CN115844891A - Disulfide bond bridged SN38 dimer prodrug, self-assembled nanoparticles thereof, preparation method and application - Google Patents
Disulfide bond bridged SN38 dimer prodrug, self-assembled nanoparticles thereof, preparation method and application Download PDFInfo
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Abstract
Disulfide bond bridged SN38 dimer prodrug and self-assembled nanoparticles thereof, a preparation method and application, which belong to the technical field of medicine, and relate to the preparation of disulfide bond bridged SN38 dimer prodrug and self-assembled nanoparticles thereof, and the application thereof in medicine delivery. The preparation method is simple and easy to implement, and influences on chemical stability and self-assembly capacity of the SN38 dimer prodrug and the drug release behavior, cytotoxicity, pharmacokinetics, tissue distribution and anti-tumor effect of the prodrug nano assembly caused by the influences are examined by the length of the connecting chain containing the disulfide bond. Provides a new idea for developing SN38 nanometer preparations, solves the urgent need of high-efficiency and low-toxicity chemotherapy preparations in clinic and the need of enterprises for developing SN38 nanometer preparations.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to disulfide bond bridged SN38 dimer prodrugs and a preparation method and application of self-assembled nanoparticles thereof, in particular to synthesis of SN38 dimer prodrugs with disulfide bonds positioned at alpha, beta and gamma positions of adjacent carbonyls, preparation of SN38 dimer prodrugs self-assembled nanoparticles with disulfide bonds positioned at beta and gamma positions of adjacent carbonyls, and application of the SN38 dimer prodrugs self-assembled nanoparticles in drug delivery.
Background
Cancer is a serious threat to human health. Drug therapy remains one of the most common strategies for cancer treatment today, especially for advanced tumors, tumors that cannot be surgically excised, and tumors that have metastasized to spread. The existing preparation technology in clinic has low delivery efficiency, and the problems of poor curative effect and serious adverse reaction of the anti-tumor medicine exist. For example, SN38 has very strong pharmacodynamic activity, but has extremely low water solubility and is hardly dissolved in pharmaceutical excipients, thus seriously limiting the development of the preparation. Irinotecan (a water-soluble prodrug of SN 38) which is a clinically used preparation cannot be efficiently converted into SN38 in vivo, and has limited curative effect and serious toxic and side effects. Although the research on SN38 drug delivery systems is endless, the affinity of SN38 with most nano-carriers is poor, so that the nano-formulations coated with SN38 have the defects of low drug loading, poor stability and the like. Therefore, the construction of a novel SN38 delivery system with high efficiency and low toxicity has important significance.
The micromolecule prodrug self-assembly nanoparticles combine the advantages of a prodrug and nanotechnology, the obtained hydrophobic drug can be spontaneously assembled into a nano preparation in water, the drug loading capacity is high, adverse reactions caused by carrier materials are avoided, and the preparation process is simple, good in reproducibility and good in application transformation prospect. In particular to a homodimer prodrug self-assembly nano-drug which has ultrahigh drug loading (more than 50 percent) and unique structural characteristics and is expected to efficiently deliver SN38. However, poor self-assembly ability becomes a key factor that restricts the application of homodimer prodrug self-assembly nanoparticles. Designing and developing dimeric prodrug self-assembly nano-scale with good stability is still a great challenge, especially for SN38 which is a drug with very strong structural rigidity.
The self-assembly performance of the prodrug is obviously influenced by the flexible performance of the prodrug structure, the longer the carbon chain length is, the more sigma bonds which can freely rotate in the prodrug structure are, the more flexible the prodrug structure is, the more favorable the prodrug can be adjusted to the state with the lowest energy in the self-assembly process, and a stable nano structure is formed. Therefore, by increasing the length of the connecting chain, the self-assembly capability of the prodrug is expected to be improved, and the stability, the in vivo fate and the anti-tumor effect of the nanoparticle are further improved. In order to efficiently and specifically release active drugs in tumor tissues, disulfide bonds are used for constructing intelligent response type prodrugs sensitive to tumor microenvironment. The intelligent response type prodrug exists in an inactive prodrug form in body circulation, so that toxic and side effects on normal tissues of an organism are avoided; after reaching the tumor part, the disulfide bond is rapidly broken under the stimulation of the highly expressed glutathione in the tumor microenvironment to release the drug, thereby playing the role of high-efficiency anti-tumor.
