CN114796513A - Di-selenium bond bridged docetaxel dimer prodrug and self-assembled nanoparticles thereof - Google Patents

Di-selenium bond bridged docetaxel dimer prodrug and self-assembled nanoparticles thereof Download PDF

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CN114796513A
CN114796513A CN202110072005.5A CN202110072005A CN114796513A CN 114796513 A CN114796513 A CN 114796513A CN 202110072005 A CN202110072005 A CN 202110072005A CN 114796513 A CN114796513 A CN 114796513A
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docetaxel
prodrug
diselenide
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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 medicinal preparations, and relates to a diselenide bond bridged docetaxel dimer prodrug and a preparation method thereofAssembled nanoparticles, in particular to synthesis of a diselenide bond bridged docetaxel dimer prodrug, construction of self-assembled nanoparticles containing the dimer prodrug, and application of the self-assembled nanoparticles in drug delivery. The redox double-sensitive small-molecule prodrug containing the blood circulation stable diselenide bond bridging selects docetaxel as a simulated medicine, selects (a)4,4 '-diselenide dibutyrate 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 carboxyl groups of the chemical bridging and hydroxyl at C (2') position of the docetaxel, and the structure is as follows. 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 a high-efficiency low-toxicity chemotherapy preparation in clinic.

Description

Di-selenium bond bridged docetaxel dimer prodrug and self-assembled nanoparticles thereof
Technical Field
The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, and relates to a diselenide bond bridged docetaxel dimer prodrug and self-assembled nanoparticles thereof, in particular to synthesis of the diselenide bond bridged docetaxel dimer prodrug, construction of the docetaxel dimer prodrug self-assembled nanoparticles containing the docetaxel dimer prodrug, and application of the docetaxel dimer prodrug in medicament delivery.
Background
Cancer has become a major threat to human health, and in china, there are approximately over 350 million new cancer cases and 200 million death cases each year. Chemotherapy is one of the most effective strategies in cancer treatment. However, most of the current clinical antitumor drugs 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) is a taxane antitumor drug, widely used for the treatment of breast cancer, ovarian cancer, lung cancer, and the like, and also used as a neoadjuvant treatment for advanced triple negative breast cancer. However, the use of docetaxel causes severe neutropenia and neurotoxicity. Furthermore, since docetaxel is poorly soluble in water, the clinical formulation (taxotere) must use the non-ionic surfactants tween 80 and ethanol as solubilizers, which can lead to an undesirable hypersensitivity reaction. Even with the aid of solubilizers, taxotere has poor stability, the formulation needs to be ready for use and is easily precipitated after dilution. These disadvantages limit the clinical use of docetaxel.
To increase the delivery efficiency of chemotherapeutic drugs, prodrug strategies have been developed to improve the poor properties of chemotherapeutic drugs in terms of solubility, stability, and tumor selectivity. The nano drug delivery system is also widely applied to improve the blood circulation time and tumor targeting of the chemotherapy drugs. Combining the advantages of both the nano-drug and prodrug strategies, prodrug-based self-assembled nano-drug delivery systems have received increasing attention in recent years. Homodimer prodrugs are prepared by coupling two drug molecules together using a special linker chain. The prodrug is used as a carrier and can specifically release active drugs, so that the homodimer prodrug nano-drug delivery system has ultrahigh drug loading rate which can reach 60%. In addition, the prodrug nanomedicine delivery system avoids the use of biocompatible solubilizers, which would help improve drug safety and patient compliance.
The intermediate linking chain of the homodimer has great influence on the assembly, drug release, in vivo fate and antitumor activity of the prodrug. In our previous studies, three docetaxel dimer prodrugs bridged with a diselenide bond, a disulfide bond and a two carbon bond, respectively, were designed and synthesized. Due to the fact that the diselenide bond has a special bond angle and a special dihedral angle, the structure flexibility of drug molecules can be improved, intermolecular force of the drugs can be balanced, and self-assembly of the docetaxel dimer prodrug can be promoted. The diselenide bond has oxidation-reduction double sensitivity, can intelligently respond to the high oxidation-reduction state of the tumor cells and specifically releases the medicine. We also found that disulfide bonds of different chain lengths affect the redox sensitivity of paclitaxel-citronellol monomer prodrugs, which in turn affects the antitumor activity of the prodrug self-assembled nanoparticles. The rigid chemical structure of homodimeric prodrugs limits their self-assembly ability and exhibits different drug release mechanisms compared to monomeric prodrugs. Therefore, diselenide bonds with different chain lengths can affect the assembly capacity of the homodimer prodrug, and further affect the in vivo fate and antitumor activity of the nanoparticles.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the redox double-sensitive prodrug containing the blood circulation stable diselenide bond, and the prodrug is used for self-assembled nanoparticles, so that the effects of high drug loading, good stability and low toxic and side effects are realized, and the anti-tumor activity is further improved. The differences of the diselenide bonds with different chain lengths in the aspects of bond angle/dihedral angle, redox sensitive response capability, antitumor activity and the like are inspected, and the influences on the stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the prodrug self-assembled nanoparticles are also inspected.
