CN111484501A - Hydroxycamptothecin linoleate micromolecule prodrug and construction of self-assembled nanoparticles thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and relates to a hydroxycamptothecin linoleate micromolecule prodrug and construction of self-assembled nanoparticles thereof. Meanwhile, the shape representation of the prodrug self-assembly nanoparticles and the in-vivo and in-vitro anti-tumor effects are inspected by taking the hydroxycamptothecine solution as a control. More choices are provided for designing camptothecin drug nano-preparations with high drug-loading rate, a new strategy is provided for developing a high-efficiency low-toxicity drug delivery system, the clinical service life of first-line chemotherapeutic drugs is prolonged, and the urgent need of high-end cancer chemotherapeutic preparations in clinic is met.

Description

Construction of a small molecule prodrug of hydroxycamptothecin linoleate and its self-assembled nanoparticles

technical field

The invention belongs to the field of new auxiliary materials and new dosage forms for pharmaceutical preparations, and includes the construction of hydroxycamptothecin linoleate small molecule prodrugs and self-assembled nanoparticles, and their application in drug delivery.

Background technique

Cancer threatens the health of all human beings. According to the World Health Organization (WHO), more than 8 million people worldwide die of cancer every year. Chemotherapy is an important tool in cancer treatment, especially for those tumors that cannot be removed by surgery and metastatic spread. Camptothecins can act as good antitumor drugs by inhibiting DNA topoisomerase I. In the exploration of camptothecin and its derivatives, it was found that the 10-position hydroxylation of camptothecin can greatly enhance the antitumor activity of camptothecin, so 10-hydroxycamptothecin (referred to as hydroxycamptothecin) and 7 -Ethyl-10-hydroxycamptothecin has become the first choice of camptothecin anticancer drugs. However, due to its poor water solubility and ester solubility, and strong urotoxicity, it is not easy to achieve high-efficiency delivery of camptothecin drugs. Although camptothecin drugs have the potential to be applied to various solid tumors, the development of camptothecin drug preparations has been stalled.

With the development of nanotechnology, the development of camptothecin drugs by domestic and foreign counterparts still starts with traditional nano preparations. However, traditional nanoformulations still have some problems, such as low drug loading, leakage in systemic circulation and stability. Therefore, new ideas are needed for the development of camptothecin drugs with high drug loading and good stability. Small-molecule prodrug self-assembled nano-drug delivery system is composed of small-molecule prodrug as drug carrier and can release active parent drug. Small-molecule prodrug self-assembled nano-drug delivery system exhibits ultra-high drug loading and low excipient correlation The advantage of toxicity has become a hot spot in chemotherapy drug delivery research in recent years. However, the paclitaxel-docosahexaenoic acid prodrug has entered the clinical phase III, and its phase III clinical results are not satisfactory. Since the parent drug is difficult to release quickly from the prodrug, it is not comparable to the first-line drug in inhibiting the growth of melanoma. Compared with the anticancer drug dacarbazine, there is no obvious advantage.

By introducing redox-sensitive disulfide bonds between fatty acids and chemotherapeutics, the constructed small-molecule prodrugs bridged by disulfide bonds can efficiently release the parent drug by utilizing the highly expressed redox environment in the tumor microenvironment. Therefore, the development of redox-sensitive hydroxycamptothecin prodrugs is aimed at solving the difficulties of low solubility of camptothecin drugs and difficulty in developing formulations, and improving their druggability. The platform has certain universality and can also be applied to the development of other camptothecin and its derivative pharmaceutical preparations, reversing the current limited clinical application of camptothecin drugs and prolonging the clinical life of camptothecin drugs.

SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to provide a kind of hydroxycamptothecin linoleate prodrug with redox sensitivity. As shown in Table 1, before and after PEGylation of different degrees, the self-assembled nano-formulation has extremely high drug load. Using the prodrug in self-assembled nanoparticles can achieve the effects of high drug loading, good stability, and low toxic and side effects, thereby improving antitumor activity.

The purpose of the present invention is to design and synthesize high drug-loaded hydroxycamptothecin linoleate prodrugs with redox sensitivity, prepare prodrug self-assembled nanoparticles, and study the prodrug self-assembled nanoparticles compared with solutions The characteristics and morphology of the preparations and their effects on in vitro and in vivo pharmacodynamics, explore the superiority of redox dual-sensitive prodrugs, and provide new strategies and more choices for the development of intelligent responsive drug delivery systems in the tumor microenvironment to meet clinical needs. There is an urgent need for high-efficiency chemotherapeutic agents in China.

