Preparation method and application of camptothecin-elastin-like peptide conjugate capable of being self-assembled

Abstract

The invention provides a preparation method and application of a camptothecin-elastin-like peptide conjugate capable of being self-assembled, and belongs to the field of nano-drugs. The camptothecin self-assembled prodrug is synthesized through a drug-connexon conjugate, and the obtained camptothecin self-assembled prodrug can be self-assembled in an aqueous solution through pi-pi interaction among camptothecin molecules to form a one-dimensional nanotube structure. The camptothecin self-assembled prodrug adopts the design concept of self-assembled prodrug, camptothecin is used as a structural unit, the camptothecin self-assembled prodrug with hydrophilic and hydrophobic balance is obtained by simply connecting hydrophilic polypeptides with different sequences, the prodrug has high drug loading capacity and improved solubility, and a clearly defined one-dimensional nano structure can be formed by simply dissolving the prodrug in water. The method has the advantages that the method is simple and easy to operate, the repeatability is excellent, the tumor inhibition effect is obviously superior to that of clinical medicine irritecan in in-vivo anti-tumor treatment, nearly 90% of tumor growth inhibition can be achieved, the biological safety is good, and the method has important significance in nano-medicine production preparation and clinical conversion.

Description

Technical Field

[0001] This invention belongs to the field of nanomedicine, specifically relating to a method for preparing and using a self-assembled camptothecin-elastin peptide conjugate. Background Technology

[0002] Cancer is a global health problem, with its high incidence and mortality rates imposing a huge economic burden on countries worldwide. Chemotherapy is currently the main treatment for cancer, often using hydrophobic small molecule drugs with a molecular weight of less than 1 kDa, such as doxorubicin and paclitaxel, administered via intravenous infusion to directly inhibit the proliferation and growth of tumor cells, thereby controlling the further development of cancer. During intravenous administration, drugs encounter a series of biological barriers, and their physicochemical properties affect their ability to efficiently penetrate these barriers and achieve the desired therapeutic effect. Small molecule drugs are rapidly cleared by the kidneys, have short circulation times, low drug utilization, and may not achieve the expected therapeutic effect. Furthermore, the low target specificity of small molecule drugs leading to systemic toxicity is a known cause of high incidence of adverse reactions and high mortality rates in cancer patients. Therefore, chemotherapy drugs require more efficient and safer delivery methods to reduce side effects and improve therapeutic efficacy.

[0003] Self-assembled prodrugs represent a novel class of drug delivery systems capable of spontaneously assembling into well-defined nanostructures in aqueous solutions, enabling self-formulation and self-delivery. These typically consist of a hydrophobic active pharmaceutical ingredient (API) and a hydrophilic prodrug fragment. However, in traditional self-assembled prodrug systems, enhancing the solubility of hydrophobic drugs usually requires the use of hydrophilic components such as charged peptide sequences or oligoethylene glycol (OEG). The charge readily binds to plasma proteins, affecting the in vivo fate of the nanodrug, while OEG possesses potential physiological toxicity.

[0004] In particular, in the prior art, to improve the water solubility and drug-likeness of camptothecin (CPT) through hydrophilic modification, the reported camptothecin-peptide conjugates primarily use charged peptides (such as polylysine, polyglutamic acid, etc.). While these charged peptides can improve water solubility, they may introduce additional risks of cytotoxicity and immunogenicity, and affect the in vivo distribution and circulation time of the drug due to non-specific binding to plasma proteins.

[0005] Elastin-like peptides (ELPs), derived from natural proteins, possess excellent biocompatibility and water solubility. They can be used as hydrophilic fragments to conjugate small molecule drugs to form self-assembled prodrugs, making them a highly promising drug delivery material. Current research on ELPs as drug delivery materials mainly utilizes biosynthetic methods to synthesize high-molecular-weight long ELP peptides, resulting in low drug loading rates. Research is largely limited to using hydrophilic-hydrophobic interactions to drive the formation of spherical prodrug particles, with limited studies on the directional non-covalent interactions between drugs driving the assembly of ELP prodrugs. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of current self-assembled prodrug systems, particularly to overcome the potential toxicity and in vivo fate uncertainty of existing camptothecin-peptide conjugates due to the use of charged peptides. This invention provides a method for preparing and using self-assembled camptothecin-elastin-like peptide conjugates, offering new ideas for the design of nanoprodrugs with high drug loading and high biocompatibility.