The invention aims to design and synthesize a redox double-sensitive micromolecular prodrug containing a blood circulation stable diselenide bond bridging, prepare prodrug self-assembly nanoparticles, discuss the influence of diselenide bonds with different chain lengths on the self-assembly capacity, the assembly stability, the drug release, the cytotoxicity, the pharmacokinetics, the tissue distribution and the pharmacodynamics of the prodrug self-assembly nanoparticles, comprehensively screen out the diselenide bond chemical bridging with the best effect, provide a new strategy and more choices for developing an intelligent response type tumor microenvironment drug delivery system, and meet the urgent needs of high-efficiency chemotherapy preparations in clinic.
The invention realizes the aim through the following technical scheme:
the redox double-sensitive small-molecule prodrug containing the blood circulation stable diselenide bond bridging selects docetaxel as a simulated medicament, selects (a)4,4 '-diselenide dibutyrate 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 carboxyl groups of the chemical bridging and hydroxyl at C (2') position of the docetaxel. For the chemical bridges 4,4' -diselenodibutanoic acid, 3' -diselenodipropionic acid and 2,2' -diselenodiacetic acid, the selenium atoms are located at the γ, β and α positions of the carbonyl group, respectively, thus designating the corresponding prodrugs as γ -DSeSeD, β -DSeSeD and α -DSeSeD, respectively, having the structural formulae:
Figure BDA0002905552910000031
the invention provides a synthesis method of a diselenide bond bridged docetaxel dimer prodrug, which comprises the following steps: firstly, binary acid containing diselenide bond and one molecule of docetaxel form ester to obtain an intermediate product. And then the intermediate product and another molecule of docetaxel form ester to obtain a final product.
Further, the invention provides a specific synthesis method of the series docetaxel dimer small molecule prodrug:
dissolving docetaxel in dichloromethane, adding 4,4' -diselenodibutyric acid, 3' -diselenodipropionic acid or 2,2' -diselenodiacetic acid in equal amount, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in twice amount and 4-dimethylaminopyridine in equal amount, stirring at room temperature for 2-3 hours, adding docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in equal amount and 4-dimethylaminopyridine in equal amount into the intermediate product, stirring at room temperature for 24-30 hours, separating and purifying the obtained product by a preparation liquid phase, and carrying out the whole reaction under the protection of nitrogen.
The invention also provides a synthesis method of the 4,4' -diseleno-dibutyrate, which comprises the following steps: firstly, reacting selenium powder with sodium borohydride, and then reacting with the second part of selenium powder to obtain an intermediate product. And (4) reacting the intermediate product with bromobutyric acid to obtain a final product.
Specifically, the invention provides a synthesis method of 4,4' -diselenodibutyric acid, which comprises the following steps:
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 110 ℃ at the temperature of 100 ℃, stirring for 30-60 minutes, cooling to room temperature, dropwise adding an aqueous solution of bromobutyric acid, reacting for 3-4 hours, filtering the reaction solution, diluting with water, adding ethyl acetate for extraction for three times, drying the ethyl acetate layer, performing reduced pressure rotary evaporation to remove the solvent to obtain a product, wherein the whole reaction process is performed under the protection of nitrogen.
The invention also provides self-assembled nanoparticles of the diselenide bond bridged docetaxel dimer micromolecule prodrug, and the self-assembled nanoparticles of the micromolecule prodrug can be non-PEGylated prodrug nanoparticles and PEG modified prodrug nanoparticles.
The docetaxel of the invention can be replaced by other anticancer drugs containing active hydroxyl or amino, such as taxane compounds, nucleoside compounds, anthracycline compounds or camptothecin compounds.
