CN114796513B - Diselenide bridge Lian Duo cetime dimer prodrug and self-assembled nanoparticles thereof - Google Patents

Diselenide bridge Lian Duo cetime dimer prodrug and self-assembled nanoparticles thereof Download PDF

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CN114796513B
CN114796513B CN202110072005.5A CN202110072005A CN114796513B CN 114796513 B CN114796513 B CN 114796513B CN 202110072005 A CN202110072005 A CN 202110072005A CN 114796513 B CN114796513 B CN 114796513B
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prodrug
docetaxel
diselenide
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nanoparticles
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CN114796513A (en
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孙进
何仲贵
李凌霄
孙丙军
左诗意
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the field of new auxiliary materials and new dosage forms of pharmaceutical preparations, relates to a diselenide-bridged docetaxel dimer prodrug and self-assembled nanoparticles thereof, and in particular relates to synthesis of a diselenide-bridged docetaxel dimer prodrug, construction of self-assembled nanoparticles containing the dimer prodrug and application of the dimer prodrug in drug delivery. The redox double-sensitive small molecule prodrug containing blood circulation stable diselenide linkage bridging selects docetaxel as a simulated drug, selects (a) 4,4 '-diselenide dibutyric acid or (b) 3,3' -diselenide dipropionic acid or (C) 2,2 '-diselenide diacetic acid as chemical bridging, and connects two molecules of docetaxel together by forming ester bonds by chemically bridged carboxyl groups and C (2') hydroxyl groups of the docetaxel. The docetaxel dimer prodrug provides a new strategy and more choices for developing an intelligent response type drug delivery system in a tumor microenvironment, and meets the urgent need of high-efficiency low-toxicity chemotherapy preparations in clinic.

Description

Diselenide bridge Lian Duo cetime dimer prodrug and self-assembled nanoparticles thereof
Technical Field
The invention belongs to the field of new auxiliary materials and new dosage forms of pharmaceutical preparations, relates to a diselenide-bridged docetaxel dimer prodrug and self-assembled nanoparticles thereof, and in particular relates to synthesis of a diselenide-bridged docetaxel dimer prodrug, construction of self-assembled nanoparticles containing the dimer prodrug and application of the dimer prodrug in drug delivery.
Background
Cancer has become a major threat to human life and health, and more than 350 new cancer cases and 200 death cases are about increased per year in China. Chemotherapy is one of the most effective strategies in cancer treatment. However, most of the antitumor drugs clinically used at present have the problems of poor stability, poor pharmacokinetic properties, lack of target specificity and the like, so that the treatment effect is poor and the toxic and side effects are serious. For example, docetaxel (DTX) belongs to a taxane antitumor drug, and is widely used for the treatment of breast cancer, ovarian cancer, lung cancer, and the like, and is also used as a novel adjuvant treatment for advanced triple negative breast cancer. However, the use of docetaxel can cause severe neutropenia and neurotoxicity. Furthermore, since docetaxel is poorly soluble in water, the clinical formulation (taxotere) must use the nonionic surfactant tween 80 and ethanol as solubilizers, which leads to adverse hypersensitivity reactions. Even with the aid of solubilizers, the stability of taxotere is still poor, the formulation needs to be prepared on site and is easy to precipitate after dilution. These drawbacks limit the clinical application of docetaxel.
In order to increase the delivery efficiency of chemotherapeutic agents, prodrug strategies have been developed to improve the adverse properties of chemotherapeutic agents in terms of solubility, stability, and tumor selectivity. Nano-drug delivery systems are also widely used to improve blood circulation time and tumor targeting of chemotherapeutic drugs. Self-assembled prodrug-based nanomedicine delivery systems have received increasing attention in recent years, combining the advantages of nanomedicine and prodrug strategies. Homodimeric prodrugs are the use of special linking chains to couple two drug molecules together. The prodrug can be used as a carrier and can specifically release active drugs, and the homodimer prodrug nano-drug delivery system has ultrahigh drug loading which can reach 60%. Furthermore, the prodrug nano-drug delivery system avoids the use of biocompatible solubilizing agents, which would help to improve drug safety and patient compliance.
The linking chain between homodimers has a great impact on prodrug assembly, drug release, in vivo fate and antitumor activity. In our previous studies, three docetaxel dimer prodrugs bridged with diselenide, disulfide, and dicarbo linkages, respectively, were designed and synthesized. Because the diselenide bond has special bond angles and dihedral angles, the structural flexibility of medicine molecules can be improved, the intermolecular acting force of the medicine can be balanced, and the self-assembly of the docetaxel dimer prodrug can be further promoted. The diselenide bond has oxidation-reduction double sensitivity, and can intelligently respond to the high oxidation-reduction state of tumor cells and specifically release medicines. We have also found that disulfide bonds of different chain lengths affect the redox sensitivity of the paclitaxel-citronellol monomer prodrug, and thus the antitumor activity of the prodrug self-assembled nanoparticle. The rigid chemical structure of homodimeric prodrugs limits their ability to self-assemble compared to monomeric prodrugs and exhibits a different drug release mechanism. Thus, diselenide linkages of different chain lengths affect the ability of the homodimer prodrug to assemble, and thus affect the in vivo fate and antitumor activity of the nanoparticle.
