WO2022227556A1 - 多西他赛-脂肪醇小分子前药及其自组装纳米粒的构建 - Google Patents

多西他赛-脂肪醇小分子前药及其自组装纳米粒的构建 Download PDF

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WO2022227556A1
WO2022227556A1 PCT/CN2021/133828 CN2021133828W WO2022227556A1 WO 2022227556 A1 WO2022227556 A1 WO 2022227556A1 CN 2021133828 W CN2021133828 W CN 2021133828W WO 2022227556 A1 WO2022227556 A1 WO 2022227556A1
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docetaxel
prodrug
fatty alcohol
small molecule
self
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French (fr)
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罗聪
王永军
杨金诚
马宏达
孙进
何仲贵
冯尧
马志宁
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苏州裕泰医药科技有限公司
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the invention belongs to the field of new excipients and new dosage forms for pharmaceutical preparations, relates to the construction of docetaxel-fatty alcohol prodrugs and self-assembled nanoparticles thereof, and in particular relates to docetaxel-fatty alcohol prodrugs with tumor reduction response characteristics and the same Application of self-assembled nanoparticles in the preparation of drug delivery systems.
  • Docetaxel is one of the important taxane chemotherapy drugs and has been widely used in the treatment of various types of cancers such as locally advanced or metastatic breast cancer, non-small cell lung cancer, prostate cancer, and gastric cancer.
  • docetaxel formulations are currently on the market. Tween 80 and ethanol are used as solubilizers, and the selectivity to tumor cells is low, which brings many adverse side effects to clinical chemotherapy.
  • Tween 80 and ethanol are used as solubilizers, and the selectivity to tumor cells is low, which brings many adverse side effects to clinical chemotherapy.
  • With the development of pharmaceutical technology there is an urgent need to develop new docetaxel formulations with high efficiency and low toxicity.
  • nanoformulations have been successfully launched, such as paclitaxel albumin nanoparticles, doxorubicin liposomes, etc.
  • nanoformulations have significant advantages such as prolonging the blood circulation time of drugs, enhancing tumor accumulation through EPR effect, and improving uptake efficiency.
  • prodrug strategies can improve the undesirable properties of drugs and reduce the toxicity of drugs through chemical structure modification. A variety of drugs based on prodrug strategies have been successfully launched.
  • the present invention provides a small molecule prodrug of docetaxel fatty alcohol. It can be stably existing in the form of prodrugs in the circulation and in normal tissues, and can be rapidly broken in the abnormally high reducing environment in tumor cells, so as to achieve the characteristics of specific release of the parent drug in tumor cells and exert strong anti-tumor activity.
  • the synthesized prodrug is further prepared into prodrug self-assembled nanoparticles by one-step nanoprecipitation method.
  • the preparation process is very simple, and the prepared nano-formulation has high drug loading (>50%), small and uniform particle size, good stability, can quickly release the parent drug in a reducing environment, and can significantly reduce doxorubicin.
  • the toxicity of Thaxar has excellent prospects for clinical translation.
  • the present invention realizes above-mentioned purpose through following technical scheme:
  • the invention provides a docetaxel-fatty alcohol small molecule prodrug with tumor reduction response characteristics: the docetaxel is bridged with the fatty alcohol through a disulfide bond at the ⁇ position, and its structural formula is as follows:
  • R is C 3 -C 30 saturated or unsaturated chain hydrocarbon group
  • R is a C 3 -C 22 alkenyl group; the alkenyl group contains 1-5 ethylenic bonds;
  • n 7-29;
  • R is C 3 -C 22 alkenyl
  • said R includes but is not limited to propenyl, allyl, 2-butenyl, 4-pentenyl, 2-hexenyl, 4-decenyl , 2-dodecenyl, 9,10-tetradecenyl, 9-tetradecenyl, 9-hexadecenyl, 9-octadecenyl, eicosatetraene, docosyl Carbopentene, linoleic.
  • the present invention provides the docetaxel-stearyl alcohol small molecule prodrug of the following structure:
  • the present invention provides a method for synthesizing the docetaxel-fatty alcohol small molecule prodrug, which includes the following steps: firstly, dithiodiacetic acid is formed into an acid anhydride, and then an ester is formed with a fatty alcohol to obtain an intermediate product. Then the intermediate product undergoes ester-forming reaction with docetaxel to obtain the final product.
