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CN112604002A - Disulfide-bond bridged docetaxel-fatty acid prodrug and self-assembled nanoparticles thereof - Google Patents

Disulfide-bond bridged docetaxel-fatty acid prodrug and self-assembled nanoparticles thereof Download PDF

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CN112604002A
CN112604002A CN202011492954.0A CN202011492954A CN112604002A CN 112604002 A CN112604002 A CN 112604002A CN 202011492954 A CN202011492954 A CN 202011492954A CN 112604002 A CN112604002 A CN 112604002A
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docetaxel
disulfide
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孙进
王悦全
何仲贵
王永军
邱诗
罗聪
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Suzhou Yutai Pharmaceutical Technology Co ltd
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Abstract

本发明设计并合成了一系列还原敏感的二硫键桥连的多西他赛‑脂肪酸前药，这一系列的前药均能通过一步纳沉淀法自组装成纳米递药系统。该纳米递药系统具备以下几种优势：将多西他赛制备成二硫键连接的前药，降低了多西他赛母药的系统毒性，并且能够在肿瘤细胞内的高还原环境下特异性释放母药，实现增效减毒的效果；载药量高，且避免了毒性较大的增溶剂的使用，有望提高患者的耐受性和依从性；通过一步纳米沉淀法制备，制备工艺简单，易于规模化生产；纳米粒粒径小且均匀，易于通过EPR效应富集于肿瘤部位；易于表面修饰，可以通过PEG等修饰以减慢网状内皮系统的清除。

Figure 202011492954

The present invention designs and synthesizes a series of reduction-sensitive disulfide bridged docetaxel-fatty acid prodrugs, and the series of prodrugs can be self-assembled into a nanometer drug delivery system through a one-step nanoprecipitation method. The nano-drug delivery system has the following advantages: the preparation of docetaxel into a disulfide-linked prodrug reduces the systemic toxicity of the parent drug of docetaxel, and can be specific in the highly reducing environment in tumor cells It can release the parent drug sexually to achieve the effect of synergism and detoxification; the drug load is high, and the use of toxic solubilizers is avoided, which is expected to improve the tolerance and compliance of patients; it is prepared by one-step nanoprecipitation method, and the preparation process Simple, easy to scale production; small and uniform nanoparticle size, easy to be enriched in tumor sites through EPR effect; easy to surface modification, can be modified by PEG to slow down the clearance of the reticuloendothelial system.

Figure 202011492954

Description

Disulfide-bond bridged docetaxel-fatty acid 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 disulfide bond bridged docetaxel-fatty acid prodrug, construction of self-assembled nanoparticles of the disulfide bond bridged docetaxel-fatty acid prodrug, and application of the disulfide bond bridged docetaxel-fatty acid prodrug in medicament delivery.
Background
Cancer remains one of the diseases with high mortality rate today, seriously threatening human health. Common cancer treatment regimens include primarily surgical resection, chemotherapy, radiation therapy, and biological therapy. Among them, surgical resection has significant efficacy for early stage tumors, but chemotherapy has significant advantages for late stage or metastatic tumors. Taxane chemotherapeutic drugs are a class of antineoplastic drugs acting on microtubules, can promote the rapid aggregation of tubulin into microtubules, and bind to the microtubules to inhibit the depolymerization of the microtubules, thereby terminating the mitosis of the cells and inducing the apoptosis of tumor cells, and represent drugs of Paclitaxel (PTX) and Docetaxel (DTX). The research proves that DTX shows outstanding curative effect in the chemotherapy treatment of tumors regardless of single medicine or combined medicine. The DTX injection Taxotere (Taxotere) applied to clinic at present has good anti-tumor activity, is mainly applied to the treatment of advanced or metastatic breast cancer and non-small cell lung cancer, but is easy to generate systemic toxicity such as anaphylactic reaction, hemolysis and the like, and seriously influences the clinic application of the DTX injection Taxotere (Taxotere).
In recent years, prodrug strategies and nanotechnology have been widely used to reduce the systemic toxicity of taxanes and to improve drug potency. Wherein, the nanometer preparation of paclitaxel comprises paclitaxel liposome, paclitaxel albumin nanometer particle, etc. which are already applied to the clinical treatment of cancer; paclitaxel-docosahexaenoic acid prodrugs have also been subjected to phase III clinical studies, but docetaxel-based nano-dosage forms have not been clinically applied. At present, a stimulus-responsive drug delivery system based on a tumor microenvironment becomes a hot spot for research in the anti-tumor field. Glutathione (GSH) is present in tumor cells at higher concentrations than in normal cells, and this special tumor cell reducing microenvironment has been widely used to achieve specific drug release at the tumor site. Research finds that disulfide bonds have reduction sensitivity and can be rapidly broken in the presence of GSH, so that the insertion of disulfide bonds into the design of a prodrug is expected to realize tumor-specific drug release.
