the actual value is 188.1.

[0077] 2) Preparation of Pyr-SS-NO2: The Pyr-SS-OH (1 eq.) obtained in step 1), 4-dimethylaminopyridine (DMAP, 1 eq.), and 4-nitrobenzoyl chloride (1.5 eq.) were mixed in anhydrous dichloromethane and stirred overnight at room temperature. The mixture was concentrated under vacuum to remove the solvent, and the residue was further purified by silica gel chromatography (petroleum ether / ethyl acetate = 7 / 3) to give Pyr-SS-NO2 (colorless oil). MS (ESI-MS) m / z: [M+H] + The theoretical value is C 14 H 12 N2O5S2, 352.0; actual value is 353.0.

[0078] 3) Preparation of Boc-SN38: SN38 (1 eq.) was suspended in a dichloromethane solution of di-tert-butyl dicarbonate (1.3 eq.) and triethylamine (2 eq.). After stirring at room temperature for 48 h, it was washed three times with 0.5 M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain BOC-SN38 (pale yellow solid). MS (ESI-MS) m / z: [M+H] + The theoretical value is C 34 H 42 N2O 12 , 492.2; the actual value is 493.2.

[0079] 4) Preparation of Boc-SN38-SS-Pyr: Boc-SN38 (1 eq.) obtained in step 3), Pyr-SS-NO2 (1.5 eq.) obtained in step 2), and 4-dimethylaminopyridine (0.5 eq.) were dissolved in dichloromethane, heated to 55°C, and stirred overnight. The yellow solution was concentrated under vacuum, and the residue was further purified by column chromatography (dichloromethane / ethyl acetate = 1 / 1) to obtain Boc-SN38-SS-Pyr (pale yellow solid). MS (ESI-MS) m / z: [M+H] + The theoretical value is C 35 H 35 N3O9S2, 705.2; actual value is 706.2.

[0080] 5) Preparation of SN38-SS-Pyr: Trifluoroacetic acid (10 eq.) was added dropwise to a dichloromethane solution of Boc-SN38-SS-Pyr (1 eq.) obtained in step 4), and reacted at room temperature for 1-2 hours. After the reaction was complete, the mixture was washed with saturated NaHCO3 solution and dried with anhydrous sodium sulfate. The mixture was concentrated under vacuum to obtain SN38-SS-Pyr (bright yellow powder). MS (ESI-MS) m / z: [M+H] + The theoretical value is C 30 H 27 N3O7S2, 605.1; actual value is 606.2. 1 H NMR(400MHz,Chloroform-d)δ8.35(dt,1H),7.99(d,1H),7.59(dd,2H),7.37(dd,1H),7.18(s,2H),6.99(h,1H),5.64(d, 1H),5.32(d,1H),4.99(s,2H),4.35–4.18(m,2H),2.98(t,2H),2.92(d,2H),2.23–2.05(m,2H),1.23(t,3H),0.93(t,3H).

[0081] Example 2: Preparation of small molecule self-assembled prodrug

[0082] Synthetic routes such as Figure 2 As shown. Seven hydrophilic small molecules with terminal thiol groups (1.2 eq) were dissolved in acetonitrile solution purged with N2, and SN38-SS-Pyr (1.0 eq) was added and stirred overnight at room temperature. After rotary evaporation, the solutions were purified by column chromatography (eluent was a mixture of dichloromethane and methanol = 9:1, v / v) to obtain the corresponding seven small molecule self-assembled pre-drugs, the structures of which are as follows:

[0083]

[0084] The following experimental examples demonstrate the beneficial effects of the present invention.

[0085] Experimental Example 1: Structural and Performance Characterization of Small Molecule Self-Assembled Pre-Drugs

[0086] 1. Experimental Methods

[0087] (1) The microstructure of the SAPD samples was observed using transmission electron microscopy (TEM).