  • step (2) dissolving the product obtained in step (1) in methylene chloride, and adding aliphatic alcohol, adding 4-dimethylaminopyridine (DMAP) as a catalyst, stirring at room temperature for 12-18 hours, and using cyclohexane after the completion of the reaction
  • the alkane-acetone elution system was separated by column chromatography to obtain the intermediate product; the intermediate product, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzene Triazole (HOBt) and 4-dimethylaminopyridine (DMAP), dissolved in anhydrous dichloromethane, activated under ice bath for 2-4 hours, then added docetaxel, nitrogen protection, at 25-30
  • the reaction is carried out under the condition of °C for 48-60 hours, and the obtained product is purified by preparative liquid phase separation.
  • the fatty alcohol described in step (2) can be C 3 -C 30 saturated or unsaturated fatty alcohol, such as n-dodecanol, tridecanol, tetradecanol, 1-pentadecanol, hexadecanol, ten Hepta alcohol, stearyl alcohol, 1-nonadecanol, 1-eicosanol, behenyl alcohol, 1-docosanol, behenyl alcohol, behenic alcohol, tetracosanol, twenty-five alcohol, 1-hexadecanol, oleyl alcohol, linoleyl alcohol.
  • saturated or unsaturated fatty alcohol such as n-dodecanol, tridecanol, tetradecanol, 1-pentadecanol, hexadecanol, ten Hepta alcohol, stearyl alcohol, 1-nonadecanol, 1-eicosanol, behenyl alcohol, 1-doc
  • R is a C 3 -C 30 saturated or unsaturated chain hydrocarbon group.
  • the present invention also provides the self-assembled nanoparticles of the docetaxel-fatty alcohol small molecule prodrug, and the small molecule prodrug self-assembled nanoparticles can be non-PEGylated docetaxel-fatty alcohol small molecules Prodrug nanoparticles, PEG-modified docetaxel-fatty alcohol small molecule prodrug nanoparticles, small molecule prodrug nanoparticles loaded with fluorescent substances or hydrophobic drugs, and active targeting small molecule prodrug nanoparticles ; Described PEG modifier is TPGS, PLGA-PEG, PE-PEG, DSPE-PEG-AA or DSPE-PEG 2k , the mass ratio of described docetaxel-fatty alcohol small molecule prodrug and PEG modifier It is: 90:10 ⁇ 70:30.
  • the present invention also provides a preparation method of docetaxel-fatty alcohol small molecule prodrug self-assembled nanoparticles:
  • the ethanol solution is slowly added dropwise to water, and the prodrug can spontaneously assemble into nanoparticles with uniform particle size; microfluidic equipment can also be used to prepare ultra-small nanoparticles: before the preparation of small molecules containing docetaxel-fatty alcohol
  • the ethanol solution of the drug is used as the organic phase; ultrapure water is used as the water phase, and the mixture is prepared according to the proportion of the water phase and the organic phase, and finally the docetaxel-fatty alcohol small molecule prodrug nanoparticles are obtained.
  • the particle size of the self-assembled nanoparticles of the docetaxel-fatty alcohol small molecule prodrug prepared by the invention is below 100 nm.
  • Docetaxel is prepared into a disulfide-linked stearyl alcohol prodrug, and it is prepared into nanoparticles, which not only improves the curative effect of docetaxel, but also reduces the toxicity of the docetaxel parent drug;
  • the nanoparticles are prepared by a one-step nanoprecipitation method, the preparation process is extremely simple, and the large-scale production of the preparation is easy; (3) no carrier material is required, the drug loading is high, and the use of a highly toxic solubilizer is avoided.
  • the nanoparticle size is small and uniform, the PEG modification can prolong the circulation time of the drug in the blood, and it is easy to be enriched in the tumor site through the EPR effect; (5) using Disulfide bridges can achieve specific and rapid release of the parent drug in a highly reducing environment in tumor cells.
  • FIG. 1 is a mass spectrum of docetaxel-stearyl alcohol prodrug (DTX-SS-SAL) of Example 1 of the present invention.
