CN114939175B - Supermolecule nano prodrug based on anionic water-soluble biphenyl expansion column and preparation method and application thereof - Google Patents

Supermolecule nano prodrug based on anionic water-soluble biphenyl expansion column and preparation method and application thereof Download PDF

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CN114939175B
CN114939175B CN202210470438.0A CN202210470438A CN114939175B CN 114939175 B CN114939175 B CN 114939175B CN 202210470438 A CN202210470438 A CN 202210470438A CN 114939175 B CN114939175 B CN 114939175B
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丁月
于威
马宇轩
朱吕明
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Abstract

The invention discloses a supermolecule nano prodrug based on an anionic water-soluble biphenyl expansion column, a preparation method and application thereof, wherein the supermolecule nano prodrug is prepared from anionic water-soluble biphenyl expansion column [6] arene and IR 806-chlorambucil; the structural formula of the anionic water-soluble biphenyl expansion type column [6] arene is shown as a formula I. The anionic water-soluble biphenyl expansion type column [6] arene has a larger inner cavity than the traditional water-soluble column [6] arene, and can complex more kinds of anticancer drugs. According to the invention, through the host-guest body recognition effect of the anionic water-soluble biphenyl expansion type column [6] arene and chlorambucil, the host anionic water-soluble biphenyl expansion type column [6] arene and a guest drug-drug conjugate IR 806-chlorambucil self-assemble to form a Supramolecular Nano Prodrug (SNP), which is used for triple combination treatment of photodynamic therapy-photothermal therapy-chemotherapy, and has a synergistic anti-tumor effect.