[0088] SAPD samples were dissolved in ultrapure water at a concentration of 1 mM and left to stand overnight at room temperature. For TEM sample preparation, 6 μL of the solution was dropped onto a copper mesh (300 mesh) and then blotted dry with filter paper. The samples were negatively stained with uranium acetate (20 mg / mL aqueous solution) following a similar procedure. The copper mesh was then dried overnight at room temperature before TEM imaging (Talos FEI200i, Thermo Scientific, USA).

[0089] (2) Observation of molecular arrangement of SAPD sample using circular dichroism (CD) spectroscopy

[0090] SAPDs were prepared into 1 mM solutions and left to stand overnight. All SAPD solutions were diluted to 200 μM on-site for measurement, tested using 1 mm quartz cuvettes (Hellma Analytics), and spectra were recorded in the 190 nm to 450 nm range with a 2 nm bandwidth. The average of three measurements was used, and the pure water background was subtracted to obtain the final result. The final spectrum was normalized to the actual concentration of each sample.

[0091] (3) The critical micelle concentration (CMC) of the SAPD sample was measured by dynamic light scattering (DLS).

[0092] The stock solution was prepared to 1 mM and then diluted to 50, 20, 10, 5, 2, 1, 0.5, 0.2, and 0.1 μM. After aging overnight, the solutions were placed in Marvin cuvettes with a 10 mm path length, and the count rate values ​​were recorded using a DLS (Malvern Nano ZS ZEN3690). The obtained count rates were plotted as a function of concentration; the data showed abrupt changes when the concentration exceeded the CMC.

[0093] (4) The Zeta potential of the SAPD nanostructure was measured using DLS.

[0094] All SAPD solutions were dissolved in ultrapure water at a concentration of 1 mM and then aged overnight. Immediately before measurement, the solutions were diluted in-situ to 200 μM and placed in a pleated capillary cell (DTS1070). Potential values ​​were recorded using a Zetasizer Nano ZS ZEN3690.

[0095] (5) High performance liquid chromatography was used to evaluate the drug release of SAPD.

[0096] Prepare a 400 μM deionized aqueous solution of SAPD and incubate at room temperature for 24 hours. Then, at the start of the experiment, dilute to 200 μM with PBS (20 mM), with or without GSH (20 mM). Incubate the solution in a 37°C water bath and sample at 0, 10, 20, 30, 50, 1, 2, 4, 8, 12, and 24 hours. For each collected sample, add 0.2 μL of 2 M hydrochloric acid solution to stop the reduction release. Rapidly freeze the samples with liquid nitrogen and store at -20°C until analysis by HPLC. The concentration of the residue ratio is determined by measuring the ratio of the HPLC peak area to the initial peak area.

[0097] (6) The cytotoxicity of SAPD was evaluated using the CCK-8 assay.

[0098] Cytotoxicity was assessed using a CCK-8 assay. HT-29 / CT26 cells were seeded into 96-well plates (5000 cells / well) and allowed to adhere overnight. All SAPDs were diluted with fresh medium and immediately incubated with cells to achieve final binder concentrations of 1, 10, 100, 1000, 5000, 10000, 50000, and 100000 nM. Cells were also cultured in SN38 at the same concentration gradients of 0.1, 1, 10, 100, 500, 1000, 5000, and 10000 nM, with untreated cells (medium only) serving as the control and medium (cell-free) as the blank control. Additionally, irinotecan at concentrations of 100, 1000, 5000, 10000, 50000, 100000, and 500000 nM served as a second control. After 48 hours of incubation, all cells were co-incubated with CCK-8 solution at 37°C for 4 hours. After stirring for 15 minutes, the absorbance at 450 nm for each well was measured using a microplate reader (Spark, TECAN, Switzerland). Cell viability was calculated using the following formula:

[0099]

[0100] AbsSAPDs, Absblack, and Abscontrol represent the absorbance of cells treated with SAPDs, culture medium, and untreated cells, respectively.