  • FIG. 2 is the 1 HNMR spectrum of docetaxel-stearyl alcohol prodrug (DTX-SS-SAL) in Example 1 of the present invention.
  • FIG. 3 is a particle size measurement diagram of the PEG-modified prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • Figure 4 is a blood concentration-time curve diagram of the PEG-modified prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • FIG. 5 is a graph of the in vivo anti-tumor experiment of the PEG-modified prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • A Tumor growth curve graph
  • B Tumor photograph graph
  • Example 6 is a safety evaluation diagram of the PEG-modified prodrug nanoparticles of Example 3 of the present invention.
  • A Body weight change diagram
  • B Spleen photograph diagram
  • the structure of the prodrug in Example 1 was determined by mass spectrometry and proton nuclear magnetic resonance spectroscopy, and the results are shown in FIG. 1 and FIG. 2 .
  • the solvent selected for nuclear magnetic resonance is CDCl 3 , and the spectral analysis results are as follows:
  • Example 3 Preparation of DSPE-PEG 2k -modified DTX-SS-SAL prodrug self-assembled nanoparticles
  • the particle size of the prepared nanoparticles was measured by a Malvern particle sizer. The results are shown in Figure 3.
  • the particle size of the prodrug nanoparticles is about 75 nm, and the particle size distribution PDI ⁇ 0.2.
  • the moderate particle size of the nanoparticles is beneficial to blood circulation and Tumor accumulation.
  • DTX-SS-SAL prodrug self-assembled nanoparticles modified with different PEG modifiers were prepared according to the method of Example 3, and the prepared nanoparticles had an average particle size At 70 ⁇ 100nm, the particle size distribution PDI ⁇ 0.2.
  • Example 5 Preparation of ultra-small docetaxel-stearyl alcohol small molecule prodrug nanoparticles using a microfluidic device:
  • An ethanol solution containing DSPE-PEG2000 and docetaxel-stearyl alcohol small molecule prodrug is prepared as an organic phase, wherein the concentration of docetaxel stearyl alcohol prodrug is 10mg/ml, and the concentration of DSPE-PEG2000 is 2mg/ml ; Using ultrapure water as the water phase, mixing and preparing according to the ratio of the flow rate ratio of the water phase and the organic phase to 5:1, and finally obtaining docetaxel-stearyl alcohol small molecule prodrug nanoparticles.
  • SD rats with a body weight of 180-220 g were randomly divided into two groups, fasted for 12 hours before administration, and had free access to water.
  • Docetaxel solution and PEGylated prodrug self-assembled nanoparticles prepared in Example 3 were injected intravenously, respectively.
  • the equivalent dose of docetaxel is 5 mg/kg.
  • 0.083, 0.25, 0.5, 1, 2, 4, 8, and 12 h 0.5 mL of orbital blood was collected, and the plasma was obtained by centrifugation. Drug concentrations in plasma were determined by liquid chromatography-mass spectrometry.
  • Example 7 In vivo anti-tumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles
  • the adherent cells of 4T1 cells were digested and resuspended in PBS solution to prepare a cell suspension (5x 10 6 cells/100 ⁇ L), which was inoculated subcutaneously on the ventral side of balb/c mice.
  • the tumor - bearing mice were randomly divided into 7 groups, with five mice in each group, and were given normal saline, docetaxel solution 10 mg/kg, docetaxel solution 20 mg/kg, and more.
  • the low, middle and high groups in the prodrug nanoparticle group still survived well after 5 administrations.
  • the body weight of the low-dose docetaxel solution group decreased significantly, while the weight loss of the high-dose prodrug nanoparticle group was comparable to that of the low-dose docetaxel solution group.
  • the high-dose group of prodrug nanoparticles showed comparable toxicity to the low-dose group of docetaxel solution as judged by the spleen of mice. The above results show that the prodrug nanoparticles prepared by the present invention can greatly reduce the toxicity of docetaxel, thereby increasing the dosage and greatly improving the anti-tumor effect.