The preparation method of the docetaxel dimer micromolecular prodrug self-assembly nanoparticles provided by the invention comprises the following steps:
dissolving a certain amount of mixture of the docetaxel dimer micromolecule prodrug and the PEG modifier into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming the prodrug into uniform nanoparticles. Finally, ethanol in the preparation is removed by adopting a reduced pressure rotary evaporation method to obtain the nano colloidal solution without any organic solvent. 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, with a preferred PEG molecular weight of 2000. The weight ratio of the small molecule prodrug to the PEG modifier is as follows: the ratio of docetaxel to docetaxel is 90: 10-70: 30, and the docetaxel can exert the best anti-tumor effect under the condition.
(1) The preparation method of the non-PEG small molecule prodrug self-assembly 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. Removing ethanol from the preparation by reduced pressure rotary evaporation to obtain nano colloidal solution without any organic solvent.
(2) The preparation method of the PEG modified micromolecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of PEG modifier (TPGS, DSPE-PEG, PLGA-PEG or PE-PEG) and prodrug into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles from the prodrug. Removing ethanol from the preparation by reduced pressure rotary evaporation to obtain nano colloidal solution without any organic solvent.
The invention has the following beneficial effects: (1) the di-selenium bond bridged docetaxel dimer micromolecular prodrug is designed and synthesized, and the synthesis method is simple and feasible; the prodrug can keep stable in blood circulation and has redox double-sensitive property; (2) the self-assembled nanoparticles of the docetaxel dimer micromolecule prodrug bridged by diselenide bonds are prepared, the preparation method is simple and feasible, 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 antitumor activity, as well as on the stability, drug release, cytotoxicity, pharmacokinetics, tissue distribution and pharmacodynamics of the prodrug self-assembled nanoparticles is investigated. The results show that the antitumor activity of the prodrug obtained by bridging diselenide bonds with different chain lengths is 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 need of a high-efficiency low-toxicity chemotherapy preparation in clinic is met.
Drawings
FIG. 1 is a mass spectrum and sum of the mass spectra of 4,4' -diselenobibutanoic acid bridged docetaxel dimer prodrug (γ -DSeSeD) of example 1 of the present invention 1 HNMR spectrogram.
FIG. 2 is a mass spectrum and mass spectra of 3,3' -diselenopimaric acid bridged docetaxel dimer prodrug (. beta. -DSeSeD) of example 2 of the present invention 1 HNMR spectrogram.
FIG. 3 is a mass spectrum and the sum of the mass spectra of 2,2' -diselenodiacetic acid bridged docetaxel dimer prodrug (. alpha. -DSeSeD) of example 3 of the present invention 1 HNMR spectrogram.
Fig. 4 is a photograph of a non-pegylated small molecule prodrug self-assembled nanoparticle of example 4 of the present invention after centrifugation.
Fig. 5 is a particle size diagram and a transmission electron microscope diagram of PEG-modified small molecule prodrug self-assembled nanoparticles of example 5 of the invention.
Fig. 6 is a graph of the particle size change of PEG-modified small molecule prodrug of example 6 of the present invention after incubation with blank rat plasma.
FIG. 7 is a graph of in vitro release assay for PEG-modified small molecule prodrug self-assembled nanoparticles of example 8 of the present invention
Fig. 8 is a cytotoxicity diagram of PEG-modified small molecule prodrug self-assembled nanoparticles of example 9 of the invention.
Fig. 9 is a tumor cell drug release profile of PEG-modified small molecule prodrug self-assembled nanoparticles of example 9 of the present invention. (statistical significance of differences is indicated by P < 0.05.)
*P<0.05，**P<0.01。
Fig. 10 is a blood concentration-time curve diagram of 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 embodiment 10 of the invention. (statistical significance of differences is indicated by P < 0.05.)
*P<0.05，**P<0.01，***P<0.001，****P<0.0001；
n.s. the difference is not statistically significant.
Fig. 12 is a safety experiment chart of PEG-modified small molecule prodrug self-assembled nanoparticles of example 11 of the present invention. (statistical significance of differences is indicated by P < 0.05.)