[0101] 2. Experimental Methods

[0102] The results are as follows Figure 3-12As shown in the figure. The results indicate that the small molecule self-assembly prodrug prepared in this invention possesses a low critical micelle concentration and strong self-assembly ability, and can be directly dissolved in water to obtain well-defined fibrous nanomedicines. The small molecule self-assembly prodrug prepared in this invention allows for the control of the morphology and surface properties of the assembled nanostructure by simply changing the type and surface properties of the hydrophilic fragments, thus addressing different application scenarios. The small molecule self-assembly prodrug prepared in this invention can achieve controllable and efficient drug release in the presence of glutathione. The small molecule self-assembly prepared in this invention exhibits high cytotoxicity against colorectal cancer cell lines, significantly superior to the clinically used small molecule prodrug irinotecan.

[0103] In summary, this invention provides a small-molecule self-assembled prodrug, its preparation method, and its applications. This invention synthesizes a small-molecule self-assembled prodrug via a drug-linker conjugate, and the resulting small-molecule prodrug spontaneously assembles into nanofibers in an aqueous solution. The method disclosed in this invention provides a novel strategy for preparing self-assembled prodrugs. This strategy features simple molecular design, significantly reducing the difficulty of preparation while ensuring high drug loading of the overall prodrug molecule. Furthermore, the method utilizes a wide range of hydrophilic small molecule forms, exhibiting excellent tunability to address various application scenarios.

Claims

1. A small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer, characterized in that, The structure of the small molecule self-assembled prodrug is shown in Formula I: Where L is selected from z is selected from integers between 0 and 20, and m is selected from integers between 0 and 20; R is selected from amino, carboxyl, amino acid residues, and glycoside groups. R1 is an amino or carboxyl group, and R2 is a C group. 1-6 Alkyl group, x is selected from an integer between 0 and 20, and y is selected from an integer between 0 and 20.

2. The small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer according to claim 1, characterized in that, The structure of the small molecule self-assembled prodrug is shown in Formula II, Formula III or Formula IV:

3. The small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer according to claim 1 or 2, characterized in that, The z is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, and the m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; The R is selected from amino, carboxyl, amino acid residues, glycosides, etc. R1 is an amino or carboxyl group, and R2 is a C group. 1-3 Alkyl group, x is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, and y is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

4. The small molecule self-assembled prodrug, its pharmaceutically acceptable salt, and its stereoisomer according to claim 3, characterized in that, The structure of the small molecule self-assembled prodrug is selected from one of the following structures:

5. A method for preparing the small molecule self-assembled prodrug of any one of claims 1-4, its pharmaceutically acceptable salt, and its stereoisomer, characterized in that, The L is selected from The preparation method includes the following steps: reacting RSH and SN38-SS-Pyr to obtain a small molecule self-assembled prodrug; SN38-SS-Pyr is...

6. The method according to claim 5, characterized in that, The molar ratio of RSH to SN38-SS-Pyr is 1-2:1; the solvent for the reaction is an organic solvent; the reaction temperature is 10-40℃ and the reaction time is 5-20 hours.

7. The method according to claim 6, characterized in that, The molar ratio of RSH to SN38-SS-Pyr is 1.2:1; the solvent for the reaction is acetonitrile; the reaction temperature is 20–30°C, and the reaction time is 7–17 hours.

8. The method according to claim 5, characterized in that, The preparation of the SN38-SS-Pyr includes the following steps: (1) Boc-SN38 reacts with Pyr-SS-NO2 to give Boc-SN38-SS-Pyr. (2) Boc-SN38-SS-Pyr reacts with acid to obtain SN38-SS-Pyr.

9. Use of the small molecule self-assembled prodrug of any one of claims 1-4, its pharmaceutically acceptable salt, or its stereoisomer in the preparation of a medicament for the prevention and / or treatment of cancer.

10. The use according to claim 9, characterized in that, The cancers mentioned are selected from colon cancer, rectal cancer, small cell lung cancer, gastric cancer, and pancreatic cancer.

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