Disclosure of Invention
Based on this, we design and synthesize a series of disulfide bond bridged docetaxel-fatty acid prodrugs by combining with prodrug strategies, connect docetaxel with multiple fatty acids through reduction-sensitive disulfide bonds respectively, can stably exist in normal physiological environment, and rapidly break in abnormal high-reduction environment in tumor cells, thereby realizing specific release of the parent drug in the tumor cells. The synthesized prodrug is further prepared into prodrug self-assembly nanoparticles by a one-step nano precipitation method. The prepared prodrug self-assembly nanoparticles have the advantages of high drug loading rate (> 50%), small and uniform particle size, good stability, capability of quickly releasing parent drugs in a reducing environment and the like, and have excellent clinical transformation prospect.
The invention aims to design and synthesize a series of disulfide bond bridged docetaxel-fatty acid prodrugs, and respectively prepare the prodrugs into prodrug self-assembled nanoparticles to investigate the influence of different fatty acid side chains on the properties of the prodrugs. Provides a new strategy for developing a tumor microenvironment stimulus response type drug delivery system, and meets the requirement of synergy and attenuation of docetaxel preparation in clinic.
The invention realizes the aim through the following technical scheme:
the invention provides a series of disulfide bond bridged docetaxel-fatty acid prodrugs, wherein the fatty acid is stearic acid, oleic acid, elaidic acid, linoleic acid, alpha-linolenic acid, docosahexaenoic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, pearlescent aliphatic acid, arachidic acid, behenic acid, (E) -11-eicosenoic acid, erucic acid or nervonic acid.
The series of disulfide-bridged docetaxel-fatty acid prodrugs of the present invention comprise: (a) disulfide bridged docetaxel-stearic acid prodrug (n ═ 17), (b) disulfide bridged docetaxel-oleic acid prodrug (n ═ 7), (c) disulfide bridged docetaxel-elaidic acid prodrug, (d) disulfide bridged docetaxel-linoleic acid prodrug, (e) disulfide bridged docetaxel- α -linolenic acid prodrug, (f) disulfide bridged docetaxel-docosahexaenoic acid prodrug, having the following structures:
Figure BDA0002845330290000021
the invention provides a method for synthesizing series disulfide bond bridged docetaxel-fatty acid small molecule prodrugs, which comprises the following steps:
fatty acid reacts with glycol under the catalysis of p-toluenesulfonic acid to obtain fatty acid-glycol ester, the fatty acid-glycol ester reacts with 2,2' -dithiodiacetic anhydride under the catalysis of HOBt, EDCI and DMAP to obtain an intermediate product, the intermediate product reacts with docetaxel under the catalysis of HOBt and EDCI to obtain the compound, and the compound is separated and purified, wherein the reaction process is carried out in the whole process of N2Under protection. Ethylene glycol may also be replaced with ethylene diamine.
The preparation method of the series of disulfide bond bridged docetaxel-fatty acid small molecule prodrug self-assembly nanoparticles provided by the invention comprises the following steps:
dissolving a certain amount of small molecule prodrug into a proper amount of ethanol solution, slowly dripping the ethanol solution into deionized water under the stirring of a magnetic stirrer, and spontaneously assembling the prodrug into nanoparticles with uniform particle size.
The small molecule prodrug nanoparticles can be non-PEG small molecule prodrug nanoparticles and PEG modified small molecule prodrug nanoparticles.
(1) The preparation method of the non-PEG small molecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of small molecule prodrug into a proper amount of ethanol solution, slowly dropwise adding the ethanol solution into deionized water under the stirring of a magnetic stirrer, spontaneously assembling the prodrug into nanoparticles with uniform particle size, and removing ethanol in the preparation by adopting a reduced-pressure rotary evaporation method to obtain ethanol-free nanoparticles.
(2) The preparation method of the PEG micromolecule prodrug self-assembly nanoparticle comprises the following steps: mixing a certain amount of small molecule prodrug and DSPE-PEG2000Dissolving the mixture into a proper amount of ethanol solution, slowly dropwise adding the ethanol solution into deionized water under the stirring of a magnetic stirrer, spontaneously assembling the prodrug into nanoparticles with uniform particle size, and removing ethanol in the preparation by adopting a reduced-pressure rotary evaporation method to obtain the PEG nanoparticles without ethanol.
