WO2022227554A1 - Larotaxel-fatty alcohol small molecule prodrug and construction of self-assembling nanoparticle thereof - Google Patents

Larotaxel-fatty alcohol small molecule prodrug and construction of self-assembling nanoparticle thereof Download PDF

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WO2022227554A1
WO2022227554A1 PCT/CN2021/133825 CN2021133825W WO2022227554A1 WO 2022227554 A1 WO2022227554 A1 WO 2022227554A1 CN 2021133825 W CN2021133825 W CN 2021133825W WO 2022227554 A1 WO2022227554 A1 WO 2022227554A1
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fatty alcohol
prodrug
small molecule
larottaxel
peg
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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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    • A—HUMAN NECESSITIES
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • 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
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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, and relates to the synthesis of larottaxel-fatty alcohol small molecule prodrugs with tumor reduction response characteristics and the construction of self-assembled nanoparticles, and their application in the preparation of drug delivery systems .
  • Larotaxel (Larotaxel, XRP9881, PRP109881) is a novel taxane cell cycle-specific chemotherapeutic drug developed by Sanofi-Aventis and obtained by a semi-synthetic method, with a broad tumor-inhibiting spectrum. Up to now, the drug has no definite curative preparations on the market at home and abroad. Similar to other taxanes, lalotaxel acts on spindle tubulin during cell division, binds to free tubulin, promotes the assembly of tubulin into stable microtubules and inhibits microtubule depolymerization , thereby inhibiting the mitosis of cancer cells.
  • larottaxel can effectively kill drug-resistant cells, and can also pass through the blood-brain barrier, which has a good anti-tumor application prospect.
  • In vitro studies have shown that the antitumor activity of larottaxel is stronger than that of paclitaxel, and it has strong inhibitory and killing effects on multidrug-resistant tumor cells.
  • Existing clinical research results show that after dissolving larottaxel with Tween, larottaxel as a second-line treatment or rescue therapy drug is more effective than docetaxel and doxorubicin in the treatment of metastatic breast cancer.
  • larottaxel has good antitumor effect and clinical treatment prospect, like other taxanes, larottaxel also has the disadvantage of poor water solubility.
  • larottaxel preparations used in clinical trials abroad are generally added with surface polysorbate for solubilization.
  • the injection used by Sanodi-Avents in its Phase II clinical trial uses polysorbate (Tween-80) as a solubilizer.
  • Teween-80 polysorbate
  • the solubilizer solves the problem of the insolubility of lalotaxel to a certain extent, the introduction of the solubilizer often causes severe allergic reactions in patients, coupled with the toxicity of anticancer drugs themselves, simple anticancer drug solutions The drug can cause further damage to the already debilitated body of a cancer patient. Therefore, how to design a high-efficiency and low-toxicity larottaxel preparation is still the key to its good clinical anti-tumor effect.
  • the technical problem to be solved by the present invention is to overcome the defect of low solubility of lalotaxel, and to better exert the anti-tumor effect of lalotaxel, thereby achieving the purpose of enhancing efficacy and reducing toxicity.
  • larottaxel-fatty alcohol prodrug provided by the present invention, larottaxel and fatty alcohol are connected together by chemically sensitive linking arms, and these chemically sensitive bonds can be rapidly broken in tumor cells and tumor microenvironment to release the drug.
  • the larottaxel-fatty alcohol prodrug has tumor reduction response properties.
  • this larottaxel-fatty alcohol prodrug can self-assemble into ultra-small particle size (60-100 nm) nanoparticles in water.
  • the prodrug nanoparticle system since the prodrug itself serves as both the carrier material and the encapsulated drug, the drug loading capacity is very high, exceeding 50%.
  • the present invention realizes above-mentioned purpose through following technical scheme:
  • the present invention provides larottaxel-fatty alcohol small molecule prodrugs with tumor reduction responsive properties or pharmaceutically acceptable salts, isomers, solvates thereof:
  • 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 1-3;
  • 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-tetradecenyl, 9-hexadecenyl, 9-octadecenyl, eicosatetraene, docosapentaene, linoleyl.
  • the present invention preferably has the following structures of larottaxel-fatty alcohol small molecule prodrugs or pharmaceutically acceptable salts, isomers and solvates thereof:
  • n 1-3.
  • the invention provides a synthetic method of larottaxel-fatty alcohol prodrug, comprising the following steps:
  • 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 larottaxel, 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, tetradecanol, pentadecanol, hexadecanol, heptadecanol, stearyl alcohol, 1-Nadecanol, 1-eicosanol, 1-docosanol, 1-docosanol, oleyl alcohol, linoleyl alcohol or linolenic alcohol, etc.
  • the present invention provides the nanoparticle of the larottaxel-fatty alcohol small molecule prodrug
  • the larottaxel-fatty alcohol prodrug nanoparticle can be non-PEGylated larottaxel- Fatty alcohol prodrug nanoparticles, PEG modifier-modified larottaxel-fatty alcohol small molecule prodrug nanoparticles, drug-encapsulated larottaxel-fatty alcohol small molecule prodrug nanoparticles, and actively targeted lalotaxel Thaxa-Fatty Alcohol Small Molecule Prodrug Nanoparticles.
  • the larottaxel-fatty alcohol prodrug nanoparticles are prepared by the following method:
  • Preparation method of non-PEGylated small-molecule prodrug self-assembled nanoparticles dissolve a certain amount of prodrug into an appropriate amount of ethanol, slowly add the ethanol solution dropwise to water under stirring, and the prodrug spontaneously forms Uniform nanoparticles; microfluidic equipment can also be used for the preparation of ultra-small nanoparticles: prepare an ethanol solution containing larottaxel-fatty alcohol prodrug as the organic phase, ultrapure water as the aqueous phase, according to the aqueous phase and The organic phase ratio is mixed and prepared, and finally the nanoparticle of lalotaxel stearyl alcohol prodrug is obtained.
  • Preparation method of PEG-modified small-molecule prodrug self-assembled nanoparticles Dissolve a certain amount of PEG modifier and prodrug in an appropriate amount of ethanol, slowly add the ethanol solution to water with stirring, and add the prodrug into water.
  • Spontaneous formation of uniform nanoparticles; ultra-small nanoparticles can also be prepared using a microfluidic device: prepare an ethanolic solution containing a PEG modifier and a larotaxel-fatty alcohol prodrug as the organic phase, and ultrapure water as the water phase, according to the proportion of the aqueous phase and the organic phase to mix and prepare, and finally obtain larottaxel stearyl alcohol prodrug nanoparticles.