The present invention realizes above-mentioned purpose through following technical scheme:

The redox-sensitive hydroxycamptothecin linoleate (HCPT-SS-LA) prodrug of the present invention uses hydroxycamptothecin as a simulated drug and is linked through 2,2'-dithiodiethanol Synthetic prodrug, its structural formula is:

Further, the present invention provides a method for synthesizing the hydroxycamptothecin linoleate prodrug, comprising the following steps: firstly, linoleic acid and 2,2'-dithiodiethanol are esterified to obtain an intermediate product. Then the intermediate product forms carbonate with one molecule of hydroxycamptothecin to obtain the final product.

Specifically, the present invention provides a synthetic method of an ester intermediate product of linoleic acid and 2,2'-dithiodiethanol:

Linoleic acid was added to the toluene solution in which p-toluenesulfonic acid and 2,2'-dithiodiethanol had been dissolved, and the reaction system was heated to 110 °C under the protection of N ₂ . After the reaction was detected by TLC, it was extracted with saturated NaHCO ₃ solution, and the excess water was removed with anhydrous Na ₂ SO ₄ . Finally, the intermediate product was obtained by column chromatography.

The invention provides a method for synthesizing a small molecule prodrug of hydroxycamptothecin linoleate:

The intermediate product was dissolved in dichloromethane, and DIPEA and p-nitrophenyl chloroformate were added under ice bath conditions, and the mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation under reduced pressure, the system was reconstituted with DMF, ice-bathed to 0°C, the hydroxycamptothecin solution dissolved in DMF was slowly added, anhydrous triethylamine was added, and the reaction was carried out at room temperature for 24 hours. The resulting product was purified by preparative liquid phase separation.

The linoleic acid described in the present invention can be replaced with oleic acid, stearic acid, trans-oleic acid, α-linolenic acid, γ-linolenic acid, docosahexaenoic acid and arachidonic acid.

The present invention also provides the hydroxycamptothecin linoleate small molecule prodrug self-assembled nanoparticle and a preparation method thereof.

The small molecule prodrug nanoparticles can be non-PEGylated prodrug nanoparticles and PEG-modified prodrug nanoparticles.

The hydroxycamptothecin described in the present invention can be replaced by other anticancer drugs containing active hydroxyl or amino groups, such as camptothecins, nucleosides, anthracyclines or taxanes.

The preparation method of the hydroxycamptothecin linoleate small molecule prodrug self-assembled nanoparticles provided by the invention is as follows:

Dissolve a certain amount of hydroxycamptothecin linoleate small molecule prodrug alone or in a mixture with a PEG modifier into an appropriate amount of tetrahydrofuran, slowly add the tetrahydrofuran solution dropwise to the water under stirring, and the prodrug spontaneously forms uniform of nanoparticles. Finally, the tetrahydrofuran in the preparation is removed by a rotary evaporation method under reduced pressure to obtain a nanocolloid solution without any organic solvent.

The PEG modifiers are TPGS, DSPE-PEG, PLGA-PEG, PE-PEG, etc. The preferred PEG modifier is TPGS. The molecular weight of the PEG is 1000-5000, specifically 1000, 2000 and 5000, and the preferred molecular weight of the PEG is 2000. The weight ratio of the small molecule prodrug to the PEG modifier is 92:8 to 70:30. Under this range, hydroxycamptothecin can exert the best anti-tumor effect.

(1) The preparation method of non-PEGylated small-molecule prodrug self-assembled nanoparticles: dissolve a certain amount of prodrug into an appropriate amount of tetrahydrofuran, slowly add the tetrahydrofuran solution to water under stirring, and the prodrug spontaneously forms uniform nanoparticles. The tetrahydrofuran in the preparation is removed by a rotary evaporation method under reduced pressure to obtain a nanocolloid solution without any organic solvent.

(2) Preparation method of PEG-modified small molecule prodrug self-assembled nanoparticles: a certain amount of PEG modifier (TPGS, DSPE-PEG, PLGA-PEG or PE-PEG) and prodrug are dissolved in an appropriate amount of tetrahydrofuran, With stirring, the tetrahydrofuran solution was slowly added dropwise to water, and the prodrug spontaneously formed uniform nanoparticles. The tetrahydrofuran in the preparation is removed by a rotary evaporation method under reduced pressure to obtain a nanocolloid solution without any organic solvent.