[0007] The core of this invention lies in the creative use of neutral (i.e., uncharged) elastin-like peptide (ELP) sequences as hydrophilic fragments, coupled with camptothecin (CPT) via disulfide linkers to construct a series of novel self-assembling prodrug molecules. This design abandons the traditional strategy of relying on charged peptides, utilizing the excellent water solubility and biocompatibility of neutral ELPs. While ensuring the self-assembly capability of the prodrug molecules, it fundamentally avoids the toxicity risks, enhanced immunogenicity, and non-specific binding of plasma proteins caused by the introduction of charged fragments, significantly improving the biosafety of the nanoprodrug system.

[0008] This invention provides a camptothecin self-assembly prodrug, which is composed of a camptothecin (CPT) pharmacophore, a neutral elastin peptide (ELP) fragment, and a cleavable linker conjugating the two; the structure of the camptothecin self-assembly prodrug is shown in Formula I: Formula I Wherein, a and b are each independently selected from 0 or 1; R are each independently selected from amino acid residues of valine (V), alanine (A), glycine (G), asparagine (N), lysine (K) or glutamic acid (E); and n is selected from 1, 2, 3 or 4.

[0009] Furthermore, the structure of the camptothecin self-assembly precursor is shown in Formula I-1, Formula II-2, or Formula III-3: Formula I-1 Formula II-2 Formula III-3 In this context, R is independently selected from amino acid residues of valine, alanine, glycine, asparagine, lysine, or glutamic acid, and n is selected from 1, 2, 3, or 4.

[0010] Furthermore, the structure of the camptothecin self-assembly precursor is selected from one of the following structures: .

[0011] The present invention also provides a method for preparing the above-mentioned camptothecin self-assembly precursor, the preparation method comprising the following steps: (1) Preparation of neutral elastin peptides: Rink Amide MBHA resin was swollen in an organic solvent and the protecting group was removed using an alkaline deprotection solution; activated glycine derivatives were added and reacted, and after the coupling reaction was completed, the protecting group of the glycine derivatives was removed using an alkaline deprotection solution; the above amide condensation process and deprotection process were repeated, and the amino acid derivatives were linked to the resin one by one according to the designed peptide sequence; then, the peptides were removed from the resin using an acidic elution buffer, the peptides were precipitated by a poor solvent, centrifuged and the supernatant was discarded; after drying the precipitate, the neutral elastin peptides were obtained by preparative high performance liquid chromatography. (2) The neutral elastin peptide and the drug-linker conjugate CPT-SS-Pyr were reacted to obtain the camptothecin self-assembled prodrug; the structure of CPT-SS-Pyr is as follows: .

[0012] Furthermore, the molar ratio of the neutral elastin peptide to CPT-SS-Pyr is 1:1-5; the solvent for the reaction is an organic solvent; the reaction temperature is 10~40℃, and the reaction time is 4~24 hours.

[0013] Furthermore, the molar ratio of the neutral elastin peptide to CPT-SS-Pyr is 1:1.1, 1:2.3, or 1:4.5; the solvent for the reaction is dimethyl sulfoxide; the reaction temperature is 10~30℃, and the reaction time is 6~24 hours.

[0014] Furthermore, the preparation of the CPT-SS-Pyr includes the following steps: (a) Reaction of mercaptoethanol and 2,2'-dithiopyridine yields Pyr-SS-OH; (b) Camptothecin, Pyr-SS-OH, bis(trichloromethyl) carbonate and catalyst were reacted to obtain CPT-SS-Pyr.

[0015] Further, in step (a), the molar ratio of mercaptoethanol to 2,2'-dithiopyridine is 1:1 to 3; the solvent for the reaction is an alcohol solvent; the reaction temperature is 15 to 35°C, and the reaction time is 1 to 5 hours. In step (b), the molar ratio of camptothecin, bis(trichloromethyl) carbonate and catalyst is 1:0.2~0.6:1~5; the solvent for the reaction is an organic solvent; the reaction temperature is 15~35℃ and the time is 2~8 hours.