The series disulfide bond bridged docetaxel-fatty acid prodrug self-assembly nano drug delivery system has the following advantages: (1) docetaxel is prepared into a prodrug connected by disulfide bonds, so that the systematic toxicity of docetaxel is reduced, the parent drug can be specifically released in a high-reduction environment in tumor cells, and the effects of synergy and attenuation are realized; (2) the drug loading is high, the use of a solubilizer with high toxicity is avoided, and the tolerance and compliance of patients are expected to be improved; (3) the preparation is prepared by a one-step nano precipitation method, the preparation process is simple, and the large-scale production of the preparation is easy; (4) the nanoparticles have small and uniform particle size and are easy to enrich in tumor parts through an EPR effect; (5) is easy to surface modify, and can be modified by PEG and the like to slow down the clearance of the reticuloendothelial system.
Drawings
FIG. 1 is a high resolution mass spectrum of the disulfide bridged docetaxel-stearic acid prodrug (DTX-S-S-SA) of example 1
FIG. 2 is a high resolution mass spectrum of disulfide bridged docetaxel-oleic acid prodrug (DTX-S-S-OA) of example 2
FIG. 3 is a high resolution mass spectrum of the disulfide bridged docetaxel-elaidic acid prodrug (DTX-S-S-EA) of example 3
FIG. 4 is a high resolution mass spectrum of the disulfide bridged docetaxel-linoleic acid prodrug (DTX-S-S-LA) of example 4
FIG. 5 is a high resolution mass spectrum of the disulfide bridged docetaxel-linolenic acid prodrug (DTX-S-S-LNA) of example 5
FIG. 6 is a high resolution mass spectrum of the disulfide-bridged docetaxel-docosahexaenoic acid prodrug (DTX-S-S-DHA) of example 6
FIG. 7 is a transmission electron microscope micrograph of PEG-modified small molecule prodrug self-assembled nanoparticles of example 8
FIG. 8 is a graph of particle size versus storage time for PEG-modified small molecule prodrug self-assembled nanoparticles of example 9
Fig. 9 is a graph of an in vitro release assay for PEG-modified small molecule prodrug self-assembled nanoparticles of example 10.
Fig. 10 is a cytotoxicity diagram of PEG-modified docetaxel prodrug self-assembly nanoparticles of example 11 of the present invention.
Fig. 11 is a blood concentration-time curve diagram of PEG-modified docetaxel prodrug self-assembled nanoparticles of example 12 of the present invention.
Fig. 12 is an in vivo anti-tumor experimental graph of PEG-modified docetaxel prodrug self-assembly nanoparticles of example 13 of the present invention
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Example 1: synthesis of disulfide bridged docetaxel-stearic acid prodrugs (DTX-S-S-SA)
Excess ethylene glycol was measured and placed in a 50mL three-necked flaskIn a bottle, adding a proper amount of p-toluenesulfonic acid into a three-necked bottle, refluxing by a spherical condenser pipe, and performing reaction on N2And (4) protecting, heating to 110 ℃, slowly dripping a stearic acid solution dissolved in toluene into a reaction bottle through a constant pressure dropping funnel, and reacting for 2 hours. After the reaction is finished, standing for layering, extracting for three times by using methylbenzene, combining methylbenzene layers, and then using saturated NaHCO for3Washing the solution to be neutral, drying the solution by anhydrous sodium sulfate, filtering the solution, evaporating the solution to dryness, separating and purifying the solution to obtain the stearic acid-2-hydroxyethyl ester. Using CH for 2,2' -dithiodiacetic anhydride2Cl2Dissolving and transferring to 100mL eggplant-shaped bottle, adding HOBt, EDCI and 2-hydroxyethyl stearate, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolving DMAP, stirring for 30min, transferring to room temp, reacting for 12 hr, TLC monitoring reaction, evaporating, acidifying with diluted hydrochloric acid, and reacting with CH2Cl2Extracting until TLC of water layer has no product point, washing CH with saturated NaCl solution2Cl2The layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate (2-oxo-2- (2-stearoyloxy-ethoxy) ethanedithiol) acetic acid. Dissolving (2-oxo-2- (2-stearoyloxy) ethoxy) ethyldithio) acetic acid, EDCI, HOBt and docetaxel in CH2Cl2Then put into a 100mL eggplant-shaped bottle, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolved DMAP, stirred for 1 hour, then transferred to 25 ℃ for reaction for 48 hours, monitored by TLC for completion of the reaction, and washed with saturated NaCl solution2Cl2The layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to give a white solid.