The present invention investigates the optimal formulation and characterization of the hydroxycamptothecin linoleate prodrug, as well as the antitumor activity of the prodrug self-assembled nanoparticles.

The results showed that the prodrug could self-assemble into nanoparticles with or without PEGylation. When non-PEGylated, HCPT-SS-LA can also form stable nanoparticles with a particle size of about 160 nm. The particle size of the PEGylated nanoparticles was significantly reduced, and the particle size was about 140 nm when 8% PEGylated, and about 135 nm when 20% PEGylated. The colloidal stability of nanoparticles was better when 20% PEGylated, compared to the poor colloidal stability of non-PEGylated and 8% PEGylated nanoparticles. Compared with traditional nanoformulations, the small molecule self-assembled prodrug strategy significantly improved the drug loading, and the drug loading of three nanoparticles was above 35%. The introduction of disulfide bonds enabled the nanoparticles to have an obvious oxidation-sensitive release, which could selectively release the active parent drug in tumor cells. HCPT-SS-LA nanoparticles showed good antitumor activity and significantly reduced the toxicity of HCPT.

The hydroxycamptothecin linoleate small molecule prodrug or the pharmaceutical composition or the self-assembled nanoparticle of the small molecule prodrug of the present invention can be used to prepare a tumor microenvironment intelligent response drug delivery system. And can be used for injection administration, oral administration or topical administration.

The invention has the following beneficial effects: (1) the redox double sensitive small molecule prodrugs bridged by disulfide bonds are designed and synthesized, and the synthesis method is simple and feasible; (2) uniform small molecule prodrug self-assembled nanoparticles are prepared, The preparation method is simple and easy to operate, has good stability, and realizes the efficient encapsulation of hydroxycamptothecin; (3) The morphological characterization of the prodrug self-assembled nanoparticles bridged by disulfide bonds and the antitumor effect in vitro and in vivo were investigated. It highlights the advantages of small molecule self-assembled prodrugs bridged by disulfide bridges, provides new strategies and more options for the development of intelligent responsive drug delivery systems in the tumor microenvironment, and meets the urgent need for high-efficiency and low-toxicity chemotherapeutic agents in clinical practice. .

Description of drawings

FIG. 1 is the ¹ HNMR spectrum of hydroxycamptothecin linoleate (HCPT-SS-LA) in Example 1 of the present invention.

2 is a mass spectrum of hydroxycamptothecin linoleate (HCPT-SS-LA) of Example 1 of the present invention.

3 is a transmission electron microscope image of the self-assembled nanoparticles of small molecule prodrugs without PEG modification in Example 2 of the present invention.

4 is a transmission electron microscope image of the 8% PEG-modified small molecule prodrug self-assembled nanoparticles of Example 2 of the present invention.

5 is a transmission electron microscope image of the 20% PEG-modified small-molecule prodrug self-assembled nanoparticles of Example 2 of the present invention.

6 is a transmission electron microscope image of the hydroxycamptothecin nanocrystals in Example 2 of the present invention.

FIG. 7 is a graph of the cytotoxicity of the PEG-modified small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.

FIG. 8 is a graph showing the changes in mouse tumor volume in the in vivo anti-tumor experiment of the PEG-modified small molecule prodrug self-assembled nanoparticles of Example 4 of the present invention.

FIG. 9 is a graph of tumor burden in mice in the in vivo anti-tumor experiment of the PEG-modified small molecule prodrug self-assembled nanoparticles of Example 4 of the present invention.

FIG. 10 is a graph showing the changes in the body weight of mice in the in vivo anti-tumor experiment of the PEG-modified small-molecule prodrug self-assembled nanoparticles of Example 4 of the present invention.

11 is a comparison diagram of mouse tumors in the in vivo anti-tumor experiment of the PEG-modified small molecule prodrug self-assembled nanoparticles of Example 4 of the present invention.

FIG. 12 is a safety experiment diagram of the PEG-modified small molecule prodrug self-assembled nanoparticles of Example 4 of the present invention.

Detailed ways

The present invention is further described below by way of examples, but the invention is not limited to the scope of the described examples.