  • Described PEG modifier is selected from including but not limited to DSPE-PEG, TPGS, PLGA-PEG, PE-PEG or DSPE-PEG-AA, may preferably be DSPE-PEG 2k , DSPE-PEG 5k , TPGS 2K , prodrugs.
  • the mass ratio with the PEG modifier is 90:10 to 70:30.
  • the preparation method of active targeting small molecule prodrug self-assembled nanoparticles a certain amount of PEG modifier, hydrophobic target modified PEG and prodrug are dissolved in an appropriate amount of ethanol, and the ethanol solution is stirred under stirring. Slowly added dropwise to water, the prodrug spontaneously forms uniform nanoparticles; the PEG modifier is selected from DSPE-PEG 2k , DSPE-PEG 5k , TPGS 2K , and the target-modified PEG includes but is not limited to cRGD -PEG-PLL, DSPE-PEG 2K -Pep-1, DSPE-PEG-CREKA.
  • the larottaxel-fatty alcohol small molecule prodrugs described in the present invention were found for the first time to self-assemble to form uniform nanosystems.
  • the advantages of this nano-drug delivery system are:
  • a series of new larottaxel-fatty alcohol small molecule prodrugs are provided, which can self-assemble into nanoparticles;
  • nanoparticles formed by the self-assembly of larottaxel-fatty alcohol small molecule prodrugs are ultra-small (about 60-100 nm) and uniform in size, which is conducive to the enrichment of nanoparticles in tumor sites through the EPR effect, thereby improving the antitumor effect;
  • the sensitivity of the prodrug to the intracellular environment of the tumor site is increased by reducing the sensitive chemical linker, so as to realize the specific drug release of larottaxel in the tumor cells and the tumor microenvironment, improve the curative effect and reduce the toxic and side effects.
  • FIG. 1 is the 1 HMR spectrum of the disulfide-linked laroxetazol-stearyl alcohol prodrug (LTX-SS-SA) of Example 1 of the present invention.
  • FIG. 2 is a mass spectrum of the disulfide-linked larrotaxel-stearyl alcohol prodrug (LTX-SS-SA) of Example 1 of the present invention.
  • Example 3 is a particle size-storage time diagram of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • FIG. 4 is a blood concentration-time curve diagram of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • FIG. 5 is a graph showing the change of tumor volume in the anti-tumor experiment of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • FIG. 6 is a graph showing the body weight change of mice in the in vivo anti-tumor experiment of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
  • Example 1 Synthesis of Tumor Reduction Sensitive Disulfide Linked Lalotaxel-Stearyl Alcohol Prodrug (LTX-SS-SA)
  • n 1.
  • the intermediate product 5mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 5mmol of 1-hydroxybenzotriazole (HOBt) and 1mmol of 4-dimethylaminopyridine ( DMAP) was dissolved in 50 mL of anhydrous dichloromethane, ice bathed for 1 hour, then an appropriate amount of lalotaxel was added, and the reaction was carried out at room temperature for 24 hours under nitrogen protection.
  • the final product was prepared by liquid phase, using acetonitrile-water (90 -99:1) Separation and purification of the elution system to obtain the final product with a purity of >99.5%.
  • the structure of the prodrug in Example 1 was determined by nuclear magnetic resonance measurement of 1 H-NMR hydrogen spectrum and liquid chromatography-mass spectrometry. The results are shown in FIG. 1 and FIG. 2 .
  • Example 2 Preparation of non-PEGylated larottaxel-stearyl alcohol prodrug small molecule prodrug self-assembled nanoparticles
  • the DSPE-PEG 2K can also be replaced by amphiphilic polymers or targeting groups such as TPGS, PLGA-PEG, PE-PEG or DSPE-PEG-AA.
  • Example 4 Using microfluidic equipment to prepare ultra-small larotaxet stearyl alcohol small molecule prodrug nanoparticles:
  • Example 3 Twelve healthy, male rats, weighing 200-250 g, were randomly divided into 2 groups, fasting for 12 hours before administration, and drinking water freely.
  • the larottaxel solution and the PEGylated small molecule prodrug self-assembled nanoparticles (80 nm in particle size) prepared in Example 3 were injected intravenously, respectively.
  • Lalotaxel was dosed at 4 mg/kg.
  • Orbital blood was collected at specified time points 0.083h, 0.25h, 0.50h, 1.00h, 2.00h, 4.00h, 8.00h, 12.00h, 24.00h and 48.00h, and plasma was obtained by separation. Drug concentrations in plasma were determined by liquid chromatography-mass spectrometry.
  • Example 6 In vivo antitumor experiments of PEG-modified small molecule prodrug self-assembled nanoparticles
  • a suspension of mouse breast cancer cells (4T1, 5x10 6 cells/100ul) was inoculated subcutaneously on the ventral side of female BALB/c mice.
  • the tumor-bearing mice were randomly divided into five groups, five in each group: blank control group (PBS), larottaxel solution group (8mg/kg), LTX-SS- SA nanoparticles low dose group (4mg/kg), LTX-SS-SA nanoparticles medium dose group (8mg/kg) and LTX-SS-SA nanoparticles high dose group (12mg/kg).
  • the nanoparticles used for administration were the PEG-modified small-molecule prodrug self-assembled nanoparticles prepared in Example 3. Administer once every 1d, 5 times in a row. The survival status of the mice was observed every day after administration, the body weight was weighed, and the tumor volume was measured. Data pooling and analysis were performed after mice were sacrificed one day after the last dose.
  • the tumor volume of the blank control group increased rapidly and reached 600-700 mm 3 on the 10th day.
  • the larottaxel solution group Free-LTX
  • the nanoparticle formulation group could significantly inhibit tumor growth, and the tumor volume in the high-dose formulation group was only 130 mm 3 . This reflects the good antitumor effect of our designed larottaxel-stearyl alcohol nanoparticles.

Abstract

The synthesis of a larotaxel-fatty alcohol small molecule prodrug with a tumor reduction response characteristic and the construction of a self-assembling nanoparticle, and the use thereof in the preparation of a drug delivery system. Provided is a larotaxel-stearyl alcohol small molecule prodrug, which is prepared into a larotaxel-fatty alcohol prodrug nanoparticle. The larotaxel-fatty alcohol prodrug nanoparticle can be a non-PEGylated larotaxel-fatty alcohol prodrug nanoparticle, a PEG-modified larotaxel-fatty alcohol prodrug nanoparticle, a drug-loaded larotaxel-fatty alcohol prodrug nanoparticle, and an active targeting larotaxel-fatty alcohol prodrug nanoparticle. The larotaxel-fatty alcohol prodrug has few synthetic steps, a simple process, reduced synthesis costs, a high yield and easy purification, and the nanoparticle formed by the self-assembly of the larotaxel-fatty alcohol small molecule prodrug has an ultra-small particle size, which reduces the toxicity and side effects while improving the curative effect of larotaxel.