Description

Supermolecule nano prodrug based on anionic water-soluble biphenyl expansion column and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a supermolecule nano prodrug based on an anionic water-soluble biphenyl expansion column, and a preparation method and application thereof.
Background
The traditional nano drug delivery system mostly encapsulates anticancer drugs inside nano carriers, and uses the EPR effect to deliver the drugs to tumor sites. Although the method improves the anti-tumor effect to a certain extent, the method has the problems of low drug loading rate, premature drug leakage, poor stability and the like. Therefore, two small molecular medicines are linked together through a stimulus-responsive chemical bond to prepare an amphiphilic medicine-medicine conjugate, and a prodrug nano-drug delivery system which does not need any carrier and has the activity and nano characteristics of the small molecular anticancer medicines is constructed, so that the medicine carrying efficiency is improved, the solubility and stability of the medicines are enhanced, the systemic toxicity of the medicines is reduced, and the linked chemical bond can responsively release the medicines under the action of an internal or external stimulus source, so that the controlled release of the medicines is realized, and the treatment effect is improved. However, such amphiphilic drug-drug conjugates require that both drugs be hydrophilic and hydrophobic, respectively, while most anticancer drugs are hydrophobic, which greatly limits the application of amphiphilic drug-drug conjugates in the field of cancer treatment. Therefore, the water-soluble macrocyclic compound is used for constructing an amphipathic guest-host complex through a guest-host recognition effect complexing agent-agent conjugate, and then the amphipathic guest-host complex is self-assembled to form the supramolecular nano prodrug, and the drug-agent conjugate can use two hydrophobic anticancer drugs, so that the selectivity of the anticancer drugs is greatly improved, and different types of supramolecular nano prodrugs are constructed. At present, the commonly used macrocyclic compounds comprise cyclodextrin, calixarene, cucurbituril, column arene and the like, but the preparation process is difficult to control accurately, and the traditional macrocyclic compounds are difficult to functionalize. In addition, to meet the requirements for building supramolecular nano-prodrugs, the host macrocyclic compound needs to have a sufficiently large lumen to decomplex different guest drug-drug conjugates, which also limits the use of traditional macrocyclic compounds in supramolecular nano-prodrugs.
Document search finds that the subject group of Nanjing university Wang Leyong in China is entitled < Construction of drug-drug conjugate supramolecular nanocarriers based on water-soluble pilar [6]arene for combination chemotherapy > (construction of supramolecular nanocarriers for combined treatment based on water-soluble column [6] arene) in paper (Wei Shao et al chem. Commun.2018,54, 9462-9465) constructs a supramolecular nanocarrier based on water-soluble column [6] arene, and a nano drug is prepared through the main-guest recognition effect and the performance and anti-tumor combined treatment effect of the supramolecular nanocarrier are studied. However, the water-soluble column [6] arene used in the system has the advantages of complex preparation process, low yield, smaller macrocyclic inner cavity and limited complexable anticancer drugs. Only chemotherapeutic drugs are used, and the anti-tumor effect is poor by one chemotherapeutic means, so that the expected effect is difficult to achieve.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a supermolecule nanometer prodrug based on an anionic water-soluble biphenyl expansion column, a preparation method and application thereof, wherein the anionic water-soluble biphenyl expansion column [6] arene has a larger inner cavity than the traditional water-soluble column [6] arene, can complex more kinds of anticancer drugs through the other actions of a host and a guest, and the preparation process is easier to control and has higher yield. Meanwhile, the invention prepares a drug-drug conjugate IR 806-chlorambucil (IR 806-DB) by reducing a responsive disulfide linkage near infrared photosensitizer IR806 and a chemotherapeutic drug chlorambucil (DB). The main anionic water-soluble biphenyl expansion column [6] arene and the guest drug-drug conjugate IR 806-chlorambucil self-assemble to form a Supramolecular Nano Prodrug (SNP) through the main guest body recognition function of the anionic water-soluble biphenyl expansion column [6] arene and chlorambucil, and the supramolecular nano prodrug is used for triple combination therapy of photodynamic therapy-photothermal therapy-chemotherapy.
The invention is realized by the following technical scheme:
a supermolecule nanometer prodrug based on an anionic water-soluble biphenyl expansion column, which is prepared from anionic water-soluble biphenyl expansion column [6] arene and IR 806-chlorambucil; the structural formula of the anionic water-soluble biphenyl expansion type column [6] arene is shown as the following formula I:
preferably, the particle size of the supramolecular nano-prodrug is 157.6±6.2nm.
A preparation method of supermolecule nanometer prodrug based on anion water-soluble biphenyl expansion column prepares anion water-soluble biphenyl expansion column [6] arene; dissolving IR 806-chlorambucil in N, N-dimethylformamide solvent, dripping deionized water solution of anionic water-soluble biphenyl expansion column [6] arene, stirring, and dialyzing to obtain the supermolecule nanometer prodrug.
Preferably, the preparation process of the anionic water-soluble biphenyl extended column [6] arene is shown in the following formula II:
the method comprises the following steps:
(1) 3g of biphenyl expansion column [6] arene modified with 8 hydroxyl groups, 21g of potassium carbonate and 50mg of potassium iodide are added with 300mL of acetonitrile and 10mL of methyl 2-bromopropionate under the protection of nitrogen, and reacted for 48 hours at 65 ℃; filtering after the reaction is finished, spin-drying filtrate, and purifying by a column chromatography to obtain a product;
(2) 1.4g of the product obtained in the step (1) and 1.5g of sodium hydroxide are dissolved in 200mL of a mixed solvent of deionized water/ethanol with the volume ratio of 1:1, the mixture is stirred at 60 ℃ for reaction overnight, after the reaction is finished, the reaction liquid is cooled and settled, then suction filtration is carried out to obtain a solid, the solid is dissolved in ammonia water, and spin drying is carried out to obtain the product, namely the anionic water-soluble biphenyl extended column [6] arene.