P <0.05, P <0.01, n.s.the difference is not statistically significant;
fig. 13 is a graph showing HE staining pathological section results of mouse tissues after the drug effect experiment of the PEG-modified small molecule prodrug self-assembled nanoparticle of example 11 of the present invention is completed.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Example 1: synthesis of 4,4' -diselenodibutyric acid bridged docetaxel dimer small molecule prodrug (gamma-DSeSD)
Dissolving docetaxel in dichloromethane, adding 4,4' -diselenodibutyric acid with the same amount, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride with twice amount and 4-dimethylaminopyridine with the same amount, stirring for 2 hours at room temperature, adding docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine with the same amount into an intermediate product, stirring for 24 hours at room temperature, separating and purifying an obtained product by a preparation liquid phase, and carrying out the whole reaction under the protection of nitrogen.
Mass spectrometry and NMR spectroscopy were used to determine the structure of the prodrug of example 3, and the results are shown in FIG. 3. The solvent selected for nuclear magnetic resonance isDeuterated chloroform (CDCl) 3 ) The results of the spectrum analysis were 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' -diselenopimaric acid bridged docetaxel dimer small molecule prodrug (beta-DSeSeD)
Dissolving docetaxel in dichloromethane, adding 3,3' -diselenopimaric acid with the same amount, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride with the same amount as twice and 4-dimethylaminopyridine with the same amount, stirring at room temperature for 2 hours, adding docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine with the same amount into an obtained intermediate product, stirring at room temperature for 24 hours, separating and purifying an obtained product by a preparation liquid phase, and carrying out the whole reaction under the protection of nitrogen.
Mass spectrometry and NMR spectroscopy were used to determine the structure of the prodrug of example 2, and the results are shown in FIG. 2. The solvent selected for nuclear magnetic resonance is CDCl 3 The results of the spectrum analysis were 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 docetaxel small molecule prodrug (alpha-DSeSeD)
Dissolving docetaxel in dichloromethane, adding equal amount of 2,2' -diselenodiacetic acid, twice amount of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and equal amount of 4-dimethylaminopyridine, stirring at room temperature for 2 hours, adding equal amount of docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and 4-dimethylaminopyridine into an obtained intermediate product, stirring at room temperature for 24 hours, separating and purifying an obtained product by a preparation liquid phase, and carrying out the whole reaction under the protection of nitrogen.
Mass spectrometry and NMR spectroscopy were used to determine the structure of the prodrug of example 1, and the results are shown in FIG. 1. The solvent selected for nuclear magnetic resonance is CDCl 3 The results of the spectrum analysis were 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 non-PEG small molecule prodrug self-assembled nanoparticles
1.6mg of the prodrug was weighed out precisely, dissolved in 1mL of ethanol, and the ethanol solution was added dropwise to 4mL of deionized water with stirring. The organic solvent in the nano preparation is removed by rotary evaporation under reduced pressure at 25 ℃. The prepared small molecule prodrug self-assembly nanoparticles are centrifuged (3000rpm, 10 minutes) and observed.
As shown in fig. 4, γ -DSeSeD can form stable nanoparticles, which remain clear and transparent after centrifugation; the alpha-DSeSeD nano-particles and the beta-DSeSeD nano-particles generate obvious precipitates after centrifugation.
Example 5: preparation of PEG (polyethylene glycol) -modified small-molecule prodrug self-assembled nanoparticles
Precision (precision)Weighing DSPE-PEG 2k 1mg and prodrug 4mg, dissolving with 1mL of ethanol, slowly dripping the ethanol solution into 4mL of deionized water under stirring, and spontaneously forming uniform nanoparticles (gamma-DSeSeD nanoparticles, beta-DSeSeD nanoparticles, alpha-DSeSeD nanoparticles). The organic solvent in the nano preparation is removed by rotary evaporation under reduced pressure at 25 ℃.
As shown in Table 1, the particle size of the nanoparticles is about 80nm, the particle size distribution is less than 0.2, the surface charge is about-20 mV, and the drug loading is more than 65%. The particle size and morphology of the small molecule prodrug self-assembled nanoparticles prepared in example 5 were measured by a transmission electron microscope, and the results are shown in fig. 5, where the transmission electron microscope shows that the drug-loaded nanoparticles are uniform spheres with 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
Figure BDA0002905552910000081
Figure BDA0002905552910000091
Example 6: colloidal stability test of PEG modified small molecule prodrug self-assembled nanoparticles
The PEG-modified small molecule prodrug self-assembled nanoparticles prepared in example 5 were taken out 500 μ l, added to 5mL of blank rat plasma, incubated at 37 ℃ for 48 hours, and the change in particle size was measured by dynamic light scattering at a predetermined time point. As shown in FIG. 6, the colloidal stability of the gamma-DSeSeD nanoparticles was the best, and the particle size of the nanoparticles did not change significantly until 48 hours. In contrast, α -DSeSD nanoparticles and β -DSeSD nanoparticles have poor colloidal stability.