Description

拉洛他赛-脂肪醇小分子前药及其自组装纳米粒的构建Larottaxel-Fatty Alcohol Small Molecule Prodrug and Construction of Self-Assembled Nanoparticles 技术领域technical field
本发明属于药物制剂新辅料和新剂型领域，涉及具有肿瘤还原响应特性的拉洛他赛-脂肪醇小分子前药的合成以及自组装纳米粒的构建，以及其在制备药物传递系统中的应用。The invention belongs to the field of new excipients and new dosage forms for pharmaceutical preparations, and relates to the synthesis of larottaxel-fatty alcohol small molecule prodrugs with tumor reduction response characteristics and the construction of self-assembled nanoparticles, and their application in the preparation of drug delivery systems .
背景技术Background technique
拉洛他赛(Larotaxel，XRP9881，PRP109881)是由Sanofi-Aventis公司开发的通过半合成方法得到的一种新型紫杉烷类细胞周期特异性化疗药，具有较广的抑瘤谱。截至目前为止，该药在国内外均无疗效确切的制剂上市。拉洛他赛疗效与其他紫杉烷类化合物类似，作用于细胞分裂过程中的纺锤体微管蛋白，与游离的微管蛋白结合，促进微管蛋白装配成稳定微管并抑制微管解聚，从而抑制癌细胞的有丝分裂。与其他紫杉烷类化合物不同的是，拉洛他赛能够有效杀伤耐药细胞，还能够通过血脑屏障，具有良好的抗肿瘤应用前景。体外研究表明，拉洛他赛的抗肿瘤活性强于紫杉醇，对于多药耐药肿瘤细胞具有较强的抑制和杀伤作用。现有的临床研究结果表明，将拉洛他赛用吐温溶解后，拉洛他赛作为二线治疗或补救治疗药物，治疗转移性乳腺癌的疗效优于多西他赛和多柔比星。Larotaxel (Larotaxel, XRP9881, PRP109881) is a novel taxane cell cycle-specific chemotherapeutic drug developed by Sanofi-Aventis and obtained by a semi-synthetic method, with a broad tumor-inhibiting spectrum. Up to now, the drug has no definite curative preparations on the market at home and abroad. Similar to other taxanes, lalotaxel acts on spindle tubulin during cell division, binds to free tubulin, promotes the assembly of tubulin into stable microtubules and inhibits microtubule depolymerization , thereby inhibiting the mitosis of cancer cells. Different from other taxane compounds, larottaxel can effectively kill drug-resistant cells, and can also pass through the blood-brain barrier, which has a good anti-tumor application prospect. In vitro studies have shown that the antitumor activity of larottaxel is stronger than that of paclitaxel, and it has strong inhibitory and killing effects on multidrug-resistant tumor cells. Existing clinical research results show that after dissolving larottaxel with Tween, larottaxel as a second-line treatment or rescue therapy drug is more effective than docetaxel and doxorubicin in the treatment of metastatic breast cancer.
尽管拉洛他赛具有良好的抗肿瘤效果和临床治疗前景，但与其他紫杉烷类化合物一样，拉洛他赛同样具有水溶性很差的缺陷。而国外用于临床试验的拉洛他赛制剂为了克服这一缺陷，一般加入表面聚山梨酯对其进行增溶处理。例如Sanodi-Avents公司在其二期临床试验中应用的注射剂便采用了聚山梨酯(吐温-80)作为增溶剂。尽管增溶剂在一定程度上解决了拉洛他赛难溶性的问题，但是增溶剂的引用往往会引起患者产生严重的过敏反应，再加上抗癌药本身具有的毒性，简单的抗癌药物溶液剂会对癌症患者本就虚弱的身体造成进一步的伤害。因此，如何设计出高效低毒的拉洛他赛制剂仍然是其能够在临床发挥良好抗肿瘤效果的关键。Although larottaxel has good antitumor effect and clinical treatment prospect, like other taxanes, larottaxel also has the disadvantage of poor water solubility. In order to overcome this defect, larottaxel preparations used in clinical trials abroad are generally added with surface polysorbate for solubilization. For example, the injection used by Sanodi-Avents in its Phase II clinical trial uses polysorbate (Tween-80) as a solubilizer. Although the solubilizer solves the problem of the insolubility of lalotaxel to a certain extent, the introduction of the solubilizer often causes severe allergic reactions in patients, coupled with the toxicity of anticancer drugs themselves, simple anticancer drug solutions The drug can cause further damage to the already debilitated body of a cancer patient. Therefore, how to design a high-efficiency and low-toxicity larottaxel preparation is still the key to its good clinical anti-tumor effect.
发明内容SUMMARY OF THE INVENTION
针对以上技术背景，本发明所解决的技术问题是克服拉洛他赛低溶解性的缺陷，更好地发挥拉洛他赛抗肿瘤效果，从而达到增效减毒的目的。本发明提供的拉洛他赛-脂肪醇前药，拉洛他赛和脂肪醇是通过化学敏感连接臂连接在一起，这些化学敏感键能够在肿瘤细胞以及肿瘤微环境中快速断裂，释放药物。所述的拉洛他赛-脂肪醇前药具有肿瘤还原响应特性。与此同时，这种拉洛他赛-脂肪醇前药能够在水中自组装成为超小粒径(60-100nm)的纳米粒。这种前药纳米粒系统，由于前药自身即作为载体材料又作为被包载药物，其载药量非常高，超过了50％。In view of the above technical background, the technical problem to be solved by the present invention is to overcome the defect of low solubility of lalotaxel, and to better exert the anti-tumor effect of lalotaxel, thereby achieving the purpose of enhancing efficacy and reducing toxicity. In the larottaxel-fatty alcohol prodrug provided by the present invention, larottaxel and fatty alcohol are connected together by chemically sensitive linking arms, and these chemically sensitive bonds can be rapidly broken in tumor cells and tumor microenvironment to release the drug. The larottaxel-fatty alcohol prodrug has tumor reduction response properties. At the same time, this larottaxel-fatty alcohol prodrug can self-assemble into ultra-small particle size (60-100 nm) nanoparticles in water. In this prodrug nanoparticle system, since the prodrug itself serves as both the carrier material and the encapsulated drug, the drug loading capacity is very high, exceeding 50%.