[0016] Further, in step (a), the molar ratio of mercaptoethanol to 2,2'-dithiopyridine is 1:2; the solvent for the reaction is methanol; the reaction temperature is 20~30°C, and the reaction time is 3 hours; In step (b), the molar ratio of camptothecin, bis(trichloromethyl) carbonate and catalyst is 1:0.43:2.8; the solvent for the reaction is dichloromethane; the reaction temperature is 20~30℃ and the reaction time is 4~6 hours.

[0017] The present invention also provides the use of the above-mentioned camptothecin self-assembled prodrug in the preparation of medicaments for the prevention and / or treatment of cancer.

[0018] Furthermore, the cancer is selected from stomach cancer, liver cancer, colon cancer, and rectal cancer.

[0019] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) This invention adopts the design concept of camptothecin self-assembly prodrug. By first synthesizing the drug linker conjugate CPT-SS-Pyr, and then conjugating it with a neutral elastin peptide with a thiol group, a series of camptothecin self-assembly prodrugs are obtained through synthesis and purification. The operation is simple, and while ensuring high drug loading, it significantly reduces the immunogenicity and potential biotoxicity of the material, overcoming the limitations of using charged peptides.

[0020] (2) The camptothecin self-assembly precursor prepared by the present invention has a low critical micelle concentration and a strong self-assembly ability. It can be obtained by directly dissolving it in water to obtain a well-defined one-dimensional nanotube nanomedicine.

[0021] (3) The camptothecin self-assembled prodrug prepared in this invention has high cytotoxicity to colorectal cancer cell lines, which is significantly better than the small molecule prodrug irinotecan used in clinical practice.

[0022] Experimental results show that this invention synthesizes a self-assembled prodrug of camptothecin via a drug-linker conjugate. The resulting prodrug molecules can spontaneously assemble into a one-dimensional nanotube structure in an aqueous environment. The method disclosed in this invention provides a new strategy for preparing self-assembled prodrugs of camptothecin. This strategy is simple to operate, ensures a high drug loading of the prodrug molecules, and uses a neutral elastin-like peptide as a hydrophilic fragment, effectively avoiding the side effects of charged peptides and significantly reducing the immunogenicity and potential biotoxicity of the material.

[0023] The method of this invention uses CPT as the structural unit and neutral elastin-like peptide as the hydrophilic fragment. A series of camptothecin self-assembling prodrugs are obtained by linking drugs and peptides through glutathione-sensitive linkers. These prodrugs have high drug loading capacity and can assemble into nanotube structures in an aqueous environment, which is of great significance for the production and clinical translation of nanomedicines.

[0024] 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.

[0025] "Amino acid residues" refers to the part of an amino acid molecule that remains after removing the amino and / or carboxyl groups.

[0026] 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.

[0027] 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

[0028] Figure 1 Schematic diagrams of synthetic routes for drug-linker conjugates: (A) Schematic diagram of synthetic route for Pyr-SS-OH; (B) Schematic diagram of synthetic route for CPT-SS-Pyr.

[0029] Figure 2 This is a schematic diagram of the synthetic route for the self-assembled precursor of camptothecin.

[0030] Figure 3 The (A) HPLC and (B) LCMS spectra of the camptothecin self-assembly precursor [K]CPT.

[0031] Figure 4 The (A) HPLC and (B) LCMS spectra of the camptothecin self-assembly precursor [NN]CPT.

[0032] Figure 5 The (A) HPLC and (B) LCMS spectra of the camptothecin self-assembly precursor [AA]dCPT are shown.

[0033] Figure 6 (A) HPLC and (B) LCMS spectra of the camptothecin self-assembly precursor [NN]dCPT.

[0034] Figure 7 The HPLC and LCMS spectra of the camptothecin self-assembly precursor [VVKK]qCPT are shown in (A) and (B) respectively.

[0035] Figure 8 Transmission electron microscopy image of [NN]CPT, the self-assembled precursor of camptothecin.

[0036] Figure 9 Transmission electron microscopy image of [AA]dCPT, a self-assembled precursor of camptothecin.

[0037] Figure 10 Transmission electron microscopy image of [VVKK]qCPT, a self-assembled precursor of camptothecin.