Example 7: bond angle, dihedral angle and binding energy of diselenide bonds in small molecule prodrugs
By optimizing molecular conformation, bond angles and diselenide bonds of two selenium atoms in three chemical bridges in small molecule prodrugThe dihedral angles formed were calculated as shown in table 2, and the results were: 2,2' -diselenodiacetic acid (97.9 °/98.3 °,98.3 °), 3' -diselenodipropionic acid (95.5 °/96.9 °,95.6 °), and 4,4' -diselenodibutanoic acid (90.1 °/90.5 °,93.6 °). The bond angle and the dihedral angle of diselenide bonds in the 4,4' -diselenide dibutyrate are closest to 90 degrees, so that structural defects are caused in the structure of the homodimer prodrug, the flexibility of the molecular structure is effectively improved, the acting force among molecules is balanced, and the gamma-DSeSD presents the optimal conformation in the assembling process, so that the gamma-DSeSD has strong assembling capability, and the formed nanoparticles have good stability. In addition, the binding energy of the self-assembly process of the docetaxel dimer small molecule prodrug was calculated by molecular docking, as shown in table 3, the result was γ -DSeSeD (-410.02kcal mol) -1 )<β-DSeSeD(-398.54kcal mol -1 )<α-DSeSeD(-379.39kcal mol -1 ). Gamma-DSeSeD has the minimum binding energy, which shows that the diselenide bond with the longest chain length is beneficial to constructing the optimal conformation when the prodrug is self-assembled, reducing the free energy of the system and improving the stability of the system.
TABLE 2 bond angle, dihedral angle and binding energy of diselenide bonds in small molecule prodrugs
Figure BDA0002905552910000092
Example 8: in vitro release test of PEG modified small molecule prodrug self-assembled nanoparticles.
Phosphate Buffered Saline (PBS) with the pH value of 7.4 and containing 30% ethanol is used as a release medium, and the in-vitro release condition of the small-molecule prodrug self-assembled nanoparticles is examined. The PEG-modified small molecule prodrug self-assembly nanoparticles prepared in example 5 (docetaxel content 200 μ g/mL) were added to 30mL of release medium, samples were taken at a set time point at 37 ℃, 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,10mM) or glutathione (GSH,5 μ M,50 μ M,500 μ M,5000 μ M) to investigate the release of the nanoparticles under oxidizing and reducing conditions, respectively.
The results are shown in fig. 7, and the diselenide bond bridged prodrug nanoparticles with different chain lengths have different oxidation-sensitive drug release capacities. Wherein, the oxidation sensitivity order is alpha-DSeSeD nano-particle > beta-DSeSeD nano-particle > gamma-DSeSeD nano-particle. The oxidation response drug release mechanism is that selenium atoms of diselenide bonds are oxidized into hydrophilic selenone, so that the hydrophilicity of the system is increased to promote the hydrolysis of adjacent ester bonds and the release of docetaxel. Therefore, the release rate of docetaxel is inversely proportional to the length of the carbon chain between the selenium atom and the ester bond, and the alpha-DSeSD nanoparticle shows the fastest oxidation response drug release rate. The diselenide bond bridged prodrug nanoparticles with different chain lengths have different reduction-sensitive drug release capabilities. The release amount of the alpha-DSeSD nano-particle is similar when the concentration of glutathione is lower (5-500 mu M), but the release amount of docetaxel is obviously reduced when the concentration of glutathione is higher (5000 mu M). The beta-DSeSD nano-particle only releases a small amount of docetaxel under the action of glutathione. The release amount of docetaxel of the gamma-DSeSD nano-particle is remarkably 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 the PEG modified small-molecule prodrug self-assembly nanoparticles on mouse breast cancer (4T1) cells, mouse skin melanoma (B16-F10) cells and human liver (L02) cells is examined by adopting an MTT method. Digesting the cells in a good state, diluting the cells to 1000cells/mL by using a culture solution, uniformly blowing the cells, adding 200 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. Add taxotere or prodrug nanoparticles prepared in example 5 after the cells adhere to the wall. Preparation and dilution of the drug solution and the nanoparticle preparation in experiments on mouse breast cancer (4T1) cells and human liver (L02) cells are performed by using 1640 culture solution, and preparation and dilution of the drug solution and the nanoparticle preparation in experiments on mouse skin melanoma (B16-F10) cells are performed by using DMEM culture solution and sterile-filtering by using a 0.22 mu m filter membrane. Test solution was added at 200. mu.L per well, 3 parallel wells per concentration. In the control group, 200 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. And (3) taking out the 96-well plate 48h after adding the drugs, adding 35 mu L of 5mg/mL MTT solution into each well, putting the plate in an incubator for incubation for 4h, throwing the plate, reversely buckling the 96-well plate on filter paper, fully sucking the residual liquid, adding 200 mu L DMSO into each well, and shaking the plate on a shaker for 10min to dissolve the blue-violet crystals. The A1 well (containing only 200. mu.L DMSO) was set as the zeroing well. The absorbance value after zeroing of each well was measured using a microplate reader at 490 nm.