本发明通过以下技术方案实现上述目的：The present invention realizes above-mentioned purpose through following technical scheme:
本发明提供具有肿瘤还原响应特性的拉洛他赛-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：The present invention provides larottaxel-fatty alcohol small molecule prodrugs with tumor reduction responsive properties or pharmaceutically acceptable salts, isomers, solvates thereof:
Figure PCTCN2021133825-appb-000001
Figure PCTCN2021133825-appb-000001
其中，R为C 3-C 30饱和或不饱和链烃基； Wherein, R is C 3 -C 30 saturated or unsaturated chain hydrocarbon group;
进一步地，further,
Figure PCTCN2021133825-appb-000002
或R为C 3-C 22烯基；所述烯基中含有1-5个烯键；
Figure PCTCN2021133825-appb-000002
Or R is a C 3 -C 22 alkenyl group; the alkenyl group contains 1-5 ethylenic bonds;
p＝7-29；p=7-29;
n＝1-3；n=1-3;
进一步地，当
Figure PCTCN2021133825-appb-000003
时，p＝11-27； Further, when
Figure PCTCN2021133825-appb-000003
, p=11-27;
更进一步地，当
Figure PCTCN2021133825-appb-000004
时，p＝11-17； Further, when
Figure PCTCN2021133825-appb-000004
, p=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，9-十四碳烯基，9-十六烯基，9-十八烯基,二十碳四烯，二十二碳五烯,亚油基。 When 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-tetradecenyl, 9-hexadecenyl, 9-octadecenyl, eicosatetraene, docosapentaene, linoleyl.
进一步地，本发明优选如下结构的拉洛他赛-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：Further, the present invention preferably has the following structures of larottaxel-fatty alcohol small molecule prodrugs or pharmaceutically acceptable salts, isomers and solvates thereof:
Figure PCTCN2021133825-appb-000005
n＝1-3。
Figure PCTCN2021133825-appb-000005
n=1-3.
本发明提供了拉洛他赛-脂肪醇前药的合成方法，包括如下步骤：The invention provides a synthetic method of larottaxel-fatty alcohol prodrug, comprising the following steps:
(1)将亚二硫基二乙酸溶解于乙酸酐中，氮气保护，室温下反应2-4小时，后除去多余的乙酸酐；(1) dissolving dithiodiacetic acid in acetic anhydride, under nitrogen protection, react at room temperature for 2-4 hours, and then remove excess acetic anhydride;
(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，然后加入拉洛他赛，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。(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 larottaxel, nitrogen protection, at 25-30 The reaction is carried out under the condition of ℃ for 48-60 hours, and the obtained product is purified by preparative liquid phase separation.
其反应式如下：Its reaction formula is as follows:
Figure PCTCN2021133825-appb-000006
Figure PCTCN2021133825-appb-000006
R为C 3-C 30饱和或不饱和链烃基；n＝1-3。 R is a C 3 -C 30 saturated or unsaturated chain hydrocarbon group; n=1-3.
步骤(2)中所述的脂肪醇可以为C 3-C 30饱和或不饱和脂肪醇，如正十二醇、十四醇、十 五醇、十六醇、十七醇、硬脂醇、1-十九醇、1-二十醇、1-二十二醇、1-二十六烷醇、油醇、亚油醇或亚麻醇等。 The fatty alcohol described in step (2) can be C 3 -C 30 saturated or unsaturated fatty alcohol, such as n-dodecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, stearyl alcohol, 1-Nadecanol, 1-eicosanol, 1-docosanol, 1-docosanol, oleyl alcohol, linoleyl alcohol or linolenic alcohol, etc.
进一步地，本发明提供了所述的拉洛他赛-脂肪醇小分子前药的纳米粒，所述的拉洛他赛-脂肪醇前药纳米粒可以为非PEG化的拉洛他赛-脂肪醇前药纳米粒、PEG修饰剂修饰的拉洛他赛-脂肪醇小分子前药纳米粒、包载药物的拉洛他赛-脂肪醇小分子前药纳米粒和主动靶向的拉洛他赛-脂肪醇小分子前药纳米粒。Further, the present invention provides the nanoparticle of the larottaxel-fatty alcohol small molecule prodrug, and the larottaxel-fatty alcohol prodrug nanoparticle can be non-PEGylated larottaxel- Fatty alcohol prodrug nanoparticles, PEG modifier-modified larottaxel-fatty alcohol small molecule prodrug nanoparticles, drug-encapsulated larottaxel-fatty alcohol small molecule prodrug nanoparticles, and actively targeted lalotaxel Thaxa-Fatty Alcohol Small Molecule Prodrug Nanoparticles.
所述的拉洛他赛-脂肪醇前药纳米粒通过如下方法制备：The larottaxel-fatty alcohol prodrug nanoparticles are prepared by the following method:
(1)非PEG化的小分子前药自组装纳米粒的制备方法：将一定量的前药溶解到适量的乙醇中，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；也可以采用微流控设备进行超小纳米粒的制备：配制含有拉洛他赛-脂肪醇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，最终得到拉洛他赛硬酯醇前药纳米粒。(1) Preparation method of non-PEGylated small-molecule prodrug self-assembled nanoparticles: dissolve a certain amount of prodrug into an appropriate amount of ethanol, slowly add the ethanol solution dropwise to water under stirring, and the prodrug spontaneously forms Uniform nanoparticles; microfluidic equipment can also be used for the preparation of ultra-small nanoparticles: prepare an ethanol solution containing larottaxel-fatty alcohol prodrug as the organic phase, ultrapure water as the aqueous phase, according to the aqueous phase and The organic phase ratio is mixed and prepared, and finally the nanoparticle of lalotaxel stearyl alcohol prodrug is obtained.
(2)PEG修饰的小分子前药自组装纳米粒的制备方法：将一定量的PEG修饰剂和前药溶解到适量乙醇中，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；也可以使用微流控设备进行超小纳米粒的制备：配制含有PEG修饰剂和拉洛他赛-脂肪醇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，最终得到拉洛他赛硬酯醇前药纳米粒。(2) Preparation method of PEG-modified small-molecule prodrug self-assembled nanoparticles: Dissolve a certain amount of PEG modifier and prodrug in an appropriate amount of ethanol, slowly add the ethanol solution to water with stirring, and add the prodrug into water. Spontaneous formation of uniform nanoparticles; ultra-small nanoparticles can also be prepared using a microfluidic device: prepare an ethanolic solution containing a PEG modifier and a larotaxel-fatty alcohol prodrug as the organic phase, and ultrapure water as the water phase, according to the proportion of the aqueous phase and the organic phase to mix and prepare, and finally obtain larottaxel stearyl alcohol prodrug nanoparticles.