Disclosure of Invention
The invention solves the technical problem of providing the redox double-sensitive prodrug containing the diselenide bond with stable blood circulation, and using the prodrug for self-assembling nano-particles, thereby realizing the effects of high drug loading, good stability and low toxic and side effects and further improving the anti-tumor activity. The differences of diselenide bonds with different chain lengths in terms of bond angle/dihedral angle, redox-sensitive response capability, antitumor activity and the like are examined, and the influence on the stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the prodrug self-assembled nanoparticle is also examined.
The invention aims to design and synthesize a redox double-sensitive small molecular prodrug containing blood circulation stable diselenide bond bridging, prepare prodrug self-assembly nano particles, discuss the influence of diselenide bonds with different chain lengths on self-assembly capacity, assembly stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the prodrug self-assembly nano particles, comprehensively screen out diselenide bond chemical bridging with optimal effect, provide new strategies and more choices for developing an intelligent response type drug delivery system in tumor microenvironment, and meet urgent requirements of high-efficiency chemotherapeutic agents in clinic.
The invention realizes the aim through the following technical scheme:
the redox double-sensitive small molecule prodrug containing blood circulation stable diselenide bond bridging selects docetaxel as a simulated drug, selects (a) 4,4 '-diselenide dibutyric acid or (b) 3,3' -diselenide dipropionic acid or (C) 2,2 '-diselenide diacetic acid as chemical bridging, and connects two molecules of docetaxel together by forming ester bonds between chemically bridged carboxyl groups and C (2') hydroxyl groups of the docetaxel. For chemically bridged 4,4' -diselenodibutyric acid, 3' -diselenodipropionic acid and 2,2' -diselenodiacetic acid, the selenium atoms are located at the gamma, beta and alpha positions of the carbonyl group, respectively, and thus the corresponding prodrugs are named gamma-DSeSeD, beta-DSeSeD and alpha-DSeSeD, respectively, having the structural formula:
the invention provides a method for synthesizing a diselenide bridged docetaxel dimer prodrug, which comprises the following steps: firstly, dibasic acid containing diselenide bond is esterified with one molecule of docetaxel to obtain intermediate product. The intermediate product is then further esterified with another molecule of docetaxel to give the final product.
Further, the invention provides a specific synthesis method of a series of docetaxel dimer small molecule prodrugs:
docetaxel is dissolved in dichloromethane, equal amount of 4,4' -diselenodibutyric acid, 3' -diselenodipropionic acid or 2,2' -diselenodiacetic acid, twice amount of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and equal amount of 4-dimethylaminopyridine are added, stirring is carried out for 2-3 hours at room temperature, the obtained intermediate product is added with equal amount of docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine, stirring is carried out for 24-30 hours at room temperature, and the obtained product is subjected to preparation liquid phase separation and purification, and the whole reaction process is carried out under the protection of nitrogen.
The invention also provides a synthesis method of the 4,4' -diseleno-dibutyric acid, which comprises the following steps: firstly, reacting selenium powder with sodium borohydride, and then reacting with second selenium powder to obtain an intermediate product. The intermediate product reacts with bromobutyric acid to obtain the final product.
Specifically, the invention provides a method for synthesizing 4,4' -diselenodibutyric acid:
dropwise adding an aqueous solution of sodium borohydride into the selenium powder-water suspension in an ice water bath, stirring until the solution is clear and transparent, adding a second part of selenium powder, slowly heating to 100-110 ℃, stirring for 30-60 minutes, dropwise adding an aqueous solution of bromobutyric acid after cooling to room temperature, reacting for 3-4 hours, filtering the reaction solution, diluting with water, adding ethyl acetate for extraction for three times, drying an ethyl acetate layer, and removing the solvent by reduced pressure rotary evaporation to obtain the product, wherein the whole reaction process is carried out under the protection of nitrogen.
The invention also provides self-assembled nanoparticles of the diselenide bridged docetaxel dimer small molecule prodrug, wherein the self-assembled nanoparticles of the small molecule prodrug can be non-PEG prodrug nanoparticles and PEG modified prodrug nanoparticles.
Docetaxel described in the present invention may be replaced with other anticancer drugs containing active hydroxyl or amino groups, such as taxane compounds, nucleoside compounds, anthracycline compounds or camptothecins.