Example 1: Synthesis of Hydroxycamptothecin Linoleate Small Molecule Prodrug (HCPT-SS-LA)

Linoleic acid was added to the toluene solution in which p-toluenesulfonic acid and 2,2'-dithiodiethanol had been dissolved, and the reaction system was heated to 110 °C under the protection of N ₂ . After the reaction was detected by TLC, it was extracted with saturated NaHCO ₃ solution, and the excess water was removed with anhydrous Na ₂ SO ₄ . Finally, the intermediate product was obtained by column chromatography. The intermediate product was dissolved in dichloromethane, and DIPEA and p-nitrophenyl chloroformate were added under ice bath conditions, and the mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation under reduced pressure, the system was reconstituted with DMF, ice-bathed to 0°C, the hydroxycamptothecin solution dissolved in DMF was slowly added, anhydrous triethylamine was added, and the reaction was carried out at room temperature for 24 hours. The resulting product was purified by preparative liquid phase separation.

The structure of the prodrug in Example 1 was determined by mass spectrometry and hydrogen nuclear magnetic resonance spectroscopy, and the results are shown in FIG. 1 . The solvent selected for nuclear magnetic resonance is CDCl ₃ , and the spectral analysis results are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H, Ar-H), 8.26 (d, J=9.3 Hz, 1H, Ar-H), 7.79 (d, J=2.6 Hz, 1H, Ar -H), 7.69–7.64 (m, 1H, Ar-H), 5.75 (d, J=16.4Hz, 1H, Py- H ), 5.43–5.27 (m, 4H, -CH=CH-), 4.58 (d, J=6.6 Hz, 1H, -OH), 4.37 (q, J=6.5 Hz, 2H, Py-CH ₂ -OC=O-), 3.77 (s, 2H, Py-NC H ₂ -) ,3.08(t,J=6.5Hz,2H,-CH ₂ -OC=OO-),2.98(t,J=6.6Hz,2H,-C=O- CH ₂ -),2.95–2.86(m, 4H, -CH ₂ -SS-CH ₂ -), 2.76 (s, 2H, -CH=CH- CH ₂ -CH=CH-), 2.32 (t, J=7.8Hz, 2H, -CH ₂ -C=OO-), 2.03(s, 4H, -CH=CH-CH ₂ -), 1.63(s, 2H), 1.30(s, 18H, -CH ₂ -), 1.05(t, J =7.4Hz, 3H, -CH ₂ -CH ₃ ), 0.94-0.83 (m, 3H, -(CH ₂ ) ₄ -CH ₃ ). MS(ESI) m/z for HCPT-SS-LA[M +H] ⁺ = 807.33263, [MH] ^- = 805.31754.

Example 2: Preparation of small molecule prodrug self-assembled nanoparticles

Accurately weigh an appropriate amount of TPGS _2k (0.35 mg for 8%, 1 mg for 20%, 1.7 mg for 30%) and 4 mg of the prodrug, dissolve it with 1 mL of tetrahydrofuran, and slowly add the tetrahydrofuran solution to 4 mL with stirring. In ionized water, spontaneously formed uniform nanoparticles (HCPT-SS-LA nanoparticles, HCPT-SS-LA/8%PEG nanoparticles, HCPT-SS-LA/20%PEG nanoparticles, HCPT-SS-LA/30% PEG nanoparticles). The organic solvent in the nanoformulation was removed by rotary evaporation under reduced pressure at 35°C.

Table 1. Drug loading of hydroxycamptothecin linoleate prodrugs

The formulations in Table 1 can all produce prodrug self-assembled nanoparticles, but the particle size of 30% PEGylated nanoparticles is not reproducible in different batches and fluctuates around 130-160 nm, while the 8% and 20% PEGylated nanoparticles are not reproducible in particle size. There is almost no difference in the particle size of the nanoparticles between batches. It is speculated that the surface-modified TPGS of 30% PEG nanoparticles has been saturated, and some TPGS self-assembled into micelles in the system. At the same time, considering the drug loading. factor, so the 30% PEGylated formulation was eliminated in a follow-up study.