所述的PEG修饰剂选自包括但不限于DSPE-PEG、TPGS、PLGA-PEG、PE-PEG或DSPE-PEG-AA，可以优选为DSPE-PEG 2k、DSPE-PEG 5k、TPGS 2K，前药与PEG修饰剂的质量比为90:10～70:30。 Described PEG modifier is selected from including but not limited to DSPE-PEG, TPGS, PLGA-PEG, PE-PEG or DSPE-PEG-AA, may preferably be DSPE-PEG 2k , DSPE-PEG 5k , TPGS 2K , prodrugs. The mass ratio with the PEG modifier is 90:10 to 70:30.
(3)包载疏水药物的小分子前药自组装纳米粒的制备方法：将一定量的PEG修饰剂、疏水性药物以及前药溶解到适量的乙醇中，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；所述的PEG修饰剂选自DSPE-PEG 2k、DSPE-PEG 5k、TPGS 2K，所述的疏水性药物包括但不限于前已述及的拉洛他赛及其他紫杉烷类药物-脂肪醇前药。 (3) Preparation method of small molecule prodrug self-assembled nanoparticles encapsulating hydrophobic drug: Dissolving a certain amount of PEG modifier, hydrophobic drug and prodrug into an appropriate amount of ethanol, stirring the ethanol solution slowly When added dropwise to water, the prodrug spontaneously forms uniform nanoparticles; the PEG modifier is selected from DSPE-PEG 2k , DSPE-PEG 5k , TPGS 2K , and the hydrophobic drugs include but are not limited to the aforementioned Lalotaxel and other taxane-fatty alcohol prodrugs.
(4)主动靶向的小分子前药自组装纳米粒的制备方法：将一定量的PEG修饰剂、疏水靶头修饰的PEG以及前药溶解到适量的乙醇中，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；所述的PEG修饰剂选自DSPE-PEG 2k、DSPE-PEG 5k、TPGS 2K，所述的靶头修饰的PEG包括但不限于cRGD-PEG-PLL、DSPE-PEG 2K-Pep-1、DSPE-PEG-CREKA。 (4) The preparation method of active targeting small molecule prodrug self-assembled nanoparticles: a certain amount of PEG modifier, hydrophobic target modified PEG and prodrug are dissolved in an appropriate amount of ethanol, and the ethanol solution is stirred under stirring. Slowly added dropwise to water, the prodrug spontaneously forms uniform nanoparticles; the PEG modifier is selected from DSPE-PEG 2k , DSPE-PEG 5k , TPGS 2K , and the target-modified PEG includes but is not limited to cRGD -PEG-PLL, DSPE-PEG 2K -Pep-1, DSPE-PEG-CREKA.
本发明中所述的拉洛他赛-脂肪醇小分子前药首次被发现可以自组装形成均匀的纳米体系。该纳米药物传递系统的优势在于：The larottaxel-fatty alcohol small molecule prodrugs described in the present invention were found for the first time to self-assemble to form uniform nanosystems. The advantages of this nano-drug delivery system are:
(1)提供了一系列新的拉洛他赛-脂肪醇小分子前药，该前药可以自组装成纳米粒；(1) A series of new larottaxel-fatty alcohol small molecule prodrugs are provided, which can self-assemble into nanoparticles;
(2)拉洛他赛-脂肪醇前药的合成步骤少，仅需两步即可合成带有氧化还原键的拉洛他赛-脂肪醇前药，工艺简单，降低了合成成本，产率高，易于纯化，纯化后纯度高达99.5％，具有很强的工艺放大优势；(2) There are few synthesis steps of larottaxel-fatty alcohol prodrug, only two steps are needed to synthesize larottaxel-fatty alcohol prodrug with redox bond, the process is simple, the synthesis cost is reduced, and the yield is High, easy to purify, the purity after purification is as high as 99.5%, and it has strong process amplification advantages;
(2)拉洛他赛-脂肪醇小分子前药自组装形成的纳米粒粒径超小(60-100nm左右)且粒径均一，有利于纳米粒通过EPR效应富集于肿瘤部位，从而提高抗肿瘤效果；(2) The nanoparticles formed by the self-assembly of larottaxel-fatty alcohol small molecule prodrugs are ultra-small (about 60-100 nm) and uniform in size, which is conducive to the enrichment of nanoparticles in tumor sites through the EPR effect, thereby improving the antitumor effect;
(3)超高的载药量，稳定性好，有利于减小因辅料和生物材料而引发的不良反应；(3) Ultra-high drug loading and good stability are beneficial to reduce adverse reactions caused by excipients and biological materials;
(4)易于表面修饰，可通过PEG和主动靶向修饰以有效避免网状内皮系统摄取和提高肿瘤细胞对纳米粒的摄取，有效延长拉洛他赛在血液中的循环时间；(4) It is easy to modify the surface, and it can effectively avoid the uptake of the reticuloendothelial system and improve the uptake of the nanoparticles by the tumor cells through PEG and active targeted modification, and effectively prolong the circulation time of raloxitaxel in the blood;
(5)通过还原敏感化学连接臂增加前药对于肿瘤部位细胞内环境的敏感性，实现拉洛他赛在肿瘤细胞以及肿瘤微环境中的特异性释药，提高疗效的同时降低毒副作用。(5) The sensitivity of the prodrug to the intracellular environment of the tumor site is increased by reducing the sensitive chemical linker, so as to realize the specific drug release of larottaxel in the tumor cells and the tumor microenvironment, improve the curative effect and reduce the toxic and side effects.
附图说明Description of drawings
图1为本发明实施例1的二硫键相连的拉洛他赛-硬酯醇前药(LTX-SS-SA)的 1HMR谱图。 FIG. 1 is the 1 HMR spectrum of the disulfide-linked laroxetazol-stearyl alcohol prodrug (LTX-SS-SA) of Example 1 of the present invention.
图2为本发明实施例1的二硫键相连的拉洛他赛-硬酯醇前药(LTX-SS-SA)的质谱图。FIG. 2 is a mass spectrum of the disulfide-linked larrotaxel-stearyl alcohol prodrug (LTX-SS-SA) of Example 1 of the present invention.