The preparation method of the docetaxel dimer small molecule prodrug self-assembled nanoparticle provided by the invention comprises the following steps:
a certain amount of the mixture of the docetaxel dimer small molecule prodrug and the PEG modifier is dissolved in a proper amount of ethanol, the ethanol solution is slowly dropped into water under stirring, and the prodrug spontaneously forms uniform nanoparticles. Finally, ethanol in the preparation is removed by adopting a decompression rotary evaporation method, and a nano colloid solution without any organic solvent is obtained. The PEG modifier is TPGS, DSPE-PEG, PLGA-PEG, PE-PEG and the like, and the preferable PEG modifier is DSPE-PEG. The molecular weight of the PEG is 1000, 2000 and 5000, and the preferred molecular weight of PEG is 2000. The weight ratio of the small molecule prodrug to the PEG modifier is as follows: under the condition of 90:10-70:30, docetaxel can exert the best anti-tumor effect.
(1) The preparation method of the non-PEGylated small molecule prodrug self-assembled nanoparticle comprises the following steps: dissolving a certain amount of prodrug into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug. Ethanol in the preparation is removed by adopting a decompression rotary evaporation method, and a nano colloid solution without any organic solvent is obtained.
(2) The preparation method of the PEG modified small molecule prodrug self-assembled nanoparticle comprises the following steps: dissolving a certain amount of PEG modifier (TPGS, DSPE-PEG, PLGA-PEG or PE-PEG) and prodrug into proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles. Ethanol in the preparation is removed by adopting a decompression rotary evaporation method, and a nano colloid solution without any organic solvent is obtained.
The invention has the following beneficial effects: (1) The design and synthesis of the diselenide bond bridged docetaxel dimer small molecule prodrug are simple and feasible; the prodrug can be kept stable in blood circulation and has redox double-sensitivity properties; (2) The self-assembled nanoparticle containing the diselenide bond bridged docetaxel dimer small molecule prodrug is prepared, the preparation method is simple and easy to implement, the stability is good, and the efficient entrapment of docetaxel is realized; (3) The influence of diselenide bonds with different chain lengths on bond angle/dihedral angle, redox-sensitive response capability and anti-tumor activity and on the stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the prodrug self-assembled nanoparticles is examined. The result shows that the antitumor activity of the prodrugs obtained by bridging the diselenide bonds with different chain lengths is also different, so that the optimal diselenide bond chemical bridging is obtained, a new strategy and more choices are provided for developing an intelligent response type drug delivery system in a tumor microenvironment, and the urgent requirement of a high-efficiency low-toxicity chemical therapy preparation in clinic is met.
Drawings
FIG. 1 is a mass spectrum and a spectrum of a 4,4' -diselenodibutyrate-bridged docetaxel dimer prodrug (gamma-DSeED) of example 1 of the present invention 1 HNMR spectra.
FIG. 2 is a schematic illustration of an embodiment of the present inventionMass spectra and spectra of 3,3' -diselenodipropionic acid bridged docetaxel dimer prodrug (beta-DSeSeD) of example 2 1 HNMR spectra.
FIG. 3 is a mass spectrum and a spectrum of a 2,2' -diselenodiacetic acid bridged docetaxel dimer prodrug (. Alpha. -DSeSeD) of example 3 of the present invention 1 HNMR spectra.
FIG. 4 is a photograph of non-PEGylated small molecule prodrug self-assembled nanoparticles of example 4 of the present invention after centrifugation.
FIG. 5 is a particle size diagram and a transmission electron microscope image of PEG-modified small molecule prodrug self-assembled nanoparticles of example 5 of the present invention.
FIG. 6 is a graph showing the change in particle size of PEG-modified small molecule prodrugs of example 6 of the present invention after incubation with blank rat plasma.
FIG. 7 is an in vitro release test chart of PEG-modified small molecule prodrug self-assembled nanoparticles according to example 8 of the present invention
FIG. 8 is a cytotoxicity profile of PEG-modified small molecule prodrug self-assembled nanoparticles according to example 9 of the present invention.
FIG. 9 is a graph showing the release of drug from tumor cells of the PEG-modified small molecule prodrug self-assembled nanoparticle of example 9 of the present invention. (the difference is statistically significant in terms of P < 0.05)
*P<0.05，**P<0.01。
FIG. 10 is a graph of plasma concentration versus time for PEG-modified small molecule prodrug self-assembled nanoparticles of example 9 of the present invention.
FIG. 11 is an in vivo anti-tumor experimental graph of PEG-modified small molecule prodrug self-assembled nanoparticles of example 10 of the present invention. (the difference is statistically significant in terms of P < 0.05)
*P<0.05，**P<0.01，***P<0.001，****P<0.0001；
The difference is not statistically significant.