Disclosure of Invention
The invention aims to design and synthesize SN38 dimer prodrugs bridged by connecting chains with different lengths and containing disulfide bonds, prepare SN38 dimer prodrug self-assembly nano drug delivery systems, and investigate the application of the SN38 dimer prodrugs in drug delivery. The influence of the length of the connecting chain on the stability, the drug release, the cytotoxicity, the pharmacokinetics, the tissue distribution and the pharmacodynamics of the prodrug self-assembly nanoparticle is discussed, a new thought is provided for developing a stable prodrug self-assembly nanoparticle delivery system, and the urgent requirements of high-efficiency chemotherapy preparations in clinic and the requirements of enterprises on developing SN38 nanoparticle preparations are met.
In order to achieve the above object, the present invention provides SN38 dimer prodrugs bridged by disulfide bonds at different positions as shown in general formula (I).
Wherein n =1-3.
Preferably, the disulfide-bridged SN38 dimer prodrug is an SN38 dimer prodrug with a disulfide bond located alpha, beta, or gamma to the adjacent carbonyl group prepared by linkage of SN38 through 2,2' -dithiodiacetic acid, 3,3' -dithiodipropionic acid, or 4,4' -dithiodibutanoic acid.
Disulfide bond SN38 dimer prodrug alpha to the adjacent carbonyl has the structure:
disulfide bond SN38 dimer prodrug located at the β -position of the adjacent carbonyl group has the structure:
disulfide bond SN38 dimer prodrug at the γ -position of the adjacent carbonyl group has the structure:
the invention provides a preparation method of a disulfide bond bridged SN38 dimer prodrug, which comprises the following steps:
2,2' -dithiodiacetic acid, 3,3' -dithiodipropionic acid or 4,4' -dithiodibutanoic acid are dissolved in chloroform and evenly stirred; dissolving part of 4-Dimethylaminopyridine (DMAP), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and SN38 in chloroform, uniformly stirring, mixing with the 2,2' -dithiodiacetic acid, 3,3' -dithiodipropionic acid or 4,4' -dithiodibutanoic acid solution respectively, and stirring at room temperature for 10-12h under the protection of nitrogen; and (3) supplementing the rest EDCI and DMAP into the mixed solution, continuously stirring at room temperature for 12-24h under the protection of nitrogen, and separating and purifying the obtained product by a preparation liquid phase.
A pharmaceutical composition comprising the disulfide bridged SN38 dimer prodrug, and pharmaceutically acceptable carriers and excipients.
The invention also provides application of the disulfide bond bridged SN38 dimer prodrug or a pharmaceutical composition containing the prodrug in preparation of antitumor drugs.
The invention also provides the use of the disulfide bridged SN38 dimer prodrug or a pharmaceutical composition comprising the prodrug for the preparation of a drug delivery system.
The invention also provides the use of the disulfide bridged SN38 dimer prodrug or a pharmaceutical composition comprising the prodrug for the preparation of an injectable, oral or topical delivery system.
The invention also provides self-assembled nanoparticles of the disulfide bond bridged SN38 dimer prodrug, and the self-assembled nanoparticles can be non-PEG dimer prodrug self-assembled nanoparticles and PEG-modified dimer prodrug self-assembled nanoparticles. The preparation method is a nano precipitation method, and comprises a high-speed stirring method and an ultrasonic method.
The preparation method of the disulfide bond bridged SN38 dimer prodrug self-assembly nanoparticle comprises the following steps:
dissolving a disulfide bond bridged SN38 dimer prodrug and a PEG modifier (PEG modifier is not added to non-PEGylated dimer prodrug self-assembly nanoparticles) in a solvent, slowly dropwise adding the solution into water under stirring, spontaneously forming uniform nanoparticles from the prodrug, and removing the solvent by adopting a reduced pressure distillation method to obtain a nano colloidal solution without an organic solvent.
The PEG modifier is selected from TPGS, DSPE-PEG, PLGA-PEG and PE-PEG, and the preferable PEG modifier is DSPE-PEG. The PEG has a molecular weight of 1000-5000, preferably 1000, 2000 and 5000, more preferably a molecular weight of 2000.
The solvent is selected from ethanol, dimethyl sulfoxide, N' -dimethylformamide, tetrahydrofuran and acetone.
The weight ratio of the disulfide bond bridged SN38 dimer prodrug to the PEG modifier is 90-70, and under the condition of the range, the prodrug nanoparticle can exert a better anti-tumor effect.