图3为本发明实施例3的PEG化小分子前药自组装纳米粒的粒径-存储时间图。3 is a particle size-storage time diagram of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
图4为本发明实施例3的PEG化小分子前药自组装纳米粒的血药浓度-时间曲线图。FIG. 4 is a blood concentration-time curve diagram of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
图5为本发明实施例3的PEG化小分子前药自组装纳米粒在抗肿瘤实验中肿瘤体积变化图。FIG. 5 is a graph showing the change of tumor volume in the anti-tumor experiment of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
图6为本发明实施例3的PEG化小分子前药自组装纳米粒的体内抗肿瘤实验小鼠体重变化图。FIG. 6 is a graph showing the body weight change of mice in the in vivo anti-tumor experiment of the PEGylated small molecule prodrug self-assembled nanoparticles of Example 3 of the present invention.
具体实施方式Detailed ways
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。The present invention is further described below by way of examples, but the invention is not limited to the scope of the described examples.
实施例1：肿瘤还原敏感的二硫键相连的拉洛他赛-硬脂醇前药(LTX-SS-SA)的合成Example 1: Synthesis of Tumor Reduction Sensitive Disulfide Linked Lalotaxel-Stearyl Alcohol Prodrug (LTX-SS-SA)
Figure PCTCN2021133825-appb-000007
n＝1。
Figure PCTCN2021133825-appb-000007
n=1.
将5mmol亚二硫基二乙酸加入到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5mmol硬脂醇和2mmolDMAP，25℃条件下搅拌12小时，采用环己烷-丙酮(12-15：1)洗脱体系利用硅胶柱色谱法纯化得到中间产物。最后将中间产物、5mmol1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI)、5mmol1-羟基苯并三唑(HOBt)和1mmol4-二甲氨基吡啶(DMAP)溶于50mL无水二氯甲烷中，冰浴1小时，然后加入适量拉洛他赛，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，采用乙腈-水(90-99：1)洗脱体系分离纯化，得终产物，纯度＞99.5％。采用核磁共振测定 1H-NMR氢谱和液相色谱-质谱联用仪来确定实施例1中前药的结构，结果如图1和图2所示。 5 mmol of dithiodiacetic acid was added to a 50 mL eggplant flask, dissolved with 10 mL of acetic anhydride, reacted at room temperature for 2 hours under nitrogen protection, and dried under reduced pressure to remove excess acetic anhydride. The obtained product was dissolved in 30 mL of dichloromethane, 5 mmol of stearyl alcohol and 2 mmol of DMAP were added, and the mixture was stirred at 25°C for 12 hours. The cyclohexane-acetone (12-15:1) elution system was used to purify by silica gel column chromatography. mid product. Finally, the intermediate product, 5mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 5mmol of 1-hydroxybenzotriazole (HOBt) and 1mmol of 4-dimethylaminopyridine ( DMAP) was dissolved in 50 mL of anhydrous dichloromethane, ice bathed for 1 hour, then an appropriate amount of lalotaxel was added, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. The final product was prepared by liquid phase, using acetonitrile-water (90 -99:1) Separation and purification of the elution system to obtain the final product with a purity of >99.5%. The structure of the prodrug in Example 1 was determined by nuclear magnetic resonance measurement of 1 H-NMR hydrogen spectrum and liquid chromatography-mass spectrometry. The results are shown in FIG. 1 and FIG. 2 .
实施例2：非PEG化的拉洛他赛-硬脂醇前药小分子前药自组装纳米粒的制备Example 2: Preparation of non-PEGylated larottaxel-stearyl alcohol prodrug small molecule prodrug self-assembled nanoparticles
精密称取实施例1的前药8mg，用800μL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。Precisely weigh 8 mg of the prodrug of Example 1, dissolve it with 800 μL of ethanol, and slowly drop the ethanol solution into 4 mL of deionized water with stirring to spontaneously form uniform nanoparticles.
实施例3：PEG修饰的拉洛他赛-硬脂醇前药小分子前药自组装纳米粒的制备Example 3: Preparation of PEG-modified lalotaxel-stearyl alcohol prodrug small molecule prodrug self-assembled nanoparticles
精密称取DSPE-PEG 2K 1.4mg和实施例1的前药8mg，用800μL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，自发形成粒径均匀的PEG修饰的纳米粒。且PEG用量在10％-30％时，可得到较为稳定的纳米粒，其粒径为80nm。 Precisely weigh 1.4 mg of DSPE-PEG 2K and 8 mg of the prodrug of Example 1, dissolve it with 800 μL of ethanol, and slowly drop the ethanol solution into 4 mL of deionized water with stirring to spontaneously form PEG-modified Nanoparticles. And when the amount of PEG is 10%-30%, relatively stable nanoparticles can be obtained, and the particle size is 80 nm.
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。 Change the ratio of prodrug and DSPE-PEG 2K , the results show that when the dosage of DSPE-PEG 2K is 10%-30%, that is, when the ratio of prodrug and DSPE-PEG 2K is 90:10-70:30, the prepared The particle size of the nanoparticles is 70-100 nm, and the particle size polydispersity coefficient is less than 0.2.
所述的DSPE-PEG 2K也可以以TPGS、PLGA-PEG、PE-PEG或DSPE-PEG-AA等两亲性聚合物或靶向基团代替。 The DSPE-PEG 2K can also be replaced by amphiphilic polymers or targeting groups such as TPGS, PLGA-PEG, PE-PEG or DSPE-PEG-AA.
实施例4：使用微流控设备来制备超小型拉洛他赛硬酯醇小分子前药纳米粒：Example 4: Using microfluidic equipment to prepare ultra-small larotaxet stearyl alcohol small molecule prodrug nanoparticles:
配制含有DSPE-PEG 2000和拉洛他赛硬酯醇小分子前药的乙醇溶液作为有机相，其中，拉洛他赛硬酯醇前药浓度为10mg/ml，DSPE-PEG 2000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，最终得到拉洛他赛硬酯醇小分子前药纳米粒。 Prepare an ethanol solution containing DSPE-PEG 2000 and larotaxet stearyl alcohol small molecule prodrug as an organic phase, wherein the concentration of larotaxet stearyl alcohol prodrug is 10mg/ml, and the concentration of DSPE-PEG 2000 is 2mg/ml 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 the nanoparticle of larottaxel stearyl alcohol small molecule prodrug.