As shown in Table 2, the particle sizes of the nanoparticles are all 135-165 nm, the particle size distribution of the PEGylated nanoparticles is less than 0.2, the surface charge is about -20mV, and the drug loading is more than 35%. The particle size and morphology of the small molecule prodrug self-assembled nanoparticles prepared in Example 2 and the hydroxycamptothecin nanocrystals prepared by the same method were measured by transmission electron microscopy. The results are shown in Figure 2. The transmission electron microscopy image shows that the drug-loaded nanoparticles are Uniform spherical, particle size in 120-100nm.

Table 2. Particle size, particle size distribution, surface charge and drug loading of small molecule prodrug self-assembled nanoparticles

Example 3: Cytotoxicity of PEG-modified small molecule prodrug self-assembled nanoparticles

The cytotoxicity of PEG-modified small molecule prodrug self-assembled nanoparticles on mouse breast cancer (4T1) cells was investigated by MTT assay. Digest the cells in good condition, dilute them with culture medium to a cell density of 1000 cells/mL, add 200 μL of cell suspension to each well of a 96-well plate after blowing evenly, and incubate in an incubator for 24 hours to make them adhere to the wall. Hydroxycamptothecin or the prodrug nanoparticles prepared in Example 2 were added after the cells adhered. In the experiment, 1640 culture medium was used for the preparation and dilution of drug solution and nanoparticle preparation, and was sterile filtered with 0.22 μm membrane. Add 200 μL of the test solution to each well, 3 parallel wells for each concentration. For the control group, 200 μL of culture medium was added without adding the test liquid, and the cells were incubated together in an incubator. 48 hours after dosing, the 96-well plate was taken out, 35 μL of 5 mg/mL MTT solution was added to each well, incubated in an incubator for 4 hours, and then the plate was shaken off. Add 200 μL of DMSO and shake on a shaker for 10 min to dissolve the blue-violet crystals. Set well A1 (containing only 200 μL DMSO) as the zeroing well. The absorbance value of each well after zero adjustment was measured at 490 nm using a microplate reader.

The cytotoxicity results are shown in Figure 3. Since it takes a certain time for the prodrug nanoparticles to release hydroxycamptothecin, and the hydroxycamptothecin exerts a certain limitation, the cytotoxicity of the prodrug nanoparticles is lower than that of the hydroxycamptothecin group. The cytotoxicity of HCPT-SS-LA/8%PEG nanoparticles is weaker than that of HCPT-SS-LA/20%PEG nanoparticles, because the stability of HCPT-SS-LA/20%PEG nanoparticles is better than the former, Prodrugs can persist in tumor cells for longer periods of time. As shown in Table 3, the advantages of HCPT-SS-LA/20%PEG nanoparticles are more obvious after 72 hours of incubation, which further proves that to ensure the cytotoxicity of nanoparticles, the colloidal stability of nanoparticles must be ensured first. At the same dose, 20% PEG modification can provide nanoformulations with stronger antitumor ability than 8% PEG modification.

Table 3. Half inhibitory concentration (IC ₅₀ ) of hydroxycamptothecin and prodrug nanoparticles on mouse breast cancer (4T1) cells

Example 4: In vivo antitumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles

The antitumor activity of PEG-modified small-molecule prodrug self-assembled nanoparticles on 4T1 heterotopic tumor model was investigated. The 4T1 cell suspension (5x 10 ⁶ cells/50 μL) was inoculated into the right back of female Balb/c by subcutaneous injection to establish a 4T1 ectopic tumor model. When the tumor volume grew to about 100m3, the tumor ^- bearing mice were randomly divided into groups, five mice in each group, and were respectively given physiological saline, hydroxycamptothecin solution and the PEG-modified small molecule prodrug prepared in Example 2. Assemble nanoparticles. Administered once every other day, 4 times of continuous administration, calculated according to hydroxycamptothecin, the administration dose was 2.5 mg/kg. After administration, the mice were observed for survival, weighed, and measured the tumor volume every day. Tumor-bearing mice were sacrificed two days after the last dose, and organs and tumors were harvested for further analysis and evaluation. Major organs (heart, liver, spleen, lung, kidney) and tumor tissues were collected and fixed with formalin for H&E staining.