The invention also provides application of the disulfide bond bridged SN38 dimer prodrug self-assembly nanoparticle in preparation of a drug delivery system.
The invention also provides application of the disulfide bond bridged SN38 dimer prodrug self-assembly nanoparticles in preparation of antitumor drugs.
The invention also provides application of the disulfide bond bridged SN38 dimer prodrug self-assembly nanoparticle in preparation of injection administration, oral administration or local administration systems.
The invention solves the technical problems that a disulfide bond is introduced into an SN38 dimer prodrug and a self-assembly nanoparticle, a redox double-sensitive dimer prodrug bridged by the disulfide bond is designed, and the dimer prodrug is used for constructing the self-assembly nanoparticle, so that the high drug loading capacity, the good stability, the low toxic and side effects and the specific rapid drug release of a tumor part are realized, and the treatment effect is improved. Meanwhile, the differences of disulfide bond connecting chains with different lengths in the aspect of SN38 prodrug self-assembly and the influence on the stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of prodrug self-assembly nanoparticles are examined.
The invention has the advantages that:
(1) SN38 dimer prodrugs containing disulfide bond connecting chains with different lengths are designed and synthesized, and the synthesis method is simple and easy to implement;
(2) The uniform dimer prodrug self-assembly nanoparticles are prepared, the preparation method is simple and easy to implement, the efficient entrapment of the drug is realized, and the ultra-high drug-loading rate is more than 63%;
(3) The differences of disulfide bond connecting chains with different lengths in the aspect of self-assembly are investigated, and the influences on the stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the prodrug self-assembly nanoparticles are also investigated. In combination with experimental results, SN38 dimer prodrugs with disulfide bonds located at the β -and γ -positions of adjacent carbonyls have suitable chemical stability. Meanwhile, SN38 dimer prodrug with disulfide bond located at γ -position to adjacent carbonyl group has the best assembling ability. The invention provides a new strategy and more choices for developing an intelligent response type drug delivery system of a tumor microenvironment, and meets the urgent needs of high-efficiency chemotherapy preparations in clinic and the needs of enterprises for developing SN38 nanometer preparations.
Drawings
FIG. 1 is a mass spectrum of SN38 dimer prodrug with disulfide bond located alpha to adjacent carbonyl (alpha-SN 38-SS-SN 38) of example 1 of the present invention.
FIG. 2 shows the structural confirmation of SN38 dimer prodrug (β -SN38-SS-SN 38) with disulfide bond at β -position of adjacent carbonyl group in example 2 of the present invention.
A: mass spectrum of beta-SN 38-SS-SN38.
B: of beta-SN 38-SS-SN38 1 H-NMR spectrum.
FIG. 3 is a structural confirmation of SN38 dimer prodrug (γ -SN38-SS-SN 38) with disulfide bond at γ -position of adjacent carbonyl group in example 3 of the present invention.
A: a mass spectrum of gamma-SN 38-SS-SN38.
B: of gamma-SN 38-SS-SN38 1 H-NMR spectrum.
Figure 4 is the chemical stability at room temperature of disulfide bridged SN38 dimer prodrugs of example 4 of the present invention.
FIG. 5 is a confirmation of the purity of disulfide-bridged SN38 dimer prodrugs prepared in example 5 of the present invention.
A: purity results for beta-SN 38-SS-SN38.
B: purity results of gamma-SN 38-SS-SN38.
Figure 6 is a graph of the stability results of non-pegylated disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles of the present invention in example 6.
A: stability of non-pegylated disulfide bridged SN38 dimer prodrug self-assembled nanoparticles at room temperature for 48 h.
B: the non-PEGylated prodrug nanoparticles have the preparation property of 0h.
C: the preparation property of the non-PEGylated prodrug nanoparticles is 3 h.
Figure 7 is a graph of the stability results of PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles of example 6 of the present invention.
A: stability of PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles at room temperature for 48 h.
B: the PEG modified prodrug nanoparticles have the preparation properties of 0h.
C: the PEG modified prodrug nanoparticles have preparation properties of 4 h.
Figure 8 is an in vitro release assay of PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles under reducing and oxidizing conditions in example 7 of the invention.
A: a blank medium.
B: 0.1mM DTT was added to the medium.
C: 1mM DTT was added to the medium.