将该纳米粒稀释50倍后，取1ml稀释后的样品置于粒径杯中，用Malvern Zetasizer粒度仪测定该纳米粒的粒径和分散指数，结果如图3所示。After diluting the nanoparticles by 50 times, take 1 ml of the diluted sample and place it in a particle size cup, and measure the particle size and dispersion index of the nanoparticles with a Malvern Zetasizer particle analyzer. The results are shown in Figure 3.
实施例5：小分子前药自组装纳米粒的药代动力学研究Example 5: Pharmacokinetic study of small molecule prodrug self-assembled nanoparticles
取12只健康、雄性大鼠，体重200-250g，随机分为2组，给药前禁食12h，自由饮水。分别静脉注射拉洛他赛溶液和实例3中制备的PEG化小分子前药自组装纳米粒(粒径为80nm)。拉洛他赛的剂量为4mg/kg。于规定时间点0.083h、0.25h、0.50h、1.00h、2.00h、4.00h、8.00h、12.00h、24.00h和48.00h进行眼眶取血，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。Twelve healthy, male rats, weighing 200-250 g, were randomly divided into 2 groups, fasting for 12 hours before administration, and drinking water freely. The larottaxel solution and the PEGylated small molecule prodrug self-assembled nanoparticles (80 nm in particle size) prepared in Example 3 were injected intravenously, respectively. Lalotaxel was dosed at 4 mg/kg. Orbital blood was collected at specified time points 0.083h, 0.25h, 0.50h, 1.00h, 2.00h, 4.00h, 8.00h, 12.00h, 24.00h and 48.00h, and plasma was obtained by separation. Drug concentrations in plasma were determined by liquid chromatography-mass spectrometry.
结果如图4所示，PEG化的小分子前药循环时间相较于溶液剂明显延长，生物利用度明显提高，且稳定性较好。实验结果表明，PEG化的小分子前药自组装纳米粒能够显著延长拉洛他赛在血液中的循环时间。The results are shown in Figure 4. Compared with the solution, the PEGylated small-molecule prodrug has a significantly longer circulation time, significantly improved bioavailability, and better stability. The experimental results show that the PEGylated small-molecule prodrug self-assembled nanoparticles can significantly prolong the circulation time of larottaxel in the blood.
表1 LTX-SS-SAL前药纳米粒和LTX溶液剂的药动学参数Table 1 Pharmacokinetic parameters of LTX-SS-SAL prodrug nanoparticles and LTX solutions
Figure PCTCN2021133825-appb-000008
Figure PCTCN2021133825-appb-000008
实施例6：PEG修饰的小分子前药自组装纳米粒的体内抗肿瘤实验Example 6: In vivo antitumor experiments of PEG-modified small molecule prodrug self-assembled nanoparticles
将小鼠乳腺癌细胞悬液(4T1，5x10 6cells/100ul)接种于雌性BALB/c小鼠腹侧皮下。待肿瘤体积生长至100-120mm 3，将荷瘤小鼠随机分为五组，每组五只：空白对照组(PBS)，拉洛他赛溶液剂组(8mg/kg)，LTX-SS-SA纳米粒低剂量组(4mg/kg)，LTX-SS-SA纳米粒中剂量组(8mg/kg)和LTX-SS-SA纳米粒高剂量组(12mg/kg)。给药所用的纳米粒为实施例3中制备的PEG修饰的小分子前药自组装纳米粒。每隔1d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，测肿瘤体积。最后一次给药后一天将小鼠处死后，进行数据汇总和分析。 A suspension of mouse breast cancer cells (4T1, 5x10 6 cells/100ul) was inoculated subcutaneously on the ventral side of female BALB/c mice. When the tumor volume grew to 100-120mm 3 , the tumor-bearing mice were randomly divided into five groups, five in each group: blank control group (PBS), larottaxel solution group (8mg/kg), LTX-SS- SA nanoparticles low dose group (4mg/kg), LTX-SS-SA nanoparticles medium dose group (8mg/kg) and LTX-SS-SA nanoparticles high dose group (12mg/kg). The nanoparticles used for administration were the PEG-modified small-molecule prodrug self-assembled nanoparticles prepared in Example 3. Administer once every 1d, 5 times in a row. The survival status of the mice was observed every day after administration, the body weight was weighed, and the tumor volume was measured. Data pooling and analysis were performed after mice were sacrificed one day after the last dose.
结果如图5所示，空白对照组的肿瘤体积迅速增长，并在第10天达到600-700mm 3。相比之下，拉洛他赛溶液组(Free-LTX)能够延缓肿瘤生长，而纳米粒制剂组能够显著抑制肿 瘤生长，其中高剂量制剂组的肿瘤体积仅为130mm 3。这反映出了我们设计的拉洛他赛-硬酯醇纳米粒具有良好的抗肿瘤效果。 The results are shown in FIG. 5 , the tumor volume of the blank control group increased rapidly and reached 600-700 mm 3 on the 10th day. In contrast, the larottaxel solution group (Free-LTX) could delay tumor growth, while the nanoparticle formulation group could significantly inhibit tumor growth, and the tumor volume in the high-dose formulation group was only 130 mm 3 . This reflects the good antitumor effect of our designed larottaxel-stearyl alcohol nanoparticles.
结果如图6所示，各组小鼠体重没有明显变化。结果说明这些PEG化的小分子前药自组装纳米粒在具有明显的抗肿瘤效果的同时，没有对机体造成显著的非特异性毒性，是安全有效的抗癌药物传递系统。The results are shown in Figure 6, and there was no significant change in the body weight of the mice in each group. The results show that these PEGylated small-molecule prodrug self-assembled nanoparticles have obvious anti-tumor effects without causing significant non-specific toxicity to the body, and are safe and effective anti-cancer drug delivery systems.

Claims (10)

  1. 如下结构的拉洛他赛-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：Larottaxel-fatty alcohol small molecule prodrug of the following structure or a pharmaceutically acceptable salt, isomer, solvate thereof:
    Figure PCTCN2021133825-appb-100001
    Figure PCTCN2021133825-appb-100001
    其中，R为C 3-C 30饱和或不饱和链烃基； Wherein, R is C 3 -C 30 saturated or unsaturated chain hydrocarbon group;
    优选
    Figure PCTCN2021133825-appb-100002
    或R为C 3-C 22烯基；所述烯基中含有1-5个烯键；     preferred
    Figure PCTCN2021133825-appb-100002
    Or R is a C 3 -C 22 alkenyl group; the alkenyl group contains 1-5 ethylenic bonds;
    p＝7-29；p=7-29;
    n＝1-3。n=1-3.