FIG. 12 is a safety experimental graph of PEG-modified small molecule prodrug self-assembled nanoparticles of example 11 of the present invention. (the difference is statistically significant in terms of P < 0.05)
* P <0.05, < P <0.01, n.s: the difference is not statistically significant;
fig. 13 is a graph showing the results of HE staining pathological section of mouse tissues after the drug effect experiment of PEG-modified small molecule prodrug self-assembled nanoparticles of example 11 of the present invention.
Detailed Description
The invention is further illustrated by way of examples which follow, but are not thereby limited to the scope of the examples described.
Example 1: synthesis of 4,4' -diselenodibutyric acid bridged docetaxel dimer small molecule prodrug (gamma-DSeSeD)
Docetaxel was dissolved in methylene chloride, equal amounts of 4,4' -diselenodibutyric acid, twice the amounts of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and equal amounts of 4-dimethylaminopyridine were added, stirred at room temperature for 2 hours, the obtained intermediate was added with equal amounts of docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine, stirred at room temperature for 24 hours, and the obtained product was subjected to separation and purification by preparative liquid phase, and the whole course of the above reaction was carried out under nitrogen protection.
The structure of the prodrug in example 3 was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results are shown in fig. 3. The solvent selected for nuclear magnetic resonance is deuterated chloroform (CDCl) 3 ) The results of the spectrum analysis are as follows:
1 H NMR(600MHz,CDCl 3 ):δ8.039(d,4H,Ar-H,J＝7.7Hz),7.540(t,2H,Ar-H,J＝7.5Hz),7.436(t,4H,Ar-H,J＝7.6Hz),7.327(t,4H,Ar-H,J＝7.5Hz),7.221(d,6H,Ar-H,J＝7.7Hz),6.160(s,2H,13-CH),5.605(d,2H,2-CH,J＝7.1Hz),5.398(s,2H,3’-CH),5.324(s,2H,10-CH),5.151(s,2H,2’-CH),4.905(d,2H,5-CH,J＝9.5Hz),4.251(d,2H,20-CH 2 -αH,J＝8.6Hz),4.193(dd,2H,7-CH,J＝11.2,6.6Hz),4.120(d,2H,20-CH 2 -βH,J＝8.7Hz,),3.847(d,2H,3-CH,J＝7.0Hz),2.731(m,2H,CH 2 CH 2 2 CHSeSe 2 CHCH 2 CH 2 -αH),2.652(m,2H,CH 2 CH 2 2 CHSeSe 2 CHCH 2 CH 2 -βH),2.518(m,2H, 2 CHCH 2 CH 2 SeSeCH 2 CH 2 2 CH-αH),2.451(m,2H, 2 CHCH 2 CH 2 SeSeCH 2 CH 2 2 CH-βH),2.370(s,6H,-OAc),2.249(m,2H,6-CH 2 -αH),2.086(m,2H,6-CH 2 -βH),1.914(m,4H,CH 2 2 CHCH 2 SeSeCH 2 2 CHCH 2 ),1.861(s,6H,18-CH 3 ),1.785(t,4H,14-CH 2 ,J＝12.9Hz),1.672(s,6H,19-CH 3 ),1.263(s,18H,-C(CH 3 ) 3 ),1.152(s,6H,16-CH 3 ),1.049(s,6H,17-CH 3 ).MS(ESI)m/z forγ-DSeSeD[M+Na] + ＝1935.58313.
example 2: synthesis of 3,3' -diselenodipropionic acid bridged docetaxel dimer small molecule prodrug (beta-DSeSeD)
Docetaxel was dissolved in methylene chloride, equal amounts of 3,3' -diselenodipropionic acid, twice the amounts of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and equal amounts of 4-dimethylaminopyridine were added, stirred at room temperature for 2 hours, the obtained intermediate was added with equal amounts of docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine, stirred at room temperature for 24 hours, and the obtained product was subjected to separation and purification by preparative liquid phase, and the whole course of the above reaction was carried out under nitrogen protection.