D: the medium was charged with 0.1mM H 2 O 2 。
E: 1mM H was added to the medium 2 O 2 。
Figure 9 is a cytotoxicity plot of PEG-modified disulfide-bridged SN38 dimer prodrug self-assembling nanoparticles of example 8 of the invention.
A: half inhibitory concentration of disulfide-bridged SN38 dimer prodrug self-assembling nanoparticles on 4T1 cells.
B: half inhibitory concentration of disulfide-bond bridged SN38 dimer prodrug self-assembled nanoparticles on CT26 cells.
C: half inhibitory concentration of disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles on L02 cells.
Fig. 10 shows the results of in vivo antitumor experiments of disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles of example 10 of the present invention.
A: growth curves of Balb/C tumor-bearing mice after treatment with disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles.
B: and after the disulfide bond bridged SN38 dimer prodrug is treated by the self-assembled nanoparticle, the tumor-bearing rate of Balb/C tumor-bearing mice is increased.
C: photographs of tumors of Balb/C tumor-bearing mice after treatment with disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles.
D: after treatment with disulfide-bridged SN38 dimer prodrug self-assembling nanoparticles, body weight changes in Balb/C tumor-bearing mice.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Example 1: synthesis of SN38 dimer prodrug with disulfide bond alpha to adjacent carbonyl group (alpha-SN 38-SS-SN 38)
2,2' -dithiodiacetic acid (182.2mg, 1mmol), EDCI (287.6mg, 1.5mmol) and DMAP (122.2mg, 1mmol) were charged into a 50mL round-bottomed flask and dissolved with 20mL of chloroform, and then a chloroform solution (5 mL) containing SN38 (784.8mg, 2mmol) was added dropwise and reacted at room temperature under nitrogen for 10 hours. EDCI (191.7mg, 1mmol) and DMAP (61.1mg, 0.5mmol) were then added to the reaction system and the reaction was continued for 12h under nitrogen. The progress of the reaction was monitored by thin layer chromatography. The chloroform in the system was removed by a rotary evaporator, the product was dissolved in DMF, and isolated and purified (8.5 mg, yield 0.9%) by preparative liquid phase (acetonitrile: water = 70.
Mass spectrometry was used to determine the molecular weight of α -SN38-SS-SN38 prepared in example 1, and the results are shown in FIG. 1. Detects [ M + H] + Peak 931.23, demonstrating the successful synthesis of α -SN38-SS-SN38.
Example 2: synthesis of SN38 dimer prodrug with disulfide bond at beta position adjacent to carbonyl (beta-SN 38-SS-SN 38)
Using the preparation method of example 1, the β -disulfide bridged SN38 dimer prodrug was prepared by replacing 2,2 '-dithiodiacetic acid with 3,3' -dithiodipropionic acid.
The structure of β -SN38-SS-SN38 obtained in example 2 was confirmed by mass spectrometry and hydrogen nuclear magnetic resonance spectroscopy, and the results are shown in FIG. 2.
The results of nuclear magnetic resonance spectroscopy were as follows:
1 H NMR(400MHz,CDCl 3 )ppm 7.84(d,2H,Ar-H,J＝9.14Hz),7.58(d,2H,Ar-H,J＝2.38Hz),7.42(dd,2H,Ar-H,J＝9.14,2.40Hz),7.26(s,2H,Ar-H),5.65(d,2H,22-CH 2 -αH,J＝16.38Hz),5.19(dd,4H,5-CH 2 ,J＝17.55,8.12Hz),5.07(d,2H,22-CH 2 -βH,J＝18.75Hz),3.29-3.00(m,12H,CH 2 2 CHSS 2 CHCH 2 ,23-CH 2 ),1.86(td,4H,18-CH 2 ,J＝14.28,7.02Hz),1.39(t,6H,24-CH 3 ,J＝7.66Hz),0.99(t,6H,29-CH 3 ,J＝7.38Hz).
the mass spectrum result is MS (ESI) M/z [ M + H ]] + ＝959.26367。
Example 3: synthesis of SN38 dimer prodrug with disulfide bond located gamma to adjacent carbonyl (gamma-SN 38-SS-SN 38)
Using the preparation method of example 1, the gamma disulfide bridged SN38 dimer prodrug was prepared by replacing 2,2 '-dithiodiacetic acid with 4,4' -dithiodibutanoic acid.