The prodrug structure of example 1 was determined by high resolution mass spectrometry using acetonitrile as the solvent, the result is shown in FIG. 1, and the molecular formula is C67H95NO19S2，m/z：1281.6。
Example 2: synthesis of disulfide bridged docetaxel-oleic acid prodrugs (DTX-S-S-OA)
Measuring excessive glycol, placing in a 50mL three-necked flask, adding appropriate amount of p-toluenesulfonic acid into the three-necked flask, refluxing with a spherical condenser tube, and performing N2Protecting, heating to 110 deg.C, dissolving toluene-dissolved oleic acidThe solution was slowly dripped into the reaction flask through a constant pressure dropping funnel, reacted for 2h, and the completion of the reaction was monitored by TLC. After the reaction is finished, standing for layering, extracting with toluene until no product point exists in a TLC (thin layer chromatography) of an ethylene glycol layer, combining toluene layers, and then using saturated NaHCO for carrying out secondary reaction3Washing the solution to be neutral, drying the solution by anhydrous sodium sulfate, filtering the solution, evaporating the solution to dryness, separating and purifying the solution to obtain the oleic acid-2-hydroxyethyl ester. Using CH for 2,2' -dithiodiacetic anhydride2Cl2Dissolving and transferring to 100mL eggplant-shaped bottle, adding HOBt, EDCI and oleic acid-2-hydroxyethyl ester, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolving DMAP, stirring for 30min, transferring to room temp, reacting for 12 hr, TLC monitoring reaction, evaporating, acidifying with diluted hydrochloric acid, and reacting with CH2Cl2Extracting until TLC of water layer has no product point, washing CH with saturated NaCl solution2Cl2The layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate (2-oxo-2- (2-oleoyloxy-ethoxy) ethanedithio) acetic acid. Dissolving (2-oxo-2- (2-oleoyloxy) ethoxy) ethanedithiol) acetic acid, EDCI, HOBt and docetaxel in CH2Cl2Then put into a 100mL eggplant-shaped bottle, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolved DMAP, stirred for 1 hour, then transferred to 25 ℃ for reaction for 48 hours, monitored by TLC for completion of the reaction, and washed with saturated NaCl solution2Cl2The layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to give a white solid.
The prodrug structure of example 2 was determined by high resolution mass spectrometry using acetonitrile as the solvent, the result is shown in FIG. 2, and the molecular formula is C67H93NO19S2，m/z：1279.6。
Example 3: synthesis of disulfide bridged docetaxel-elaidic acid prodrugs (DTX-S-S-EA)
Measuring excessive glycol, placing in a 50mL three-necked flask, adding appropriate amount of p-toluenesulfonic acid into the three-necked flask, refluxing with a spherical condenser tube, and performing N2And (4) protecting, heating to 110 ℃, slowly dripping the toluene-dissolved elaidic acid solution into a reaction bottle through a constant-pressure dropping funnel, reacting for 2 hours, and monitoring the reaction completion by TLC. After the reaction is finishedStanding for layering, extracting with toluene until no product is produced in TLC of ethylene glycol layer, mixing toluene layers, and adding saturated NaHCO3Washing the solution to be neutral, drying the solution by anhydrous sodium sulfate, filtering the solution, evaporating the solution to dryness, separating and purifying the solution to obtain the elaidic acid-2-hydroxyethyl ester. Using CH for 2,2' -dithiodiacetic anhydride2Cl2Dissolving and transferring to 100mL eggplant-shaped bottle, adding HOBt, EDCI and trans-oleic acid-2-hydroxyethyl ester, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolving DMAP, stirring for 30min, transferring to room temp, reacting for 12 hr, TLC monitoring reaction, evaporating, acidifying with diluted hydrochloric acid, and reacting with CH2Cl2Extracting until TLC of water layer has no product point, washing CH with saturated NaCl solution2Cl2The layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate (2-oxo-2- (2-elaidoyloxy-ethoxy) ethanedithio) acetic acid. Dissolving (2-oxo-2- (2-elaidoyloxy) ethoxy) ethanedithiol) acetic acid, EDCI, HOBt and docetaxel in CH2Cl2Then put into a 100mL eggplant-shaped bottle, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolved DMAP, stirred for 1 hour, then transferred to 25 ℃ for reaction for 48 hours, monitored by TLC for completion of the reaction, and washed with saturated NaCl solution2Cl2The layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to give a white solid.