The structure of the prodrug in example 2 was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results are shown in fig. 2. The solvent selected for nuclear magnetic resonance is CDCl 3 The results of the spectrum analysis are as follows:
1 H NMR(600MHz,CDCl 3 ):δ8.036(d,4H,Ar-H,J＝7.8Hz),7.542(t,2H,Ar-H,J＝7.5Hz),7.437(t,4H,Ar-H,J＝7.6Hz),7.324(t,4H,Ar-H,J＝7.6Hz),7.223(d,6H,Ar-H,J＝7.9Hz),6.152(s,2H,13-CH),5.602(d,2H,2-CH,J＝7.1Hz),5.406(s,2H,3’-CH),5.320(s,2H,10-CH),5.146(s,2H,2’-CH),4.902(d,2H,5-CH,J＝9.5Hz),4.249(d,2H,20-CH 2 -αH,J＝8.6Hz),4.180(dd,2H,7-CH,J＝10.8,6.8Hz),4.116(d,2H,20-CH 2 -βH,J＝8.5Hz,),3.840(d,2H,3-CH,J＝6.6Hz),2.877(m,4H,CH 2 2 CHSeSe 2 CHCH 2 ),2.821(m,2H, 2 CHCH 2 SeSeCH 2 2 CH-αH),2.729(m,2H, 2 CHCH 2 SeSeCH 2 2 CH-βH),2.515(m,2H,-OH),2.363(s,6H,-OAc),2.235(m,2H,6-CH 2 -αH),2.083(m,2H,6-CH 2 -βH),1.863(s,6H,18-CH 3 ),1.781(t,4H,14-CH 2 ,J＝12.9Hz),1.667(s,6H,19-CH 3 ),1.268(s,18H,-C(CH 3 ) 3 ),1.148(s,6H,16-CH 3 ),1.045(s,6H,17-CH 3 ).MS(ESI)m/z forβ-DSeSeD[M+H]+＝1885.562968,[M+Na]+＝1907.545985.
example 3: synthesis of 2,2' -diselenodiacetic acid bridged small molecule prodrugs of docetaxel (alpha-DSeSeD)
Docetaxel was dissolved in methylene chloride, equal amounts of 2,2' -diselenodiacetic acid, twice the amount of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and equal amounts of 4-dimethylaminopyridine were added, stirred at room temperature for 2 hours, the obtained intermediate was added with equal amounts of docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine, stirred at room temperature for 24 hours, and the obtained product was subjected to separation and purification by preparative liquid phase, and the whole course of the above reaction was carried out under the protection of nitrogen.
The structure of the prodrug of example 1 was determined by mass spectrometry and nuclear magnetic resonance hydrogen spectrometry, and the results are shown in fig. 1. The solvent selected for nuclear magnetic resonance is CDCl 3 The results of the spectrum analysis are as follows:
1 H NMR(600MHz,CDCl 3 ):δ8.042(d,4H,Ar-H,J＝7.7Hz),7.541(t,2H,Ar-H,J＝7.5Hz),7.438(t,4H,Ar-H,J＝7.6Hz),7.321(t,4H,Ar-H,J＝7.6Hz),7.237(d,6H,Ar-H,J＝7.8Hz),6.174(s,2H,13-CH),5.607(d,2H,2-CH,J＝7.0Hz),5.427(s,2H,3’-CH),5.311(s,2H,10-CH),5.152(s,2H,2’-CH),4.902(d,2H,5-CH,J＝9.6Hz),4.251(d,2H,20-CH 2 -αH,J＝8.6Hz),4.191(dd,2H,7-CH,J＝11.0,6.7Hz),4.123(d,2H,20-CH 2 -βH,J＝8.6Hz,),3.847(d,2H,3-CH,J＝3.6Hz),3.557(d,2H, 2 CHSeSe 2 CH-αH,J＝8.8Hz),3.417(d,2H, 2 CHSeSe 2 CH-βH,J＝13.9Hz),2.501(m,2H,-OH,J＝14.3,8.8Hz),2.383(s,6H,-OAc),2.270(m,2H,6-CH 2 -αH),2.085(m,2H,6-CH 2 -βH),1.877(s,6H,18-CH 3 ),1.788(t,4H,14-CH 2 ,J＝12.8Hz),1.667(s,6H,19-CH 3 ),1.250(s,18H,-C(CH 3 ) 3 ),1.150(s,6H,16-CH 3 ),1.044(s,6H,17-CH 3 ).MS(ESI)m/z forα-DSeSeD[M+H] + ＝1857.52202，[M+Na] + ＝1879.53573.
example 4: evaluation of stability of self-assembled nanoparticles of non-PEGylated small molecule prodrugs
1.6mg of the prodrug was precisely weighed, dissolved in 1mL of ethanol, and the ethanol solution was slowly added dropwise to 4mL of deionized water with stirring. The organic solvent in the nano-formulation was removed by rotary evaporation under reduced pressure at 25 ℃. The prepared small molecule prodrug was observed after centrifugation (3000 rpm,10 minutes) of the self-assembled nanoparticle.
As shown in fig. 4, gamma-DSeSeD can form stable nanoparticles that remain clear and transparent after centrifugation; the alpha-DSeSD nanoparticle and the beta-DSeSD nanoparticle generate obvious precipitation after centrifugation.
Example 5: preparation of PEG modified small molecule prodrug self-assembled nanoparticle
Precisely weighing DSPE-PEG 2k 1mg and 4mg of prodrug are dissolved by 1mL of ethanol, and the ethanol solution is slowly dropped into 4mL of deionized water under stirring to spontaneously form uniform nanoparticles (gamma-DSeSD nanoparticles, beta-DSeSD nanoparticles and alpha-DSeSD nanoparticles). The organic solvent in the nano-formulation was removed by rotary evaporation under reduced pressure at 25 ℃.