Mass spectrometry and hydrogen nuclear magnetic resonance spectroscopy were used to determine the structure of γ -SN38-SS-SN38 obtained in example 3, and the results are shown in FIG. 3.
The results of nuclear magnetic resonance spectroscopy were as follows:
1 H NMR(400MHz,CDCl 3 )δppm 7.74(d,2H,Ar-H,J＝9.13Hz),7.65(d,2H,Ar-H,J＝1.97Hz),7.35(s,2H,Ar-H),7.33(dd,2H,Ar-H,J＝9.20,2.14Hz),5.66(d,2H,22-CH 2 -αH,J＝16.39Hz),5.21(t,4H,5-CH 2 ,J＝17.00Hz),5.10(d,2H,22-CH 2 -βH,J＝18.70Hz),3.09(d,4H,CH 2 CH 2 2 CHSS 2 CHCH 2 CH 2 ,J＝7.72Hz),2.93(dt,4H,CH 2 2 CHCH 2 SSCH 2 2 CHCH 2 ,J＝6.63,1.73Hz),2.86(t,4H, 2 CHCH 2 CH 2 SSCH 2 CH 2 2 CH,J＝6.89Hz),2.33-2.20(m,4H,23-CH 2 ),1.92-1.78(m,4H,18-CH 2 ),1.43(t,6H,J＝7.59Hz),0.99(t,6H,J＝7.34Hz).
the mass spectrum result is MS (ESI) M/z [ M + H ]] + ＝987.29493。
Example 4: chemical stability Studies of disulfide-bridged SN38 dimer prodrugs
An appropriate amount of prodrug powder (α -SN38-SS-SN38, β -SN38-SS-SN38 or γ -SN38-SS-SN 38) was weighed out and dissolved in DMF, and the area of the prodrug peak was immediately recorded by high performance liquid chromatography (0 h). The sample was left at room temperature for 9h, the peak area of the prodrug was detected by liquid phase at different time points, and the relative purity (ratio of the peak area of the prodrug at different time points to the peak area of the prodrug at 0 h) was calculated. As shown in FIG. 4, the purity of the β -SN38-SS-SN38 and the γ -SN38-SS-SN38 remained substantially unchanged after being left at room temperature for 9 hours, while the purity of the α -SN38-SS-SN38 rapidly decreased to about 60%. This suggests that the position of the disulfide bond in the prodrug can significantly affect the chemical stability of SN38 dimer prodrug, and that α -SN38-SS-SN38 has very poor stability and is not druggable, so we chose β -SN38-SS-SN38 and γ -SN38-SS-SN38 for subsequent experiments.
Example 5: purity confirmation of disulfide-bridged SN38 dimer prodrugs
The purity of the beta-SN 38-SS-SN38 and the gamma-SN 38-SS-SN38 is measured by utilizing high performance liquid chromatography, and the results are shown in figure 5, the purity of the two prodrugs is more than 99.5%, and the requirements of subsequent experiments are met.
Example 6: preparation and stability study of non-PEGylation/PEG modified disulfide bond bridged SN38 dimer prodrug self-assembled nanoparticles
Precisely weighing 0.2mg of beta-SN 38-SS-SN38 or gamma-SN 38-SS-SN38, dissolving in 200 μ L of N, N-Dimethylformamide (DMF), and dripping into 2mL of deionized water at a stirring speed of 1000r/min to self-assemble the prodrug into non-PEGylated beta-SN 38-SS-SN38NPs or non-PEGylated gamma-SN 38-SS-SN38 NPs. DMF was removed by dialysis at room temperature. As shown in Table 1, the particle size of non-PEGylated β -SN38-SS-SN38NPs was about 115nm, while the particle size of non-PEGylated γ -SN38-SS-SN38NPs was smaller, about 90 nm. The stability of the non-pegylated prodrug nanoassemblies was investigated. As shown in FIG. 6, after standing at room temperature for 48 hours, the particle size of non-PEGylated γ -SN38-SS-SN38NPs was substantially unchanged, and the properties of the preparation were not significantly changed. And non-PEGylated beta-SN 38-SS-SN38NPs precipitate after being placed at room temperature for 3 hours. This shows that the position of disulfide bond in prodrug structure can affect the self-assembly ability of prodrug and the stability of nano-assembly, the self-assembly ability of gamma-SN 38-SS-SN38 is stronger, and the stability of formed nano-assembly is better.