The prodrug structure of example 3 was determined by high resolution mass spectrometry using acetonitrile as the solvent, the result is shown in FIG. 3, and the molecular formula is C67H93NO19S2，m/z：1279.6。
Example 4: synthesis of disulfide bridged docetaxel-linoleic acid prodrugs (DTX-S-S-LA)
Measuring excessive glycol, placing in a 50mL three-necked flask, adding appropriate amount of p-toluenesulfonic acid into the three-necked flask, refluxing with a spherical condenser tube, and performing N2And (4) protecting, heating to 110 ℃, slowly dripping the linoleic acid solution dissolved in toluene into a reaction bottle through a constant pressure dropping funnel, reacting for 2 hours, and monitoring the reaction completion by TLC. After the reaction is finished, standing for layering, extracting with toluene until no product point exists in TLC of an ethylene glycol layer, combining toluene layers, and then saturatingAnd NaHCO3Washing the solution to be neutral, drying the solution by anhydrous sodium sulfate, filtering the solution, evaporating the solution to dryness, and separating and purifying the solution to obtain the linoleic acid-2-hydroxyethyl ester. Using CH for 2,2' -dithiodiacetic anhydride2Cl2Dissolving and transferring to 100mL eggplant-shaped bottle, adding HOBt, EDCI and linoleic acid-2-hydroxyethyl ester, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolving DMAP, stirring for 30min, transferring to room temp, reacting for 12 hr, TLC monitoring reaction, evaporating, acidifying with diluted hydrochloric acid, and reacting with CH2Cl2Extracting until TLC of water layer has no product point, washing CH with saturated NaCl solution2Cl2The layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate (2-oxo-2- (2-linoleoyloxy-ethoxy) ethanedithio) acetic acid. Dissolving (2-oxo-2- (2-linoleoyloxy) ethoxy) ethanedithiol) acetic acid, EDCI, HOBt and docetaxel in CH2Cl2Then put into a 100mL eggplant-shaped bottle, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolved DMAP, stirred for 1 hour, then transferred to 25 ℃ for reaction for 48 hours, monitored by TLC for completion of the reaction, and washed with saturated NaCl solution2Cl2The layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to give a white solid.
The prodrug structure of example 4 was determined by high resolution mass spectrometry using acetonitrile as the solvent, the result is shown in FIG. 4, and the molecular formula is C67H91NO19S2，m/z：1277.6。
Example 5: synthesis of disulfide bridged docetaxel-alpha-linolenic acid prodrugs (DTX-S-S-LNA)
Measuring excessive glycol, placing in a 50mL three-necked flask, adding appropriate amount of p-toluenesulfonic acid into the three-necked flask, refluxing with a spherical condenser tube, and performing N2And (3) protecting, heating to 110 ℃, slowly dripping the alpha-linolenic acid solution dissolved in the toluene into a reaction bottle through a constant pressure dropping funnel, reacting for 2 hours, and monitoring the reaction completion by TLC. After the reaction is finished, standing for layering, extracting with toluene until no product point exists in a TLC (thin layer chromatography) of an ethylene glycol layer, combining toluene layers, and then using saturated NaHCO for carrying out secondary reaction3Washing the solution to neutral, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and separatingPurifying to obtain the alpha-linolenic acid-2-hydroxyethyl ester. Using CH for 2,2' -dithiodiacetic anhydride2Cl2Dissolving and transferring to 100mL eggplant-shaped bottle, adding HOBt, EDCI and alpha-linolenic acid-2-hydroxyethyl ester, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolving DMAP, stirring for 30min, transferring to room temp, reacting for 12 hr, TLC monitoring reaction, evaporating, acidifying with diluted hydrochloric acid, and reacting with CH2Cl2Extracting until TLC of water layer has no product point, washing CH with saturated NaCl solution2Cl2The layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate (2-oxo-2- (2- α -linolenoyloxy-ethoxy) ethanedithio) acetic acid. Dissolving (2-oxo-2- (2-alpha-linolenoyloxy) ethoxy) ethanedithiol) acetic acid, EDCI, HOBt and docetaxel in CH2Cl2Then put into a 100mL eggplant-shaped bottle, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolved DMAP, stirred for 1 hour, then transferred to 25 ℃ for reaction for 48 hours, monitored by TLC for completion of the reaction, and washed with saturated NaCl solution2Cl2The layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to give a white solid.