As shown in Table 1, the particle diameters of the nanoparticles are all about 80nm, the particle diameter distribution is less than 0.2, the surface charge is about-20 mV, and the drug loading is above 65%. The particle size and morphology of the small molecule prodrug self-assembled nanoparticle prepared in example 5 were measured by transmission electron microscopy, and the result is shown in fig. 5, in which the drug-loaded nanoparticle is uniformly spherical and has a particle size of about 70 nm.
TABLE 1 particle size, particle size distribution, surface Charge and drug loading of PEG-modified small molecule prodrug self-assembled nanoparticles
Example 6: colloidal stability test of PEG-modified small molecule prodrug self-assembled nanoparticles
The PEG-modified small molecule prodrug self-assembled nanoparticle prepared in example 5 was taken out 500 μl, added to 5mL blank rat plasma, incubated at 37 ℃ for 48 hours, and its particle size change was determined by dynamic light scattering at a predetermined time point. As shown in FIG. 6, the gamma-DSeSD nanoparticle has the best colloid stability, and the particle size of the nanoparticle does not change obviously until 48 hours. In contrast, the colloidal stability of α -DSeSeD nanoparticles and β -DSeSeD is poor.
Example 7: bond angle, dihedral angle and binding energy of diselenide bond in small molecule prodrugs
By optimizing the molecular conformation, the bond angle of two selenium atoms in three chemical bridges and the dihedral angle formed by the diselenide bond in the small molecule prodrug were calculated as shown in table 2, and the results are: 2,2' -diselenodiacetic acid (97.9 °/98.3 °,98.3 °), 3' -diselenodipropionic acid (95.5 °/96.9 °,95.6 °), 4' -diselenodibutyric acid (90.1 °/90.5 °,93.6 °). The bond angle and dihedral angle of diseleno bond in 4,4' -diseleno dibutyric acid are closest to 90 degrees, so that structural defect is caused in the structure of homodimer prodrug, the flexibility of molecular structure is effectively improved, intermolecular acting force is balanced, gamma-DSeSD presents optimal conformation in the assembly process, the gamma-DSeSD has strong assembly capability, and the formed nano particles are stable. In addition, the binding energy of docetaxel dimer small molecule prodrug self-assembly process was calculated by molecular docking, as shown in Table 3, resulting in gamma-DSeED (-410.02 kcal mol) -1 )<β-DSeSeD(-398.54kcal mol -1 )<α-DSeSeD(-379.39kcal mol -1 ). Gamma-DSeED has minimal binding energy, indicating that the longest chain length diselenide bond facilitates prodrug self-assemblyWhen the system is constructed, the optimal conformation is constructed, the free energy of the system is reduced, and the stability of the system is improved.
TABLE 2 bond angles, dihedral angles and binding energies of diselenide bonds in small molecule prodrugs
Example 8: in vitro release assay of PEG-modified small molecule prodrug self-assembled nanoparticles.
Taking Phosphate Buffer Solution (PBS) with pH 7.4 containing 30% ethanol as a release medium, and examining the in vitro release condition of the small molecule prodrug self-assembled nanoparticles. The PEG-modified small molecule prodrug self-assembled nanoparticle prepared in example 5 (docetaxel content: 200. Mu.g/mL) was added to 30mL of a release medium, sampled at 37℃at a set time point, and the concentration of released docetaxel was determined by high performance liquid chromatography. Adding hydrogen peroxide (H) with a certain concentration into the release medium 2 O 2 1mM,5mM,10 mM) or glutathione (GSH, 5. Mu.M, 50. Mu.M, 500. Mu.M, 5000. Mu.M) to take account of the release of the nanoparticle under oxidising and reducing conditions, respectively.
The results are shown in fig. 7, where diselenide-bridged prodrug nanoparticles of different chain lengths have different oxidation-sensitive drug release capacities. Wherein the oxidation sensitivity size sequence is alpha-DSeSD nanoparticle > beta-DSeSD nanoparticle > gamma-DSeSD nanoparticle. The oxidation response drug release mechanism is that selenium atoms of diselenide bonds are oxidized into hydrophilic selenones, so that the hydrophilicity of the system is increased to promote the hydrolysis of adjacent ester bonds and the release of docetaxel. Thus, the release rate of docetaxel is inversely proportional to the carbon chain length between the selenium atom and the ester linkage, and α -DSeSeD nanoparticles exhibit the fastest rate of oxidative response drug release. The diselenide-bridged prodrug nanoparticles with different chain lengths have different reduction-sensitive drug release capacities. The release amount of docetaxel is similar when the concentration of glutathione is low (5-500 mu M), but the release amount of docetaxel is obviously reduced when the concentration of glutathione is high (5000 mu M). The beta-dseSD nanoparticle only releases a small amount of docetaxel under the action of glutathione. The release amount of docetaxel is obviously increased along with the increase of the concentration of glutathione.