The experimental results are shown in Figure 4. The anti-tumor activity of the hydroxycamptothecin solution nanoparticles is low, which is due to the random distribution of the free drug in the body and easy removal. In contrast, HCPT-SS-LA nanoparticles can accumulate at the tumor site and release the active parent drug in tumor cells, which has a significant anti-tumor effect. However, due to the better colloidal stability, longer blood circulation and efficient drug release of HCPT-SS-LA/20%PEG nanoparticles, the antitumor activity of HCPT-SS-LA/20%PEG nanoparticles is stronger than HCPT-SS-LA/8% PEG nanoparticles. Mice treated with nanoparticles maintained a stable body weight and showed no significant impairment of physical function. This suggests that HCPT-SS-LA nanoparticles reduce the toxicity of HCPT due to the selective release of the drug in tumor cells. As shown in the tumor tissue section in Figure 5, HCPT-SS-LA nanoparticles have obvious anti-tumor effects without causing significant non-specific toxicity to the body, and are safe and effective anti-cancer drug delivery systems.

Claims (10)

1. Hydroxycamptothecin linoleate small-molecule prodrug, characterized in that, with Hydroxycamptothecin as a simulated drug, the prodrug is linked by 2,2'-dithiodiethanol to synthesize the prodrug, and its structure is as follows:

2. hydroxycamptothecin linoleate small molecule prodrug as claimed in claim 1, is characterized in that, linoleic acid can use oleic acid, stearic acid, trans-oleic acid, α-linolenic acid, γ- Linolenic acid, docosahexaenoic acid, arachidonic acid replacement. 3. hydroxycamptothecin linoleate small molecule prodrug as claimed in claim 1, is characterized in that, described hydroxycamptothecin can use other anticancer drugs containing active hydroxyl or amino group, preferably camptothecin It is replaced by compounds, nucleosides, anthracyclines or taxanes. 4. the preparation method of hydroxycamptothecin linoleate small molecule prodrug as claimed in claim 1, is characterized in that, firstly linoleic acid and 2,2'-dithiodiethanol are esterified to obtain intermediate product, then The intermediate product is then carbonated with a molecule of hydroxycamptothecin to obtain the final product. 5. preparation method as claimed in claim 3, is characterized in that, adopts following steps to prepare: The linoleic acid was added to the toluene solution in which p-toluenesulfonic acid and 2,2'-dithiodiethanol had been dissolved, and the reaction system was heated to 110 °C under the protection of _N2 ; after the completion of the reaction was detected by TLC, saturated _NaHCO3 was used. Solution extraction, then use anhydrous Na ₂ SO ₄ to remove excess water, and finally use column chromatography to separate the intermediate product; dissolve the intermediate product in dichloromethane, add DIPEA and p-nitro group under ice bath conditions Benzyl chloroformate, stirred at room temperature overnight, evaporated under reduced pressure to remove the solvent, redissolved the system with DMF, cooled to 0°C in an ice bath, slowly added a solution of hydroxycamptothecin dissolved in DMF, and added anhydrous triethylamine, The reaction was carried out at room temperature for 24 hours, and the product obtained after extraction was subjected to preparative liquid phase separation and purification. 6. A pharmaceutical composition comprising the hydroxycamptothecin linoleate small molecule prodrug of any one of claims 1-3 and a pharmaceutically acceptable carrier or excipient. 7. Hydroxycamptothecin linoleate small molecule prodrug self-assembled nanoparticle, is characterized in that, its preparation process is as follows: Dissolve a certain amount of the mixture of hydroxycamptothecin linoleate small molecule prodrug and PEG modifier into an appropriate amount of tetrahydrofuran, slowly add the tetrahydrofuran solution dropwise to the water under stirring, and the prodrug spontaneously forms a uniform nanometer Finally, the tetrahydrofuran in the preparation was removed by rotary evaporation to obtain a nanocolloid solution without any organic solvent. 8. docetaxel dimer small molecule prodrug self-assembled nanoparticle according to claim 7, is characterized in that, described PEG is TPGS, DSPE-PEG, PLGA-PEG, PE-PEG and DSPE- For PEG-AA, the ratio of small molecule prodrug to PEG modifier is 92:8 to 70:30. 9. The hydroxycamptothecin linoleate small molecule prodrug of any one of claims 1-3 or the pharmaceutical composition of claim 6 or the small molecule prodrug of any one of claims 7-8 Application of drug self-assembled nanoparticles in the preparation of drug delivery systems. 10. The hydroxycamptothecin linoleate small molecule prodrug of any one of claims 1-3 or the pharmaceutical composition of claim 6 or the small molecule prodrug of any one of claims 7-8 Application of drug self-assembled nanoparticles in the preparation of antitumor drugs.

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