1mg of the prodrug (. Beta. -SN38-SS-SN38 or. Gamma. -SN38-SS-SN 38) was precisely weighed out together with 0.25mg of DSPE-PEG 2K Dissolving in 200 μ L DMF, dropping into 2mL deionized water under stirring speed of 1000r/min, and self-assembling the prodrug into the PEGylated nano-assembly (beta-SN 38-SS-SN 38)NPs, gamma-SN 38-SS-SN38 NPs). DMF was removed by dialysis at room temperature. As shown in Table 2, the DSPE-PEG2K modified prodrug nano-assembly has the particle size of about 100nm, uniform particle size distribution and surface charge of about-20 mV, and is beneficial to preventing the aggregation of nano-particles. The change of surface charge also proves that PEG is successfully modified on the surface of the nanoparticle. The stability of the pegylated prodrug nano-assembly at room temperature was investigated. The result is shown in FIG. 7, after 4h, the beta-SN 38-SS-SN38NPs precipitate, while the particle size of the gamma-SN 38-SS-SN38NPs remains unchanged, further proving that the self-assembly performance of the gamma-SN 38-SS-SN38 dimer prodrug is better than that of the beta-SN 38-SS-SN38. The surface of the prodrug nano assembly is subjected to PEG modification, so that the stability of the prodrug nano assembly can be improved to a certain extent, but the difference of the stability of different prodrug nano assemblies cannot be changed.
TABLE 1 particle size, particle size distribution, surface charge, and drug loading of non-PEG modified dimeric prodrug self-assembled nanoparticles
Table 2 particle size, particle size distribution, surface charge, and drug loading of PEG-modified dimeric prodrug self-assembled nanoparticles
Example 7: in vitro release assay for PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles
To contain different concentrations of hydrogen peroxide (H) 2 O 2 Commonly used ROS substitute) or dithiothreitol (DTT, substitute for glutathione) in PBS (pH 7.4, containing 30% absolute ethanol) buffer as a release medium, and the drug release condition of the disulfide-bond bridged SN38 dimer prodrug self-assembled nanoparticles is examined. The specific operation is as follows: 1mL of the PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles prepared in example 5 (SN 38 equivalent mass 200 μ g) were added to a 50mL centrifuge tube,and 30mL of release medium is added, then the whole system is placed in a constant temperature shaking table at 37 ℃, the oscillation speed is 100r/min, 200 mu L of sample is taken at a preset time point, and the content of SN38 in the sample is measured by using a high performance liquid chromatograph. The reduction release results are shown in FIGS. 8A-8C, in blank media, the release rate of beta-SN 38-SS-SN38NPs is much greater than gamma; the release rate of the gamma-SN 38-SS-SN38NPs is larger than that of the beta-SN 38-SS-SN38NPs under the action of 0.1mM DTT and 1mM DTT. This is because β -SN38-SS-SN38NPs are less stable and tend to disintegrate, leading to easy hydrolysis of the prodrug, suggesting that they release the drug at low GSH levels in blood and normal tissues. The gamma-SN 38-SS-SN38NPs are stable under normal conditions, but are more sensitive to GSH, and can release the parent drug under the action of high-concentration GSH in a tumor microenvironment, so that the anti-tumor effect is ensured, and the toxic and side effects on normal tissues are reduced. The oxidation response drug release results of the prodrug nano-assembly are shown in FIGS. 8D-8E, and the release rate of the beta-SN 38-SS-SN38NPs is faster than that of the gamma-SN 38-SS-SN38NPs under the conditions of low concentration and high concentration of hydrogen peroxide.