Example 9: 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 (4T 1) cells, mouse skin melanoma (B16-F10) cells and human liver (L02) cells was examined by MTT method. The cells in good condition are digested, the cells are diluted to 1000cells/mL cell density by culture solution, 200 mu L of cell suspension is added into each well of a 96-well plate after the cells are uniformly blown, and the cells are incubated in an incubator for 24 hours to adhere to the cells. After cell attachment, taxotere or prodrug nanoparticles prepared in example 5 were added. The preparation and dilution of the drug solution and the nanoparticle preparation for the experiments of the breast cancer (4T 1) cells and the human liver (L02) cells of the mice are carried out by using 1640 culture solution, the preparation and dilution of the drug solution and the nanoparticle preparation for the experiments of the melanoma (B16-F10) cells of the skin of the mice are carried out by using DMEM culture solution, and the sterile filtration is carried out by using a 0.22 mu m filter membrane. 200 μl of each well of test solution was added, 3 wells in parallel per concentration. The control group, i.e. without adding the liquid medicine to be detected, is singly supplemented with 200 mu L of culture solution, and is placed in an incubator for incubation with cells. After 48h of dosing, the 96-well plate is taken out, 35 mu L of MTT solution with the concentration of 5mg/mL is added to each well, the plates are thrown after being incubated for 4h in an incubator, after the residual liquid is fully sucked up by reversely buckling the 96-well plate on filter paper, 200 mu L of DMSO is added to each well, and the mixture is oscillated on an oscillator for 10min to dissolve the bluish-violet crystals. A1 wells (containing only 200. Mu.L DMSO) were set as zeroed wells. Absorbance values after zeroing of each well were determined at 490nm using an enzyme-labeled instrument.
The cytotoxicity results are shown in FIG. 8. Since the prodrug nanoparticles take a certain time to release docetaxel, the efficacy of docetaxel is limited, so that the cytotoxicity of the prodrug nanoparticles is lower than that of taxotere. The cytotoxicity size order of the prodrug nanoparticles is alpha-dseSD nanoparticles > beta-dseSD nanoparticles > gamma-dseSD nanoparticles. Prodrug nanoparticle cytotoxicity correlates with the release rate of docetaxel from the nanoparticle. Thus, the release rate of docetaxel in 4T1 cells from prodrug nanoparticles was examined. From fig. 9, it can be seen that the α -dseED nanoparticles released docetaxel more rapidly than the β -dseED nanoparticles and the γ -dseED nanoparticles, which is consistent with the cytotoxicity results. The selectivity of taxotere and prodrug nanoparticles for normal and tumor cells was examined. As shown in table 3, the prodrug nanoparticles have significantly reduced toxicity to L02 cells compared to taxotere. When the Selectivity Index (SI) is greater than 1, the toxicity of the drug to tumor cells is greater than that to normal cells, and the greater the value, the more obvious the toxicity difference. The prodrug nanoparticles can distinguish tumor cells from normal cells, selectively release active parent drugs in the tumor cells, and remarkably reduce the toxicity of docetaxel.
TABLE 3 half Inhibitory Concentration (IC) of taxotere and prodrug nanoparticles on 3 cells 50 ) And Selectivity Index (SI)
Example 10: pharmacokinetic study of PEG-modified small molecule prodrug self-assembled nanoparticles
SD rats weighing 180-200g were randomly divided into 5 groups and fasted for 12h before dosing, and were given free water. The PEGylated small molecule prodrug self-assembled nanoparticles prepared in example 5 were each injected intravenously with taxotere. Docetaxel dosage was 4.0mg/kg. The orbit was bled at the prescribed time points and plasma was isolated. The drug concentration in the plasma was determined by liquid chromatography-mass spectrometry.
The experimental results are shown in fig. 10, in which docetaxel of taxotere is rapidly cleared from the blood. In contrast, the cycle time of small molecule prodrug self-assembled nanoparticles is significantly prolonged. The diselenide bonds of different chain lengths have a significant effect on the pharmacokinetic behavior of the prodrug nanoparticles. Compared with alpha-dseSD nanoparticles and beta-dseSD nanoparticles, the gamma-dseSD nanoparticles have higher AUC. Probably because the 4,4' -diselenodibutyric acid bridging bond enhances the colloidal stability of self-assembled nanoparticles. The internal circulation time is prolonged, which is helpful for the accumulation of the nano-particles at the tumor part. In addition, gamma-DSeSeD nanoparticles are most stable in blood circulation, releasing only small amounts of docetaxel. It is demonstrated that the 4,4' -diselenodibutyric acid bridging bond plays an important role in improving the in vivo fate of prodrug nanoparticles.