The cytotoxicity results are shown in fig. 8. Because the prodrug nanoparticles need a certain time to release docetaxel, the drug effect of docetaxel is limited to a certain extent, and therefore, compared with a taxotere group, the prodrug nanoparticles have low cytotoxicity. The cytotoxicity order of the prodrug nanoparticles is alpha-DSeSeD nanoparticles, beta-DSeSeD nanoparticles and gamma-DSeSeD nanoparticles. Prodrug nanoparticle cytotoxicity is related to the rate of docetaxel release from the nanoparticles. Therefore, the release rate of docetaxel from prodrug nanoparticles in 4T1 cells was examined. As can be seen from fig. 9, compared to β -DSeSeD nanoparticles and γ -DSeSeD nanoparticles, α -DSeSeD nanoparticles released docetaxel faster, which is consistent with the results of cytotoxicity. The selectivity of the taxotere and prodrug nanoparticles on normal cells and tumor cells is investigated. As shown in table 3, the prodrug nanoparticles had significantly reduced toxicity to L02 cells compared to taxotere. When the Selectivity Index (SI) is more than 1, the toxicity of the medicine to tumor cells is more than that to normal cells, and the larger the value is, the more obvious the difference of the toxicity is. 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 semi-Inhibitory Concentrations (IC) of Texodidine and prodrug nanoparticles on 3 cells 50 ) And Selectivity Index (SI)
Figure BDA0002905552910000111
Example 10: pharmacokinetics research of PEG (polyethylene glycol) -modified small-molecule prodrug self-assembled nanoparticles
SD rats with the body weight between 180-200g are taken and randomly divided into 5 groups, and fasting is performed for 12h before administration, and water is freely drunk. Taxotere and the pegylated small molecule prodrug self-assembled nanoparticles prepared in example 5 were injected intravenously, respectively. The dose of docetaxel was 4.0 mg/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 spectrometer.
Experimental results as shown in figure 10, taxotere docetaxel was rapidly cleared from the blood. In contrast, the circulation time of the small molecule prodrug self-assembled nanoparticles is significantly prolonged. Diselenide bonds with different chain lengths have a significant effect on the pharmacokinetic behavior of the prodrug nanoparticles. Compared with the alpha-DSeSeD nanoparticles and the beta-DSeSeD nanoparticles, the gamma-DSeSeD nanoparticles have higher AUC. Probably because the 4,4' -diselenodibutyric acid bridging bond enhances the colloidal stability of the self-assembled nanoparticles. The circulation time in vivo is prolonged, which is helpful for the accumulation of the nanoparticles at the tumor site. In addition, the gamma-DSeSeD nanoparticles are most stable in blood circulation, releasing only a small amount of docetaxel. The 4,4' -diseleno-dibutyrate bridging bond plays an important role in improving the in vivo fate of the prodrug nanoparticles.