The prodrug structure of example 5 was determined by high resolution mass spectrometry using acetonitrile as the solvent, the result is shown in FIG. 5, and the molecular formula is C67H89NO19S2，m/z：1277.6。
Example 6: synthesis of disulfide-bridged docetaxel-docosahexaenoic acid prodrugs (DTX-S-S-DHA)
Measuring excessive glycol, placing in a 50mL three-necked flask, adding appropriate amount of p-toluenesulfonic acid into the three-necked flask, refluxing with a spherical condenser tube, and performing N2And (3) protecting, heating to 110 ℃, slowly dripping the toluene-dissolved docosahexaenoic acid solution into a reaction bottle through a constant pressure dropping funnel, reacting for 2 hours, and monitoring the reaction completion by TLC. After the reaction is finished, standing for layering, extracting with toluene until no product point exists in a TLC (thin layer chromatography) of an ethylene glycol layer, combining toluene layers, and then using saturated NaHCO for carrying out secondary reaction3Washing the solution to neutrality, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, separating and purifying to obtain docosahexaenoic acid-2-hydroxyethyl ester. 2,2CH for' -dithiodiacetic anhydride2Cl2Dissolving and transferring into 100mL eggplant-shaped bottle, adding HOBt, EDCI and docosahexaenoic acid-2-hydroxyethyl ester, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolving DMAP, stirring for 30min, transferring to room temp, reacting for 12 hr, TLC monitoring reaction, evaporating, acidifying with diluted hydrochloric acid, and reacting with CH2Cl2Extracting until TLC of water layer has no product point, washing CH with saturated NaCl solution2Cl2The layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give intermediate (2-oxo-2- (2-docosahexenoyloxy-ethoxy) ethanedidisulfide) acetic acid. Dissolving (2-oxo-2- (2-docosahexenoyloxy) ethoxy) ethanedithiol) acetic acid, EDCI, HOBt and docetaxel in CH2Cl2Then put into a 100mL eggplant-shaped bottle, N2Cooling to 0 ℃ under the protection condition, and slowly dripping CH2Cl2Dissolved DMAP, stirred for 1 hour, then transferred to 25 ℃ for reaction for 48 hours, monitored by TLC for completion of the reaction, and washed with saturated NaCl solution2Cl2The layer was dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to give a white solid.
The prodrug structure of example 6 was determined by high resolution mass spectrometry using acetonitrile as the solvent, the result is shown in FIG. 6, and the molecular formula is C71H91NO19S2，m/z：1325.6。
Example 7: preparation of non-PEG small molecule prodrug self-assembly nanoparticles
Precisely weighing 8mg of prodrug, dissolving the prodrug in 1mL of ethanol, slowly dripping the ethanol solution into 4mL of deionized water under stirring to spontaneously form uniform nanoparticles (DTX-S-S-SA nanoparticles, DTX-S-S-OA nanoparticles, DTX-S-S-EA nanoparticles, DTX-S-S-LA nanoparticles, DTX-S-S-LNA nanoparticles, DTX-S-S-DHA nanoparticles)
Example 8: preparation of PEG small molecule prodrug self-assembly nanoparticles
Precisely weighing prodrug 8mg and DSPE-PEG20001.6mg of the compound, dissolved in 1mL of ethanol, and added slowly dropwise to 4mL of deionized water with stirring to spontaneously form uniform nanoparticles (DTX-S-S-SA)/DSPE-PEG2000Nanoparticles, DTX-S-S-OA/DSPE-PEG2000Nanoparticles, DTX-S-S-EA/DSPE-PEG2000Nanoparticles, DTX-S-S-LA/DSPE-PEG2000Nanoparticles, DTX-S-S-LNA/DSPE-PEG2000Nanoparticles, DTX-S-S-DHA/DSPE-PEG2000Nano granule)
As shown in table 1, the prodrug nanoparticles have a small particle size, a particle size distribution of less than 0.2, and a high drug loading (> 50%). The particle size and morphology of the small molecule prodrug self-assembled nanoparticles prepared in example 8 were determined by transmission electron microscopy, and the results are shown in fig. 7, where the transmission electron microscopy shows that the drug-loaded nanoparticles are uniform spheres with a particle size of about 100 nm.
TABLE 1 particle size, particle size distribution and drug loading of PEG-modified prodrug self-assembled nanoparticles
Figure BDA0002845330290000091
Example 9: storage stability test of PEG modified small molecule prodrug self-assembly nanoparticles
The PEG modified small molecule prodrug prepared in the example 8 is self-assembled nanoparticle (DTX-S-S-SA/DSPE-PEG)2000Nanoparticles, DTX-S-S-OA/DSPE-PEG2000Nanoparticles, DTX-S-S-EA/DSPE-PEG2000Nanoparticles, DTX-S-S-LA/DSPE-PEG2000Nanoparticles, DTX-S-S-LNA/DSPE-PEG2000Nanoparticles, DTX-S-S-DHA/DSPE-PEG2000Nanoparticles) were stored at 4 ℃ for 2 months. During this time, the particle size change was measured by dynamic light scattering. The results are shown in FIG. 8, where only DTX-S-S-SA/DSPE-PEG2000Nanoparticles and DTX-S-S-OA/DSPE-PEG2000The particle size of the nanoparticles showed no significant change, and the other 4 nanoparticles showed an increase in particle size. The above results show that DTX-S-S-SA/DSPE-PEG2000Nanoparticles and DTX-S-S-OA/DSPE-PEG2000The nanoparticles have good storage stability, and the prepared DTX-S-S-EA/DSPE-PEG2000Nanoparticles, DTX-S-S-LA/DSPE-PEG2000Nanoparticles, DTX-S-S-LNA/DSPE-PEG2000Nanoparticles, DTX-S-S-DHA/DSPE-PEG2000Storage of nanoparticlesThe stability is poor.