Example 11: in-vivo anti-tumor experiment of PEG modified small molecule prodrug self-assembled nanoparticle
The antitumor activity of the PEG modified small molecule prodrug self-assembled nanoparticle on a 4T1 ectopic tumor model is examined. 4T1 cell suspension (5X 10) 6 cells/100 μl) was inoculated on the right dorsal side of female Balb/c mice to construct a 4T1 ectopic tumor model. Until the tumor volume grows to 100mm 3 At this time, tumor-bearing mice were randomly grouped, five in each group, and physiological saline, taxotere and the PEG-modified small molecule prodrug self-assembled nanoparticle prepared in example 5 were administered, respectively. The administration was 1 time every 1 day, 5 times in succession, and the administration dose was 2.5mg/kg calculated as docetaxel. Following dosing, mice were observed daily for survival, weighed, and tumor volumes were measured. Tumor-bearing mice were sacrificed the day after the last dose, organs and tumors were obtained and further analyzed for evaluation. Major organs (heart, liver, spleen, lung, kidney) and tumor tissues were collected and fixed with formalin for H&E staining. Plasma was collected for liver and kidney function examination and blood was collected for blood routine examination.
The experimental results are shown in fig. 11, the antitumor activity of taxotere is between that of alpha-DSeSeD nanoparticles and beta-DSeSeD nanoparticles, and there is no significant difference compared with them. The anti-tumor activity of the beta-DSeSD nanoparticle and the gamma-DSeSD nanoparticle is stronger than that of the alpha-DSeSD nanoparticle. Although α -DSeSeD nanoparticles have the fastest intracellular drug release and strongest cytotoxicity, rapid systemic clearance and limited tumor accumulation limit their antitumor activity. Although gamma-DSeSeD NPs have minimal cytotoxicity in 4T1 cells, they have the best antitumor activity. The in vivo antitumor effect ultimately depends on the concentration of docetaxel at the tumor site. Thus, drug concentrations of taxotere and the PEG-modified small molecule prodrug self-assembled nanoparticles prepared in example 5 at tumor sites were determined by liquid chromatography-mass spectrometry. Docetaxel and prodrug at the tumor site of mice in the gamma-DSeSeD nanoparticle treated group were the most, exhibiting the strongest tumor accumulation compared to the other treated groups. Mice of the taxotere-treated group had significantly reduced body weight, had their spleens atrophic, and showed impairment of liver function, as shown in fig. 12 and 13. While the body weight of mice treated with the prodrug nanoparticles was maintained at a stable level and did not show significant impairment of liver and kidney and bone marrow function. This shows that the gamma-dseSD nanoparticle has good safety, obvious anti-tumor effect and no obvious nonspecific toxicity to the organism.

Claims (9)

1. A diselenide bridge Lian Duo sitaxe dimer prodrug characterized by the following structure:
。
2. the method of claim 1, wherein the chemical bridging is first esterified with one molecule of docetaxel to form an intermediate, and the intermediate is then esterified with another molecule of docetaxel to form the final product.
3. The method of claim 2, wherein the chemical bridge is 4,4 '-diselenodibutyric acid or 3,3' -diselenodipropionic acid.
4. The process according to claim 2, wherein docetaxel is dissolved in methylene chloride, equal amounts of 4,4 '-diselenodibutyric acid or 3,3' -diselenodipropionic acid, equal amounts of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and equal amounts of 4-dimethylaminopyridine are added, and the resulting intermediate is stirred at room temperature for 2 to 3 hours, and equal amounts of docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine are added, and stirred at room temperature for 24 to 30 hours, and the resulting product is subjected to liquid phase separation and purification, and the whole course of the reaction is performed under nitrogen protection.
5. The diselenide bridge Lian Duo docetaxel dimer prodrug self-assembled nanoparticle of claim 1, comprising non-pegylated prodrug nanoparticles and PEG-modified prodrug nanoparticles.
6. Use of a diselenide bridge Lian Duo sitaxe dimer prodrug of claim 1 or self-assembled nanoparticle of claim 5 for the preparation of a drug delivery system.
7. Use of a diselenide bridge Lian Duo sitaxe dimer prodrug of claim 1 or self-assembled nanoparticle of claim 5 in the preparation of an antitumor drug.
8. Use of a diselenide bridge Lian Duo sitaxe dimer prodrug of claim 1 or self-assembled nanoparticle of claim 5 for the preparation of an injectable, oral or topical delivery system.
9. Use of a diselenide bridge Lian Duo sitaxe dimer prodrug of claim 1 or self-assembled nanoparticle of claim 5 to improve the stability of a drug in vivo.
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