  2. 如权利要求1所述的拉洛他赛-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，其特征在于，The larottaxel-fatty alcohol small molecule prodrug or its pharmaceutically acceptable salt, isomer and solvate according to claim 1, wherein,
    其中，
    Figure PCTCN2021133825-appb-100003
    且p＝11-27，优选为p＝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，亚油酸。     in,
    Figure PCTCN2021133825-appb-100003
    and p=11-27, preferably p=11-17; or R is propenyl, allyl, 2-butenyl, 4-pentenyl, 2-hexenyl, 4-decenyl, 2 - Dodecenyl, 9-tetradecenyl, 9-hexadecenyl, 9-octadecenyl, eicosatetraene, docosapentaene, linoleic acid.
  3. 权利要求1或2所述的拉洛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：The small molecule prodrug of larottaxel fatty alcohol according to claim 1 or 2 or a pharmaceutically acceptable salt, isomer and solvate thereof:
    Figure PCTCN2021133825-appb-100004
    Figure PCTCN2021133825-appb-100004
    n＝1-3，优选为1。n=1-3, preferably 1.
  4. 如权利要求1所述的拉洛他赛脂肪醇小分子前药的制备方法，其特征在于，The preparation method of larottaxel fatty alcohol small molecule prodrug according to claim 1, wherein,
    (1)将亚二硫基二乙酸溶解于过量乙酸酐中，氮气保护，室温下反应后除去多余的乙酸酐；(1) dissolving dithiodiacetic acid in excess acetic anhydride, nitrogen protection, and removing excess acetic anhydride after the reaction at room temperature;
    (2)以4-二甲氨基吡啶作为催化剂，将步骤(1)所得产物与脂肪醇反应，反应完毕后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、1-羟基苯并三唑和4-二甲氨基吡啶，溶于无水二氯甲烷中，在冰浴下活化，然后加入拉洛他赛，氮气保护，在25-30℃条件下反应，所得产物经制备液相分离纯化，即得；(2) using 4-dimethylaminopyridine as a catalyst, the product obtained in step (1) is reacted with aliphatic alcohol, and after completion of the reaction, column chromatography is used to separate the intermediate product; the intermediate product, 1-(3-dimethylaminopropyl yl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-dimethylaminopyridine, dissolved in anhydrous dichloromethane, activated in an ice bath, and then added with lalotat Race, nitrogen protection, react under the condition of 25-30 ℃, the obtained product is separated and purified by preparation liquid phase, that is, it is obtained;
    所述的脂肪醇为C 3-C 30饱和或不饱和脂肪醇。 The fatty alcohol is C 3 -C 30 saturated or unsaturated fatty alcohol.
  5. 权利要求1-3中任何一项所述的拉洛他赛-脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物的自组装纳米粒，其特征在于，包括非PEG化的拉洛他赛-脂肪醇前药纳米粒、PEG修饰的拉洛他赛-脂肪醇前药纳米粒、包载药物的拉洛他赛-脂肪醇前药纳米粒和主动靶向的拉洛他赛-脂肪醇前药纳米粒，所述的PEG修饰剂优选为PEG为TPGS、DSPE-PEG、PLGA-PEG、PE-PEG或DSPE-PEG-AA，拉洛他赛-脂肪醇小分子前药与PEG修饰剂的质量比为90:10～70:30。The self-assembled nanoparticle of larottaxel-fatty alcohol small molecule prodrug or its pharmaceutically acceptable salt, isomer and solvate according to any one of claims 1-3, characterized in that it comprises non- PEGylated larottaxel-fatty alcohol prodrug nanoparticles, PEG-modified larottaxel-fatty alcohol prodrug nanoparticles, drug-encapsulated larottaxel-fatty alcohol prodrug nanoparticles and actively targeted Lalotaxel-fatty alcohol prodrug nanoparticle, the PEG modifier is preferably PEG, TPGS, DSPE-PEG, PLGA-PEG, PE-PEG or DSPE-PEG-AA, and larottaxel-fatty alcohol small particle. The mass ratio of molecular prodrug to PEG modifier was 90:10-70:30.
  6. 如权利要求5所述的拉洛他赛-脂肪醇小分子前药或其药学上可接受的盐的自组装纳米粒，其特征在于，通过如下方法制备：The self-assembled nanoparticle of larottaxel-fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, prepared by the following method:
    将拉洛他赛-脂肪醇小分子前药或洛他赛-脂肪醇小分子前药和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；Dissolve larotaxel-fatty alcohol small molecule prodrug or the mixture of lotaxel-fatty alcohol small molecule prodrug and PEG modifier into ethanol, slowly add the ethanol solution dropwise to water under stirring, and the prodrug Spontaneous formation of uniform nanoparticles;
    或以含有PEG修饰剂和拉洛他赛-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。Or, the ethanol solution containing PEG modifier and larottaxel-fatty alcohol small molecule prodrug is used as the organic phase, and ultrapure water is used as the aqueous phase, and the microfluidic device is used to prepare.
  7. 权利要求1-3任何一项所述的拉洛他赛-脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的小分子前药自组装纳米粒在制备药物传递系统中的应用。The larottaxel-fatty alcohol small molecule prodrug of any one of claims 1-3 or its pharmaceutically acceptable salt, isomer, solvate or the self-assembly of the small molecule prodrug of claim 5 Application of nanoparticles in the preparation of drug delivery systems.
  8. 权利要求1-3任何一项所述的拉洛他赛-脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的小分子前药自组装纳米粒在制备抗肿瘤药物中的应用。The larottaxel-fatty alcohol small molecule prodrug of any one of claims 1-3 or its pharmaceutically acceptable salt, isomer, solvate or the self-assembly of the small molecule prodrug of claim 5 Application of nanoparticles in the preparation of antitumor drugs.
  9. 权利要求1-3任何一项所述的拉洛他赛-脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的卡巴他赛脂肪醇前药的自组装纳米粒在制备提高疗效、降低毒性药物中的应用。The larottaxel-fatty alcohol small molecule prodrug of any one of claims 1-3 or a pharmaceutically acceptable salt, isomer, solvate thereof or the cabazitaxel fatty alcohol prodrug of claim 5 The application of self-assembled nanoparticles of medicines in the preparation of medicines with improved curative effect and reduced toxicity.
  10. 权利要求1-3任何一项所述的拉洛他赛-脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的小分子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。The larottaxel-fatty alcohol small molecule prodrug of any one of claims 1-3 or its pharmaceutically acceptable salt, isomer, solvate or the self-assembly of the small molecule prodrug of claim 5 The application of nanoparticles in the preparation of injectable, oral or local drug delivery systems.
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