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Abstract

涉及多西他赛-脂肪醇小分子前药及其自组装纳米粒的构建，具体涉及具有肿瘤还原响应特性的西他赛-脂肪醇小分子前药及其自组装纳米粒在制备药物递送系统中的应用。所述多西他赛-脂肪醇小分子前药通过如下方法制备:将亚二硫基二乙酸成酸酐，然后与脂肪醇成酯得到中间产物。然后中间产物再与多西他赛发生成酯反应即得，结构如下，R如权利要求和说明书所述。所述的前药是将多西他赛与脂肪醇通过还原响应断裂的二硫键连接，在血液循环以及在正常的组织中能够以前药的形式稳定存在，而在肿瘤细胞内异常高还原环境下快速断裂，从而实现肿瘤细胞内特异性释放母药的特点，发挥抗肿瘤活性,降低药物的毒性。

Description

多西他赛-脂肪醇小分子前药及其自组装纳米粒的构建 技术领域
本发明属于药物制剂新辅料和新剂型领域，涉及多西他赛-脂肪醇前药及其自组装纳米粒的构建，具体涉及具有肿瘤还原响应特性的多西他赛-脂肪醇前药及其自组装纳米粒在制备药物递送系统中的应用。
背景技术
多西他赛(Docetaxel,DTX)是重要的紫杉烷类化疗药物之一，已广泛应用于局部晚期或转移性乳腺癌、非小细胞肺癌、前列腺癌、胃癌等各种类型癌症的治疗。然而，由于多西他赛的水溶性极低，目前上市多西他赛制剂
Figure PCTCN2021133828-appb-000001
使用了吐温80和乙醇作为增溶剂，且对肿瘤细胞的选择性较低，这给临床化疗带来了许多不良的副作用。随着制药技术的发展，亟需开发新的高效低毒的多西他赛制剂。近年来，纳米技术在药物递送领域的广泛应用极大地改善了药物递送效率，且已经有多个纳米制剂成功上市，如：紫杉醇白蛋白纳米粒，阿霉素脂质体等。相比于传统的溶液剂，纳米制剂具有延长药物的血液循环时间、通过EPR效应提高肿瘤蓄积、提高摄取效率等显著的优势。此外，前药策略可以通过化学结构修饰来改善药物的不良性质，降低药物的毒性。目前已经有多种基于前药策略的药物成功上市。
然而，大多数纳米制剂存在载药量低、制备工艺复杂、存在载体相关毒性等缺点，而前药也存在母药释放缓慢等问题，这极大地限制了其临床应用。在此基础上，肿瘤响应性释放的小分子前药自组装纳米药物递送系统能够将前药策略和纳米技术的优点结合到一起，以其无需载体、载药量高、稳定性好、毒副作用低肿瘤部位快速释放母药等优势，已成为近几年化疗药物递送研究的热点。但是现有技术表明，不同结构修饰的多西他赛前药，其对于多西他赛性质的改变不同，其前药在体内的效果也不同。因此，获得最佳的多西他赛前药，使其自组装成纳米粒，从而提高疗效，降低毒性也是医药技术人员正在努力研究的方向。
发明内容
为了克服现有技术的缺陷，本发明提供一种多西他赛脂肪醇小分子前药，所述的前药是将多西他赛与脂肪醇通过还原响应断裂的二硫键连接，在血液循环以及在正常的组织中能够以前药的形式稳定存在，而在肿瘤细胞内异常高还原环境 下快速断裂，从而实现肿瘤细胞内特异性释放母药的特点，发挥强效的抗肿瘤活性。进一步将所合成的前药通过一步纳米沉淀法制备成前药自组装纳米粒。制备工艺及其简单，且所制备的纳米制剂具有载药量高(>50％)、粒径较小且均匀、稳定性良好、能够在还原环境中快速释放母药、且能明显降低多西他赛的毒性，具有极佳的临床转化前景。
本发明通过以下技术方案实现上述目的：
本发明提供一种具有肿瘤还原响应特性的多西他赛-脂肪醇小分子前药：所述多西他赛通过α位的二硫键与脂肪醇桥连，其结构式如下：
Figure PCTCN2021133828-appb-000002
其中，R为C 3-C 30饱和或不饱和链烃基；
进一步地，
Figure PCTCN2021133828-appb-000003
或R为C 3-C 22烯基；所述烯基中含有1-5个烯键；