Example 8: cytotoxicity of PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles
The cytotoxicity of the PEG modified SN38 dimer prodrug nano-assembly on two different tumor cells and a normal cell is examined by adopting an MTT method, so as to investigate whether the prodrug nano-assembly can effectively inhibit the proliferation of the tumor cells and distinguish the tumor cells from the normal cells. Firstly, digesting cells with good morphology, diluting the cells to 5000cells/mL with a culture solution, uniformly blowing the cells, adding 100 mu L of cell suspension into each hole of a 96-hole plate, and placing the cells in an incubator for incubation for 24 hours to adhere to the walls. After the cells are attached, SN38 solution or the PEG-modified disulfide-bridged SN38 dimer prodrug nanoparticles prepared in example 5 are added. In the experiment, the preparation and dilution of the drug solution and the nanoparticle preparation are carried out by using culture solution of corresponding cells and sterile filtration by using a 0.22 mu m filter membrane. Test solution was added at 100. Mu.L per well, 3 parallel wells per concentration. In the control group, 100 mul of culture solution is singly supplemented without adding the liquid medicine to be detected, and the control group is placed in an incubator to be incubated with cells together. At 48h after dosing, the 96-well plate is taken out, 20. Mu.L of MTT solution 5mg/mL is added to each well, the culture medium is discarded after incubation in the incubator for 4h, the 96-well plate is inverted on filter paper to fully suck the residual liquid, and 200. Mu.L of DMSO is added to each well and shaken on a shaker for 10min to dissolve the bluish purple crystals. The A1 wells (containing only 200. Mu.L DMSO) were set as zeroed wells. The absorbance value after zeroing of each well was measured at 570nm using a microplate reader.
As shown in FIG. 9, the inhibitory effect of both β -SN38-SS-SN38NPs and γ -SN38-SS-SN38NPs on tumor cells is stronger than that of the parent drug SN38, and the cytotoxicity of γ -SN38-SS-SN38NPs is stronger because both prodrugs are dimeric prodrugs, one prodrug contains two molecules of SN38.
Example 9: pharmacokinetics research of PEG modified disulfide bond bridged SN38 dimer prodrug self-assembled nanoparticles
SD rats with body weight of 200-250g were randomly grouped and fasted for 12h before administration, and water was freely available. SN38 solution and the pegylated SN38 dimer prodrug self-assembling nanoparticles prepared in example 5 were injected intravenously, respectively. The dosage of SN38 was 2.5mg/kg. Blood was collected from the orbit at the prescribed time points and separated to obtain plasma. The drug concentration in plasma was determined by liquid chromatography-mass spectrometry.
Since SN38 dimer prodrug has a large molecular weight, it is difficult to detect a stable ion peak under the existing mass spectrometry conditions, and it is impossible to quantify the prodrug in plasma, only the blood concentration of SN38 was detected, and the results are shown in table 3. Both dimeric prodrug nanoassemblies release SN38 with higher area and peak concentrations of the curve than SN38 solutions. Wherein, the area under the curve and the peak concentration of SN38 released by the gamma-SN 38-SS-SN38NPs are obviously higher than those of the beta-SN 38-SS-SN38NPs, which shows that the gamma-SN 38-SS-SN38NPs have better stability and can more effectively improve the pharmacokinetic behavior of the SN38.
TABLE 3 pharmacokinetic parameters of PEG-modified disulfide-bridged SN38 dimer prodrug self-assembled nanoparticles
Example 10: in vivo antitumor experiment of PEG (polyethylene glycol) -modified disulfide-bond-bridged SN38 dimer prodrug self-assembled nanoparticles
The concentration of 100 mu L is 5X 10 7 cells/mL of 4T1 cell suspension was inoculated into the right dorsal back of Balb/C mice by subcutaneous injection. The tumor volume is about 100mm 3 At this time, tumor-bearing mice were randomly divided into 4 groups (n = 5), and the tail vein was injected with physiological Saline (Saline), SN38 solution, β -SN38-SS-SN38NPs or γ -SN38-SS-SN38NPs (SN 38 equivalent dose of 2.5 mg/kg), respectively. Once every other day for a total of 5 administrations. The long and short diameters of the tumor and the body weight of the mouse were measured and recorded daily, and the tumor volume was calculated. The tumor volume was calculated as: major axis × minor axis × 0.5. The mice were sacrificed one day after the last dose, tumor tissues were isolated, weighed and photographed, and the tumor-bearing rate (tumor weight/mouse weight x 100%) was calculated.
As shown in FIG. 10, the volume of the saline group reached 600mm on the ninth day 3 The SN38 solution group has certain treatment effect, but the tumor volume still reaches 300mm 3 The tumor volume of the mice in the beta-SN 38-SS-SN38NPs group reaches 200mm 3 And the difference is not significant with the SN38 solution group. The gamma-SN 38-SS-SN38NPs have the best anti-tumor effect, can obviously inhibit tumor growth, and has a tumor bearing rate which is obviously lower than that of other preparation groups. gamma-SN 38-SS-SN38NPs showed stronger antitumor effect than SN38 solutions, determined by the pharmaceutical advantage of prodrug nanoassemblies over solutions: (1) long circulation time in vivo, higher AUC; (3) strong tumor accumulation capacity; (2) the cellular uptake efficiency is high; and (4) specific rapid drug release in tumor cells. Because the beta-SN 38-SS-SN38NPs have poor stability and can be rapidly disintegrated after entering the systemic circulation through intravenous injection, the pharmaceutical advantage of the nanoparticles is lost, and the anti-tumor effect of the nanoparticles is not as good as that of the gamma-SN 38-SS-SN38 NPs.