Example 10: in vitro release test of PEG modified small molecule prodrug self-assembled nanoparticles
The in vitro release condition of the PEG modified small molecule prodrug self-assembly nanoparticles is examined by taking pH 7.4 phosphate buffer solution containing ethanol as a release medium. The PEG-modified small molecule prodrug self-assembled nanoparticle prepared in example 8 was added to 30mL of release medium and Dithiothreitol (DTT) at a certain concentration was added to the release medium, sampling was performed at 37 ℃ at a set time point, and the concentration of released docetaxel was determined by high performance liquid chromatography to examine the release of nanoparticles under reducing conditions.
The results are shown in fig. 9, and experimental results show that the series of docetaxel-fatty acid small molecule prodrugs designed by the invention can quickly release the parent drug in a reducing environment, have the characteristic of reduction-sensitive drug release, can respond to the oxidation-reduction environment specific to a tumor part, realize the drug release specific to the tumor part, are expected to improve the anti-tumor effect of docetaxel and reduce the toxic and side effects on an organism, and the release speeds of different fatty acid coupled docetaxel prodrugs are not obviously different, which suggests that different fatty acid side chains have no obvious influence on the release of the parent drug.
Example 11: cytotoxicity experiment of PEG (polyethylene glycol) -modified docetaxel prodrug self-assembled nanoparticles
The toxicity of the PEG-modified docetaxel-fatty acid prodrug self-assembly nanoparticles on tumor cells (4T1) is examined by adopting an MTT method. Firstly, digesting cells with good state, diluting the cells with a culture solution to 1 ten thousand cells/mL, 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. Docetaxel solution diluted by culture solution or the pegylated docetaxel prodrug nanoparticle prepared in example 8 is added after the cells adhere to the wall. 200 μ L of medium containing different concentrations of drug was added to each 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 and 72h after adding the drug, adding 25 mu L of 5mg/mL MTT solution into each well, putting the plate in an incubator for incubation for 4h, throwing the plate, turning the 96-well plate over on filter paper, fully sucking the residual liquid, adding 200 mu L of DMSO into each well, and shaking the plate on a shaker for 10min to dissolve the bluish purple 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 at 490nm using a microplate reader.
The cytotoxicity results are shown in fig. 10. Compared with the docetaxel solution group, the docetaxel prodrug nanoparticles have slightly weakened cytotoxicity. However, due to the special high-reduction environment of tumor cells, docetaxel can be rapidly released from the parent drug, and docetaxel prodrug nanoparticles still have strong cytotoxicity.
Example 12: pharmacokinetic study of PEGylated docetaxel-fatty acid prodrug self-assembled nanoparticles
SD rats with the body weight between 180-220g are taken, 5 rats in each group are randomly grouped, and fasting is performed for 12h before administration, and water is freely drunk. Docetaxel solution and pegylated docetaxel-fatty acid prodrug self-assembled nanoparticles prepared in example 8 were injected intravenously, respectively. The equivalent dose was 5 mg/kg. Blood was collected from the orbit at a predetermined time point and separated to obtain plasma. The concentrations of the prodrug and the released docetaxel in the plasma were measured by ultra performance liquid chromatography-mass spectrometry (UPLC-MS).
The results are shown in figure 11, the docetaxel solution was rapidly cleared by blood. In contrast, the circulation time of the pegylated docetaxel-fatty acid prodrug nanoparticles was significantly prolonged. Meanwhile, different fatty acid side chains also have obvious influence on the circulation time of the docetaxel prodrug. DTX-S-S-SA/DSPE-PEG2000Nanoparticles and DTX-S-S-OA/DSPE-PEG2000The nanoparticles showed higher AUC. While DTX-S-S-EA/DSPE-PEG2000Nanoparticles, DTX-S-S-LA/DSPE-PEG2000Nanoparticles, DTX-S-S-LNA/DSPE-PEG2000Nanoparticles, DTX-S-S-DHA/DSPE-PEG2000The AUC of nanoparticles is relatively small due to their poor colloidal stability.