[0038] Figure 11 Zeta potential analysis diagrams for the self-assembly precursors of camptothecin, namely [AA]dCPT, [GG]dCPT, [NN]dCPT, [KK]dCPT, and [EE]dCPT.

[0039] Figure 12 Zeta potential analysis diagrams for the self-assembled precursors of camptothecin, namely [AAAA]dCPT, [GGGG]dCPT, [NNNN]dCPT, [KKKK]dCPT, and [EEEE]dCPT.

[0040] Figure 13 The diagram shows (A) cytotoxicity analysis of camptothecin pre-assembly and (B) tumor growth curve during in vivo antitumor therapy. Detailed Implementation

[0041] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0042] In this invention, "room temperature" means 25±5℃.

[0043] In this invention, "overnight" means a reaction time of 12 ± 5 hours.

[0044] Example 1: Preparation of drug-linker conjugates like Figure 1 As shown, the method for preparing drug-linker conjugates according to the present invention includes the following steps: (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 at room temperature for 3 hours, the solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow oily product, Pyr-SS-OH. MS (ESI-MS) m / z: [M+H] +The theoretical value is C7H9NOS2, 187.0; the actual value is 188.1.

[0045] (2) Preparation of CPT-SS-Pyr: CPT (1 eq.) was suspended in an ultra-dry dichloromethane solution of bis(trichloromethyl) carbonate (0.43 eq.) and stirred at room temperature. 4-Dimethylaminopyridine (DMAP, 2.8 eq.) was dissolved in ultra-dry dichloromethane and added dropwise to the above reaction mixture. The mixture was stirred at room temperature for 1 hour, and the reaction solution was a brownish-yellow suspension. Pyr-SS-OH obtained in step (1) was dissolved in ultra-dry dichloromethane and added dropwise to the above suspension. The mixture was stirred at room temperature for 4-6 hours. After the reaction was completed, the mixture was washed with dilute hydrochloric acid and deionized water and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the crude product was purified by recrystallization. After filtration and drying, a bright yellow solid product CPT-SS-Pyr was obtained. MS (ESI-MS) m / z: [M+H] + The theoretical value is C 28 H 23 N3O6S2, 561.1, actual value is 562.1.

[0046] Example 2: Preparation of the self-assembled precursor of camptothecin Synthetic routes such as Figure 2 As shown. Different polypeptide molecules (1 eq.) with different sequences were dissolved in dimethyl sulfoxide solution, and CPT-SS-Pyr (1.1 / 2.3 / 4.5 eq., corresponding to formulas I-1, II-2, and III-3, respectively) were added. After purging the mixture with N2, the mixture was stirred overnight at room temperature. After the reaction, the corresponding camptothecin self-assembled prodrugs were obtained by high-performance liquid chromatography, with the following general structural formulas: Formula I-1 Formula II-2 Formula III-3 The specific embodiments of the present invention provide the following camptothecin self-assembly prodrugs from the above three general structural formulas: [K]CPT, [NN]CPT, [AA]dCPT, [NN]dCPT, [VVKK]qCPT, [VV]dCPT, [GG]dCPT, [KK]dCPT, [EE]dCPT, [VVVV]dCPT, [AAAA]dCPT, [GGGG]dCPT, [NNNN]dCPT, [KKKK]dCPT, [EEEE]dCPT, with the following structures: The following experimental examples demonstrate the beneficial effects of the present invention.

[0047] Experimental Example 1: Structural and property characterization of camptothecin pre-assembly drug 1. Experimental Methods (1) The microstructure of the pre-assembly sample of camptothecin was observed by transmission electron microscopy (TEM).

[0048] The pre-assembly sample of camptothecin was dissolved in ultrapure water at a concentration of 0.25 mM and allowed to stand overnight at room temperature. For TEM sample preparation, 6 μL of sample solution was first dropped onto a copper mesh (300 mesh), the solution was blotted dry with filter paper, and then uranium acetate (20 mg / mL aqueous solution) was added for negative staining. After negative staining, the solution was blotted dry with filter paper, and the copper mesh was left at room temperature for 8-12 hours before TEM imaging (Talos FEI 200i, ThermoScientific, USA).