n＝7-29；
进一步地，当
Figure PCTCN2021133828-appb-000004
时，n＝11-27；
更进一步地，当
Figure PCTCN2021133828-appb-000005
时，n＝11-17；
当R为C 3-C 22烯基时，所述的R包括但不限于丙烯基，烯丙基，2-丁烯基，4-戊烯基，2-己烯基，4-癸烯基，2-十二碳烯基，9,10-十四碳烯基，9-十四碳烯基，9-十六烯基，9-十八烯基,二十碳四烯，二十二碳五烯，亚油基。
作为优选，本发明提供如下结构的多西他赛-硬脂醇小分子前药：
Figure PCTCN2021133828-appb-000006
进一步地，本发明提供所述的多西他赛-脂肪醇小分子前药的合成方法，包括如下步骤：首先将亚二硫基二乙酸成酸酐，然后与脂肪醇成酯得到中间产物。然后中间产物再与多西他赛发生成酯反应，得到终产物。
具体地，包括如下步骤：
(1)将亚二硫基二乙酸溶解于过量乙酸酐中，氮气保护，室温下反应2-4小时，后除去多余的乙酸酐；
(2)将步骤(1)所得产物溶于二氯甲烷中，并加入脂肪醇，加入4-二甲氨基吡啶(DMAP)作为催化剂，室温条件下搅拌12-18小时，反应完毕后采用环己烷-丙酮洗脱体系利用柱层析分离得到中间产物；将中间产物、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBt)和4-二甲氨基吡啶(DMAP)，溶于无水二氯甲烷中，在冰浴下活化2-4小时，然后加入多西他赛，氮气保护，在25-30℃条件下反应48-60小时，所得产物经制备液相分离纯化。
步骤(2)中所述的脂肪醇可以为C 3-C 30饱和或不饱和的脂肪醇，如正十二醇、十三醇、十四醇、1-十五醇、十六醇、十七醇、硬脂醇、1-十九烷醇、1-二十醇、二十一醇、1-二十二醇、二十二醇、二十三醇、二十四醇、二十五醇、1-二十六烷醇、油醇、亚油醇。
反应方程式如下：
Figure PCTCN2021133828-appb-000007
其中，R为C 3-C 30饱和或不饱和链烃基。
本发明还提供了所述的多西他赛-脂肪醇小分子前药的自组装纳米粒，所述的小分子前药自组装纳米粒可以是非PEG化的多西他赛-脂肪醇小分子前药纳米粒、PEG修饰剂修饰的多西他赛-脂肪醇小分子前药纳米粒、包载荧光物质或疏水性药物的小分子前药纳米粒和主动靶向的小分子前药纳米粒；所述的PEG修饰剂为TPGS、PLGA-PEG、PE-PEG、DSPE-PEG-AA或DSPE-PEG 2k，所述的多西他赛-脂肪醇小分子前药与PEG修饰剂的质量比为：90:10～70:30。
本发明还提供了多西他赛-脂肪醇小分子前药自组装纳米粒的制备方法：
将一定量的多西他赛-脂肪醇小分子前药或多西他赛-脂肪醇小分子前药和PEG修饰剂的混合物溶解到适量无水乙醇中，在磁力搅拌器的搅拌下，将该乙醇溶液缓慢滴加到水中，前药可以自发地组装成粒径均匀的纳米粒；也可以采用微流控设备进行超小纳米粒的制备：配制含有多西他赛-脂肪醇小分子前药的乙醇溶液作为有机相；以超纯水作为水相，按照水相和有机相比例混合制备，最终得到多西他赛-脂肪醇小分子前药纳米粒。
(1)非PEG化的纳米粒的制备方法：将一定量的多西他赛-脂肪醇小分子前药溶解到适量无水乙醇中，在磁力搅拌器的搅拌下，将该乙醇溶液缓慢滴加到水中，前药可以自发地组装成粒径均匀的纳米粒，采用减压旋转蒸发法除去制剂中的乙醇，得到不含乙醇的纳米粒。
(2)PEG化的纳米粒的制备方法：将一定量的多西他赛-脂肪醇前药和PEG修饰剂溶解到适量无水乙醇中，在磁力搅拌器的搅拌下，将该乙醇溶液缓慢滴加 到水中，前药可以组装成粒径均匀的PEG修饰的纳米粒，采用减压旋转蒸发法除去制剂中的乙醇，得到不含乙醇的PEG化的多西他赛-脂肪醇小分子前药纳米粒，所述的PEG修饰剂为TPGS、PLGA-PEG、PE-PEG、DSPE-PEG-AA或DSPE-PEG 2k。