Example 13: in-vivo anti-tumor experiment of PEG (polyethylene glycol) -modified docetaxel prodrug self-assembled nanoparticles
4T1 cell suspension (5 x 10)6cells/100. mu.L) was inoculated inFemale BALB/c mice were ventral subcutaneous. When the tumor volume grows to 150mm3In the meantime, tumor-bearing mice were randomly grouped into five groups, and physiological saline, a docetaxel solution and the PEG-modified docetaxel prodrug self-assembly nanoparticles prepared in example 8 were administered to each group. The administration was performed 1 time every 1 day and 5 times continuously, and the survival state of the mice was observed every day, and the tumor volume was measured by weighing.
The in vivo antitumor effect is shown in fig. 12A-B, and the docetaxel solution has a significant antitumor effect compared with the normal saline group. However, the docetaxel solution had severe side effects and the weight loss of mice was significant after administration (see fig. 12C). Compared with a docetaxel solution, the PEG docetaxel prodrug self-assembly nanoparticle has good safety, and the body weight of a mouse is not remarkably reduced. In addition, different antitumor effects are shown among different prodrug nanoparticles, SA-S-S-DTX nanoparticles and OA-S-S-DTX nanoparticles show better antitumor effects due to stronger colloidal stability and higher AUC, and other nanoparticles show poorer in vivo antitumor activity due to shorter circulation time.
In addition, a high-dose group is designed to investigate the safety of the docetaxel prodrug nanoparticles, and the results are shown in fig. 12D, so that even if the administration dose reaches 20mg/kg, mice in the prodrug nanoparticle group hardly die, and even after a docetaxel solution of 10mg/kg is administered, the mice die completely in 20 days.

Claims (9)

1. Disulfide bridged docetaxel-fatty acid prodrugs comprising (a) a disulfide bridged docetaxel-stearic acid prodrug (n ═ 17), (b) a disulfide bridged docetaxel-oleic acid prodrug (n ═ 7), (c) a disulfide bridged docetaxel-elaidic acid prodrug, (d) a disulfide bridged docetaxel-linoleic acid prodrug, (e) a disulfide bridged docetaxel- α -linolenic acid prodrug, (f) a disulfide bridged docetaxel-docosahexaenoic acid prodrug having the structure:
Figure FDA0002845330280000011
2. the disulfide bridged docetaxel-fatty acid prodrug of claim 1, wherein the docetaxel is a taxane compound.
3. The disulfide bridged docetaxel-fatty acid prodrug in accordance with claim 1, wherein the fatty acid is one or more of stearic acid, oleic acid, elaidic acid, linoleic acid, α -linolenic acid, docosahexaenoic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, perlitic acid, arachidic acid, behenic acid, (E) -11-eicosenoic acid, erucic acid, nervonic acid.
4. The disulfide bridged docetaxel-fatty acid prodrug of claim 1, wherein the disulfide bond is further one of a hydrazone bond, a carbonate bond, a monothioether bond, a spacer disulfide bond or a diselenide bond.
5. The disulfide bridged docetaxel-fatty acid prodrug of claim 1, synthesized by: reacting fatty acid with ethylene glycol under the catalysis of p-toluenesulfonic acid to obtain fatty acid-ethylene glycol ester, carrying out ring-opening esterification reaction on the fatty acid-ethylene glycol ester and 2,2' -dithiodiacetic anhydride under the catalysis of HOBt, EDCI and DMAP to obtain an intermediate product, carrying out esterification reaction on the intermediate product and docetaxel under the catalysis of HOBt and EDCI, and separating and purifying to obtain the product, wherein the reaction is carried out in the whole process of N2Under protection.
6. Disulfide-bridged docetaxel-fatty acid-series prodrug self-assembled nanoparticles comprising the disulfide-bridged docetaxel-fatty acid prodrug of any one of claims 1 to 5, prepared by the following process:
dissolving a certain amount of disulfide-bond bridged docetaxel-fatty acid prodrug and a PEG stabilizer into a proper amount of ethanol, slowly dropwise adding the ethanol solution into deionized water under stirring, and spontaneously assembling the disulfide-bond bridged docetaxel-fatty acid prodrug into nanoparticles with uniform particle size.
7. The disulfide-bridged docetaxel-fatty acid prodrug self-assembled nanoparticle of claim 6, wherein the PEG is one of TPGS, DSPE-PEG, PLGA-PEG, PE-PEG and DSPE-PEG-AA.
8. Use of the disulfide-bridged docetaxel-fatty acid prodrug of any one of claims 1 to 5 or the disulfide-bridged docetaxel-fatty acid prodrug self-assembled nanoparticle of claims 6 to 7 for the preparation of an antitumor drug.
9. Use of the disulfide bridged docetaxel-fatty acid prodrug of any one of claims 1 to 5 or the disulfide bridged docetaxel-fatty acid prodrug self-assembled nanoparticle of claims 6 to 7 in a medicament for oral, injectable or topical administration.
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