[0049] (2) The zeta potential of the pre-assembly drug sample of camptothecin was measured by nanoparticle size and zeta potential analysis.

[0050] The pre-assembly sample of camptothecin was dissolved in ultrapure water at a concentration of 100 μM and allowed to stand overnight at room temperature. Tests were performed using a folded capillary (DTS1070), and the potential values ​​were recorded using a Zetasizer Nano ZS ZEN3690.

[0051] (3) The cytotoxicity of camptothecin self-assembly pre-drug samples was evaluated using the CCK-8 method.

[0052] Cytotoxicity was assessed using the CCK-8 assay. HT-29 cells were seeded into 96-well plates (5000 cells / well) and cultured overnight at 37°C to allow adherence. Camptothecin self-assembly prodrug was prepared as a 500 μM solution and incubated overnight. All sample solutions were diluted with fresh culture medium and immediately incubated with cells for 48 hours to achieve final CPT concentrations of 1, 10, 100, 1000, 5000, 10000, 50000, and 100000 nM. Cells were also cultured in CPT at the same concentration gradients of 0.1, 1, 10, 100, 500, 1000, 5000, and 10000 nM. Untreated cells (culture medium only) served as the control group, and culture medium (cell-free) served as the blank control group. In addition, irinotecan at concentrations of 100, 1000, 5000, 10000, 50000, 100000, and 500000 nM served as a second control group. After incubation, all cells were co-incubated with CCK-8 solution at 37°C for 4 hours, and the absorbance at 450 nm for each well was measured using a microplate reader (Spark, TECAN, Swizerland). Cell viability was calculated using the following formula: AbsELPCPT, Absblank, and Abscontrol represent the absorbance of cells treated with camptothecin pre-assembly drug, culture medium, and untreated cells, respectively.

[0053] (4) Evaluation of the in vivo antitumor effect of camptothecin pre-assembly drug samples.

[0054] Inject 1.0 × 10⁻⁶ ppm into the posterior right shoulder of female BALB / c nude mice. 6 HT-29 cell line was used to establish an HT-29 tumor model. The tumor size was determined when the average tumor size reached ~100 mm. 3 Mice were randomly divided into groups of five. Camptothecin progenitor drugs were administered at 8 mg / kg (CPT equivalent), while irinotecan and saline served as control groups. Administration was repeated three times on days 0, 6, and 12. During the experiment, mice were weighed using an analytical balance, and tumor volume was measured using calipers.

[0055] 2. Experimental Results The results are as follows Figure 3-13As shown in the figure. The results indicate that the camptothecin self-assembly prodrug prepared in this invention can spontaneously assemble into a one-dimensional nanotube morphology nanodrug in an aqueous environment, exhibiting reproducibility, a low critical micelle concentration, and strong self-assembly ability. The properties of the assembled prodrug prepared in this invention can be controlled by changing the amount of hydrophobic drug and the sequence and length of the hydrophilic peptide. Particularly important, the prodrug constructed using a neutral ELP sequence demonstrates superior biocompatibility while maintaining high antitumor activity. The camptothecin self-assembly prodrug prepared in this invention exhibits high cytotoxicity against colorectal cancer cell lines, significantly superior to the clinically used small molecule prodrug irinotecan. Among them, although [NN]dCPT showed slightly better cytotoxicity in vitro, its safety profile was insufficient due to causing death in mice on day 12 after administration; in contrast, [AA]dCPT almost completely inhibited tumor growth during administration and was well-tolerated, thus exhibiting the best overall antitumor effect in vivo (balancing efficacy and safety), significantly superior to irinotecan and other prodrug control groups.

[0056] In summary, this invention provides a self-assembled prodrug of camptothecin, its preparation method, and its uses. This invention synthesizes a self-assembled prodrug of camptothecin via a drug-linker conjugate. The resulting prodrug molecules can spontaneously assemble into a one-dimensional nanotube structure in an aqueous environment. The method disclosed in this invention provides a novel strategy for preparing self-assembled prodrugs of camptothecin. This strategy is simple to operate, ensures a high drug loading capacity of the prodrug molecules, and, by using a neutral elastin-like peptide as a hydrophilic fragment, this core technical solution successfully overcomes the toxicity risks associated with the use of charged peptides in existing technologies, significantly reducing the immunogenicity and potential biotoxicity of the material.