本发明制备的多西他赛-脂肪醇小分子前药的自组装纳米粒的粒径在100nm以下。
本发明的有益效果在于：
(1)将多西他赛制备成二硫键连接的硬脂醇前药，并将其制备成纳米粒不仅提高了多西他赛的疗效，同时降低了多西他赛母药的毒性；(2)所述的纳米粒通过一步纳米沉淀法制备，制备工艺极其简单，易于制剂的规模化生产；(3)无需载体材料，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；(4)纳米粒粒径小且均匀，通过PEG修饰能够延长药物在血液中的循环时间，易于通过EPR效应富集于肿瘤部位；(5)采用二硫键桥连，能够在肿瘤细胞内高还原环境中实现特异性快速释放母药。
附图说明
图1为本发明实施例1的多西他赛-硬脂醇前药(DTX-SS-SAL)的质谱图。
图2为本发明实施例1中的多西他赛-硬脂醇前药(DTX-SS-SAL)的 1HNMR谱图。
图3为本发明实施例3的PEG修饰的前药自组装纳米粒的粒径测定图。
图4为本发明实施例3的PEG修饰的前药自组装纳米粒的血药浓度-时间曲线图。
图5为本发明实施例3的PEG修饰的前药自组装纳米粒的在体抗肿瘤实验图。
A：肿瘤生长曲线图；B：肿瘤照片图。
图6为本发明实施例3的PEG修饰的前药纳米粒安全性评价图。
A：体重变化图；B：脾照片图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将发明限制在所述的实施例范围之中。
实施例1：二硫键桥连的多西他赛-硬脂醇前药(DTX-SS-SAL)的合成
Figure PCTCN2021133828-appb-000008
将适量亚二硫基二乙酸(2mmol)加入到50mL茄形瓶中，并用10mL乙酸酐溶解，在氮气保护下室温反应2小时，进行减压蒸馏干燥除去多余的乙酸酐。将所得产物溶于30mL二氯甲烷中，并加入适量硬脂醇(1.5mmol)和DMAP(0.1mmol)，25℃条件下搅拌12小时，用硅胶柱色谱法(环己烷：丙酮3：1)纯化得到中间产物，产率为62％。最后将中间产物(1mmol)、EDCI(1.5mmol)、HOBt(1.5mmol)和DMAP(0.1mmol)溶于50mL无水二氯甲烷中，冰浴1小时，然后加入适量多西他赛(1mmol)，氮气保护的条件下在室温下反应24小时，终产物通过制备液相色谱(流动相为纯乙腈)分离纯化既得，产率为68％，纯度>99％。
采用质谱法以及核磁共振氢谱法来确定实施例1中前药的结构，结果如图1和图2所示。核磁共振选用的溶剂为CDCl 3，波谱解析结果如下：
1H NMR(600MHz,DMSO-d6)δ8.01–7.96(m,0H),7.92(s,0H),7.77–7.71(m,0H),7.67(dt,J＝11.1,5.4Hz,0H),7.50(s,0H),7.45–7.34(m,0H),7.16(q,J＝6.3Hz,0H),5.42–5.37(m,0H),5.19–5.12(m,0H),5.07(d,J＝10.8Hz,0H),5.01(dd,J＝7.5,3.7Hz,0H),4.95–4.87(m,0H),4.11–3.98(m,0H),3.73(d,J＝3.7Hz,0H),3.63(d,J＝6.8Hz,0H),3.33(d,J＝3.6Hz,0H),2.24(d,J＝3.7Hz,0H),1.72–1.63(m,0H),1.58(s,0H),1.51(d,J＝3.7Hz,0H),1.38(d,J＝3.7Hz,0H),1.31(s,1H),1.29(s,0H),1.23(d,J＝3.7Hz,1H),0.97(d,J＝3.7Hz,0H),0.91(s,1H),0.85(dt,J＝10.4,5.3Hz,0H).