Example 11: in-vivo anti-tumor experiment of PEG (polyethylene glycol) -modified small-molecule prodrug self-assembled nanoparticles
The anti-tumor activity of the PEG modified small molecule prodrug self-assembly nanoparticles on a 4T1 ectopic tumor model is investigated. 4T1 cell suspension (5X 10) 6 cells/100 μ L) were inoculated into the right dorsal side of female Balb/c mice to construct a 4T1 ectopic tumor model. When the tumor volume grows to 100mm 3 Meanwhile, tumor-bearing mice were randomly grouped into five groups, and physiological saline, taxotere and the PEG-modified small molecule prodrug self-assembled nanoparticles prepared in example 5 were administered to each group. The medicine is administered for 1 time every 1 day and 5 times continuously, and the administration dosage is 2.5mg/kg calculated according to docetaxel. After the administration, the survival state of the mice was observed every day, the body weight was weighed, and the tumor volume was measured. Tumor-bearing mice were sacrificed one day after the last dose, organs and tumors were harvested and further evaluated for analysis. Major organs (heart, liver, spleen, lung, kidney) and tumor tissues were collected and fixed with formalin for H&And E, dyeing. Collecting blood plasma for liver and kidney function examination, and collecting blood for blood routine examination.
The experimental results are shown in fig. 11, and the antitumor activity of taxotere is between that of alpha-DSeSD nanoparticles and beta-DSeSD nanoparticles, and has no significant difference compared with the alpha-DSeSD nanoparticles and the beta-DSeSD nanoparticles. The anti-tumor activity of the beta-DSeSD nano-particles and the gamma-DSeSD nano-particles is stronger than that of the alpha-DSeSD nano-particles. Although α -DSeSeD nanoparticles have the fastest intracellular drug release and the strongest cytotoxicity, their anti-tumor activity is limited by rapid systemic clearance and limited tumor accumulation. Although γ -DSeD NPs are least cytotoxic in 4T1 cells, their antitumor activity is best. The in vivo anti-tumor effect ultimately depends on the concentration of docetaxel at the tumor site. Therefore, the drug concentration of taxotere and the PEG-modified small molecule prodrug self-assembled nanoparticle prepared in example 5 at the tumor site was determined by a liquid chromatography-mass spectrometer. Compared with other treatment groups, the mice of the gamma-DSeSD nanoparticle treatment group have the most docetaxel and prodrug at the tumor part, and show the strongest tumor accumulation. Mice in the taxotere-treated group had significantly reduced body weight, spleen atrophy, and showed impairment of liver function, as shown in fig. 12 and 13. The body weight of the mice treated by the prodrug nanoparticles is maintained at a stable level, and obvious liver and kidney and bone marrow functional damage is not shown. The results show that the gamma-DSeSD nanoparticles have good safety, obvious anti-tumor effect and no obvious non-specific toxicity to organisms.

Claims (10)

1. The diselenide bond bridged docetaxel dimer prodrug is characterized by having the following structure:
Figure FDA0002905552900000011
2. the method of claim 1, wherein the chemical bridge is esterified with one molecule of docetaxel to form an intermediate product, and the intermediate product is 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, 3' -diselenodipropionic acid, or 2,2' -diselenodiacetic acid.
4. The process according to claim 2, wherein docetaxel is dissolved in methylene chloride, 4' -diselenodibutyric acid, 3' -diselenodipropionic acid or 2,2' -diselenodiacetic acid, twice the amount of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the amount of 4-dimethylaminopyridine are added and stirred at room temperature for 2-3 hours, the intermediate product obtained is added with docetaxel, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine and stirred at room temperature for 24-30 hours, the product obtained is separated and purified by preparative liquid phase separation, and the whole course of the reaction is carried out under nitrogen protection.
5. The diselenide-linked bridged docetaxel dimer prodrug of claim 1, wherein said docetaxel is replaced with a nucleoside compound, an anthracycline compound or a camptothecin compound.
6. The self-assembled nanoparticles of a diselenide-linked bridged docetaxel dimer prodrug of claim 1, comprising non-pegylated prodrug nanoparticles and PEG-modified prodrug nanoparticles.
7. Use of a diselenide-linked bridged docetaxel dimer prodrug of claim 1 or a self-assembled nanoparticle of claim 6 for the preparation of a drug delivery system.
8. The use of a diselenide-linked bridged docetaxel dimer prodrug of claim 1 or a self-assembled nanoparticle of claim 6 for the preparation of an anti-tumor drug.
9. Use of a diselenide-linked bridged docetaxel dimer prodrug of claim 1 or a self-assembled nanoparticle of claim 6 for the preparation of an injectable, oral or topical delivery system.
10. Use of a diselenide-linked bridged docetaxel dimer prodrug of claim 1 or a self-assembled nanoparticle of claim 6 for improving the stability of a drug in vivo.
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