Claims (9)
1. A disulfide-bridged SN38 dimer prodrug, or a pharmaceutically acceptable salt thereof, having a structural formula of formula (I):
wherein n is an integer of 1 to 3.
2. The disulfide bridged SN38 dimer prodrug of claim 1, or a pharmaceutically acceptable salt thereof, wherein the disulfide bridged SN38 dimer prodrug is an SN38 dimer prodrug having a disulfide bond located alpha, beta, or gamma to the adjacent carbonyl prepared by linkage of 2,2' -dithiodiacetic acid, 3,3' -dithiodipropionic acid, or 4,4' -dithiodibutanoic acid with SN38, and the corresponding prodrugs are designated as alpha-SN 38-SS-SN38, beta-SN 38-SS-SN38, gamma-SN 38-SS-SN38, respectively, and have the following structural formulas:
3. a method of preparing the disulfide bridged SN38 dimer prodrug of claim 2, comprising the steps of:
2,2' -dithiodiacetic acid, 3,3' -dithiodipropionic acid or 4,4' -dithiodibutanoic acid are dissolved in chloroform and evenly stirred; dissolving part of DMAP, EDCI and SN38 in chloroform, stirring uniformly, mixing with the 2,2' -dithiodiacetic acid, 3,3' -dithiodipropionic acid or 4,4' -dithiodibutanoic acid solution, and adding N 2 Stirring at room temperature under protection; and supplementing the rest EDCI and DMAP into the mixed solution, continuously stirring at room temperature under the protection of nitrogen, and separating and purifying the obtained product by a prepared liquid phase.
4. A disulfide-bridged SN38 dimer prodrug self-assembling nanoparticle of claim 1 or 2, which is a non-pegylated dimer self-assembling prodrug nanoparticle or a PEG-modified dimer prodrug self-assembling nanoparticle; the preparation method comprises the following steps: dissolving a disulfide bond bridged SN38 dimer prodrug and a PEG modifier into a solvent, slowly dropwise adding the solution into water while stirring, spontaneously forming uniform nanoparticles from the prodrug, and removing the solvent by a dialysis method to obtain a nano colloidal solution without an organic solvent; wherein, no PEG modifier is added in the preparation method of the non-PEG dimer prodrug nanoparticles.
5. The self-assembled nanoparticle of a disulfide-bridged SN38 dimer prodrug of claim 4, wherein the PEG modifier is selected from TPGS, DSPE-PEG, PLGA-PEG, and PE-PEG; the molecular weight of the PEG is 1000-5000; the solvent is selected from ethanol, dimethyl sulfoxide, N' -dimethylformamide, tetrahydrofuran and acetone; the weight ratio of disulfide-bridged SN38 dimer prodrug to PEG modifier is 90 to 70.
6. A pharmaceutical composition comprising the disulfide bridged SN38 dimer prodrug of claim 1 or 2 and a pharmaceutically acceptable carrier or excipient.
7. Use of the disulfide-bridged SN38 dimeric prodrug β -SN38-SS-SN38 and γ -SN38-SS-SN38 of claim 2 or the self-assembled nanoparticle of the dimeric prodrug of claim 4 or 5 or the pharmaceutical composition of claim 6 in the preparation of a drug delivery system.
8. Use of the disulfide-bridged SN38 dimeric prodrug β -SN38-SS-SN38 and γ -SN38-SS-SN38 of claim 2 or the self-assembled nanoparticle of the dimeric prodrug of claim 4 or 5 or the pharmaceutical composition of claim 6 for the preparation of an anti-tumor drug.
9. Use of the disulfide-bridged SN38 dimeric prodrug β -SN38-SS-SN38 and γ -SN38-SS-SN38 of claim 2 or the self-assembled nanoparticle of the dimeric prodrug of claim 4 or 5 or the pharmaceutical composition of claim 6 for the preparation of an injectable, oral or topical delivery system.
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