实施例2：非PEG化小分子前药自组装纳米粒的制备
精密称取多西他赛-脂肪醇前药8mg,用1mL乙醇将其溶解，搅拌下，将该乙醇溶液缓缓滴加到4ml去离子水中，自发形成均匀的纳米粒DTX-SS-SAL纳米粒。
实施例3：DSPE-PEG 2k修饰的DTX-SS-SAL前药自组装纳米粒的制备
精密称取DSPE-PEG 2k 2mg和DTX-SS-SAL 8mg，用0.5mL乙醇将其溶解，搅拌下，将该乙醇溶液缓缓滴加到4mL去离子水中，自发形成均匀的纳米粒(DTX-SS-SAL纳米粒)。随后通过减压蒸馏除去乙醇，得到不含乙醇的纳米制剂。
通过马尔文粒径仪测定所制备的纳米粒的粒径，结果如图3所示，前药纳米粒的粒径为75nm左右、粒径分布PDI<0.2，纳米粒粒径适中利于血液循环及肿瘤蓄积。
实施例4：
按照实施例3的方法制备不同PEG修饰剂(TPGS、PLGA-PEG、PE-PEG、DSPE-PEG-AA)修饰的DTX-SS-SAL前药自组装纳米粒，制备的纳米粒的粒径均在70～100nm、粒径分布PDI<0.2。
改变前药与DSPE-PEG 2K的比例，结果表明，当DSPE-PEG 2K用量在10％-30％时，即前药与DSPE-PEG 2K的比例为90：10-70：30时，所制备的纳米粒粒径为70～100nm，粒径多分散系数＜0.2。
实施例5：使用微流控设备来制备超小型多西他赛-硬酯醇小分子前药纳米粒：
配制含有DSPE-PEG2000和多西他赛-硬酯醇小分子前药的乙醇溶液作为有机相，其中，多西他赛硬酯醇前药浓度为10mg/ml，DSPE-PEG2000的浓度2mg/ml；以超纯水作为水相，按照水相和有机相流速比为5：1的比例来混合制备，最终得到多西他赛-硬酯醇小分子前药纳米粒。
实施例6：PEG修饰的小分子前药自组装纳米粒的药代动力学研究
将体重为180-220g的SD大鼠，随机分成两组，给药前禁食12h，自由饮水。分别静脉注射多西他赛溶液剂以及实施例3中制备的PEG化的前药自组装纳米粒。多西他赛等效剂量为5mg/kg。分别于0.083、0.25、0.5、1、2、4、8、12h眼眶取血0.5mL，离心分离获得血浆。通过液相色谱-质谱联用仪测定血浆中的药物浓度。
实验结果如图4所示，多西他赛溶液剂组中多西他赛被快速地从血液中清除。相比之下，DTX-SS-SAL前药自组装纳米粒组在则显示出更高的血药浓度，利于药物更多地在肿瘤部位蓄积。
表1 DTX-SS-SAL前药纳米粒和DTX溶液剂的药动学参数
Figure PCTCN2021133828-appb-000009
实施例7：PEG修饰的小分子前药自组装纳米粒的在体抗肿瘤实验
将4T1细胞贴壁细胞消化，使用PBS溶液重悬制备成细胞悬液(5x 10 6cells/100μL)，接种于balb/c小鼠腹侧皮下。待肿瘤体积生长至150mm 3时，将荷瘤小鼠随机分成7组，每组五只,分别给生理盐水、多西他赛溶液剂10mg/kg、多西他赛溶液剂20mg/kg、多西他赛溶液剂30mg/kg和实施例3中制备的PEG化前药纳米粒10mg/kg、前药纳米粒20mg/kg、前药纳米粒30mg/kg(多西他赛等效浓度)。每隔1天给药1次，连续给药5次。给药后，每天观察小鼠的存活状态，称体重，测量肿瘤体积。最后一次给药后一天将小鼠处死，获取器官和肿瘤，进行进一步分析评价。
实验结果如图5所示，与生理盐水相比，多西他赛溶液剂和前药纳米粒组均显示出强效的抗肿瘤活性。前药自组装纳米粒中剂量组(20mg/kg)和高剂量组(30mg/kg)显示出比多西他赛溶液剂更强的抗肿瘤活性，肿瘤体积几乎没有增长。此外，前药纳米粒组对于多西他赛的减毒效果也非常明显，多西他赛溶液剂组由于毒性较大，中剂量(20mg/kg)和高剂量组(30mg/kg)在给药后分别于第6天、第4天全部死亡。而前药纳米粒组低中高三组在5次给药结束后仍然存活很好。在体重变化方面，如图6所示，多西他赛溶液剂低剂量组体重降低明显，而前药纳米粒高剂量组体重下降的程度与多西他赛溶液剂低剂量组相当。此外，通过小鼠的脾脏判断，前药纳米粒高剂量组显示出与多西他赛溶液剂低剂量组相当的毒性。以上结果表明，本发明所制备的前药纳米粒能够大大减轻多西他赛的 毒性，从而能够提高给药剂量，大大提高抗肿瘤效果。