Claims

1. A self-assembling prodrug of camptothecin, characterized in that, The camptothecin self-assembly prodrug is composed of a camptothecin pharmacophore, a neutral elastin peptide fragment, and a cleavable linker that couples the two; the structure of the camptothecin self-assembly prodrug is shown in Formula I: Formula I Wherein, a and b are each independently selected from 0 or 1; R are each independently selected from amino acid residues of valine, alanine, glycine, asparagine, lysine, or glutamic acid; and n is selected from 1, 2, 3, or 4.

2. The camptothecin self-assembly prodrug according to claim 1, characterized in that, The structure of the camptothecin self-assembled precursor is shown in Formula I-1, Formula II-2, or Formula III-3: Formula I-1 Formula II-2 Formula III-3 In this context, R is independently selected from amino acid residues of valine, alanine, glycine, asparagine, lysine, or glutamic acid, and n is selected from 1, 2, 3, or 4.

3. The camptothecin self-assembly precursor according to claim 1 or 2, characterized in that, The structure of the camptothecin self-assembled prodrug is selected from one of the following structures: 。 4. A method for preparing the camptothecin self-assembly prodrug according to any one of claims 1 to 3, characterized in that, The preparation method includes the following steps: (1) Preparation of neutral elastin peptides: Rink Amide MBHA resin was swollen in an organic solvent and the protecting group was removed using an alkaline deprotection solution; activated glycine derivatives were added and reacted, and after the coupling reaction was completed, the protecting group of the glycine derivatives was removed using an alkaline deprotection solution; the above amide condensation process and deprotection process were repeated, and the amino acid derivatives were linked to the resin one by one according to the designed peptide sequence; then, the peptides were removed from the resin using an acidic elution buffer, the peptides were precipitated by a poor solvent, centrifuged and the supernatant was discarded; after drying the precipitate, the neutral elastin peptides were obtained by preparative high performance liquid chromatography. (2) The neutral elastin peptide and the drug-linker conjugate CPT-SS-Pyr were reacted to obtain the camptothecin self-assembled prodrug; the structure of CPT-SS-Pyr is as follows: .

5. The method according to claim 4, characterized in that, The molar ratio of the neutral elastin peptide to CPT-SS-Pyr is 1:1-5; the solvent for the reaction is an organic solvent; the reaction temperature is 10~40℃, and the reaction time is 4~24 hours.

6. The method according to claim 4, characterized in that, The preparation of CPT-SS-Pyr includes the following steps: (a) Reaction of mercaptoethanol and 2,2'-dithiopyridine yields Pyr-SS-OH; (b) Camptothecin, Pyr-SS-OH, bis(trichloromethyl) carbonate and catalyst were reacted to obtain CPT-SS-Pyr.

7. The method according to claim 6, characterized in that, In step (a), the molar ratio of mercaptoethanol to 2,2'-dithiopyridine is 1:1 to 3; the solvent for the reaction is an alcohol solvent; the reaction temperature is 15 to 35°C, and the reaction time is 1 to 5 hours. In step (b), the molar ratio of camptothecin, bis(trichloromethyl) carbonate and catalyst is 1:0.2~0.6:1~5; the solvent for the reaction is an organic solvent; the reaction temperature is 15~35℃ and the time is 2~8 hours.

8. The method according to claim 7, characterized in that, In step (a), the molar ratio of mercaptoethanol to 2,2'-dithiodipyridine is 1:2; the solvent for the reaction is methanol; the reaction temperature is 20~30℃ and the reaction time is 3 hours. In step (b), the molar ratio of camptothecin, bis(trichloromethyl) carbonate and catalyst is 1:0.43:2.8; the solvent for the reaction is dichloromethane; the reaction temperature is 20~30℃ and the reaction time is 4~6 hours.

9. Use of the camptothecin self-assembly prodrug of claim 1 or 2 in the preparation of medicaments for the prevention and / or treatment of cancer.

10. The use according to claim 9, characterized in that, The cancers mentioned are selected from stomach cancer, liver cancer, colon cancer, and rectal cancer.

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