Claims (10)

  1. 具有如下结构的多西他赛-脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
    Figure PCTCN2021133828-appb-100001
    R为C 3-C 30饱和或不饱和链烃基；
    优选
    Figure PCTCN2021133828-appb-100002
    或R为C 3-C 22烯基；所述烯基中含有1-5个烯键；
    n＝7-29。
  2. 权利要求1所述的多西他赛脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
    其中，
    Figure PCTCN2021133828-appb-100003
    且n＝11-27，优选n＝11-17；或R为丙烯基，烯丙基，2-丁烯基，4-戊烯基，2-己烯基，4-癸烯基，2-十二碳烯基，9-十四碳烯基，9-十六烯基，9-十八烯基,二十碳四烯，二十二碳五烯，亚油基。
  3. 权利要求1或2所述的多西他赛脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
    Figure PCTCN2021133828-appb-100004
    p优选为1。
  4. 如权利要求1所述的多西他赛-脂肪醇小分子前药的合成方法，其特征在于，首先将亚二硫基二乙酸成酸酐，然后与脂肪醇成酯得到中间产物；然后中间产物再与多西他赛发生成酯反应，得到多西他赛-脂肪醇小分子前药；
    Figure PCTCN2021133828-appb-100005
  5. 权利要求1-3任何一项所述的多西他赛-脂肪醇小分子前药的自组装纳米粒，其特征在于，所述的自组装纳米粒为非PEG化的多西他赛-脂肪醇前药纳米粒、PEG修饰剂修饰的多西他赛-脂肪醇前药前药纳米粒，所述的PEG修饰剂优选为TPGS、DSPE-PEG、PLGA-PEG、PE-PEG或DSPE-PEG-AA，多西他赛-脂肪醇小分子前药与PEG修饰剂的重量比为90：10～70：30。
  6. 如权利要求5所述的多西他赛-脂肪醇小分子前药的自组装纳米粒的制备方法，其特征在于，其制备过程如下：
    将多西他赛-脂肪醇前药或多西他赛-脂肪醇小分子前药与PEG修饰剂的混合物溶解到乙醇中，搅拌下，将该乙醇溶液缓缓滴加到水中，前药自发形成均匀的纳米粒，最后，采用减压旋蒸除去制剂中的乙醇，即得；
    或以含有PEG修饰剂和多西他赛-脂肪醇小分子前药的乙醇溶液作为有机相，以超纯水作为水相，采用微流控设备制备。
  7. 权利要求1-3任何一项所述的多西他赛-脂肪醇小分子前药或权利要求5所述的多西他赛-脂肪醇小分子前药自组装纳米粒在制备药物传递系统中的应用。
  8. 权利要求1-3任何一项所述的多西他赛-脂肪醇小分子前药或权利要求5所述的多西他赛-脂肪醇小分子前药自组装纳米粒在制备抗肿瘤药物中的应用。
  9. 权利要求1-3任何一项所述的多西他赛-脂肪醇小分子前药或权利要求5所述的多西他赛-脂肪醇小分子前药自组装纳米粒在制备提高疗效、降低毒性药物中的应用。
  10. 权利要求1-3任何一项所述的多西他赛-脂肪醇小分子前药或权利要求5所述的多西他赛-脂肪醇前药自组装纳米粒在制备注射给药、口服给药或局部给药系统中的应用。
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