Preferably, the concentration of the IR 806-chlorambucil is 4.2mg/mL and the concentration of the anionic water-soluble biphenyl extended column [6] arene is 0.58mg/mL.
Preferably, the volume ratio of the N, N-dimethylformamide solvent to the deionized water is 1:10.
Preferably, the stirring mode is as follows: stirring at room temperature for 12h.
Preferably, the dialysis is performed in the following manner: the solution was dialyzed against 500mL X1 times/8 h of deionized water for 24h using a 300 molecular weight dialysis bag.
An application of supermolecule nanometer prodrug based on anionic water-soluble biphenyl expansion column in preparing antitumor drug.
Preferably, the antitumor drug is an anti-cervical cancer drug.
The beneficial effects of the invention are as follows:
(1) The invention synthesizes a new kind of anion water-soluble macrocyclic compound with high efficiency, anion water-soluble biphenyl expansion column [6] arene has larger inner cavity than traditional water-soluble column [6] arene, and can complex more kinds of anticancer drugs.
(2) The method constructs the supermolecule nano prodrug through the host-guest recognition function, and is simple and efficient.
(3) The supramolecular nano prodrug can be rapidly disassembled and assembled in an acidic environment in tumor cells, and under the action of intracellular glutathione, a chemotherapeutic drug chlorambucil is released in a responsive way.
(4) The IR806 loaded by the supramolecular nano prodrug can raise the temperature of a tumor part under the irradiation of 808nm near infrared light, so that the tumor temperature is raised and death is realized, the photothermal therapy is realized, and meanwhile, active oxygen (singlet oxygen) can be released to kill tumor cells, so that the photodynamic therapy is realized.
(5) The photodynamic therapy-photothermal therapy-chemotherapy triple combined therapy technology is simple to operate, can realize effective treatment of tumors through intravenous injection, and has important clinical application prospect.
(6) The invention provides a simple and effective way for preparing the supermolecule nano prodrug, and provides a good experimental platform for obtaining the supermolecule nano prodrug with reduction/near infrared light dual-responsiveness photodynamic therapy-photothermal therapy-chemotherapy triple combined therapy.
Drawings
FIG. 1 is a nuclear magnetic spectrum of an anionic water-soluble biphenyl extended column [6] arene in example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of IR 806-chlorambucil in example 2;
FIG. 3 is a schematic diagram of the construction of supramolecular nano-prodrugs of example 3;
FIG. 4 is a dynamic light scattering pattern and transmission electron microscopy image of charge-reversed supramolecular nano-pro-drug of example 3.
FIG. 5 shows the results of the cellular activity test of the supramolecular nano-pro-drug on cervical cancer cells in example 4.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings and specific embodiments. It should be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The implementation conditions used in the examples may be further adjusted according to the conditions of the specific manufacturer, and the implementation conditions not specified are generally those in routine experiments.
EXAMPLE 1 preparation of anionic Water-soluble Biphenyl extended column [6] arene
The structural formula of the anionic water-soluble biphenyl expansion type column [6] arene is shown as the following formula I:
the preparation reaction formula is shown as the following formula II:
the method comprises the following specific steps:
(1) 3g of 8-hydroxyl-modified biphenyl expansion column [6] arene, 21g of potassium carbonate and 50mg of potassium iodide were reacted at 65℃for 48 hours under nitrogen protection with 300mL of acetonitrile and 10mL of methyl 2-bromopropionate. After the reaction, suction filtration was carried out, and the filtrate was dried by spin-drying, followed by purification by column chromatography to obtain 5.12g of the product in 83.7% yield.
(2) 1.4g of the product obtained in the step (1) and 1.5g of sodium hydroxide are dissolved in 200mL of a mixed solvent of deionized water/ethanol (volume ratio is 1:1), the mixture is stirred at 60 ℃ for reaction overnight, after the reaction is finished, the reaction solution is cooled and settled, then suction filtration is carried out to obtain a solid, the solid is dissolved in ammonia water, and the solid is dried by spin to obtain 0.72g of the product of anionic water-soluble biphenyl extended column [6] arene, wherein the yield is 50.5%.
The anionic water-soluble biphenyl expansion column [6] prepared in the embodiment]The aromatic hydrocarbon is shown in fig. 1, and the detailed peak position is attributed to: 1 H-NMR(400MHz,CDCl 3 ):δ7.44(d,J＝8Hz,8H),7.17(d,J＝8Hz,8H),6.83(s,4H),6.66(s,4H),4.24(s,8H),4.15(s,8H),3.92(d,J＝8Hz,12H).
EXAMPLE 2 preparation of IR 806-chlorambucil
The structural formula of the IR 806-chlorambucil is shown in the following formula III:
the preparation reaction formula is shown as the following formula IV:
the method comprises the following specific steps:
(1) IR806 is obtained by reference to the prior literature (adv.funct. Mater.2021,31,2104473). 18mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 15mg of 4-dimethylaminopyridine and 100mg of IR806 were added to 10mL of methylene chloride and reacted for 4 hours to obtain a reaction liquid A. Then, 55mg of 2-hydroxyethyl disulfide was dissolved in 1mL of methylene chloride, and added to the reaction solution A, followed by reaction at room temperature for 48 hours. After the reaction was completed, 5mL of deionized water was added, and the organic layer was separated and dried by spin-drying, followed by purification by column chromatography to give 97.4mg of the product in 82.8% yield.
(2) 38mg of chlorambucil, 20mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 15mg of 4-dimethylaminopyridine were added to 10mL of DCM solvent and stirred for 4 hours to obtain a reaction solution B. 70mg of the product obtained in step (1) was then dissolved in 1mL of methylene chloride and added to the reaction mixture B, followed by reaction at room temperature for 48 hours. After the reaction was completed, 5mL of deionized water was added, and the organic layer was separated and spin-dried, followed by purification by column chromatography to give 53.4mg of the product IR 806-chlorambucil (IR 806-2-hydroxyethyl disulfide-chlorambucil) in 76.3% yield.
The IR 806-chlorambucil prepared in this example is shown in FIG. 2, and the detailed peak positions are ascribed to: 1 H-NMR(400MHz,CDCl 3 ):δ8.60(d,J＝12Hz,2H,COOPh),7.95(d,J＝12Hz,2H,SPh),7.36(t,J＝16Hz,2H,CH),7.28(t,J＝8Hz,3H,CH),7.20(t,J＝16Hz,2H,CH),7.12(d,J＝8Hz,2H,CH),6.62(d,J＝12Hz,2H,CH),6.30(d,J＝12Hz,2H,CH),4.50(t,J＝12Hz,2H,OCH 2 ),4.30(t,J＝12Hz,2H,NCH 2 ),4.17(t,J＝16Hz,4H,CH 2 ),3.70(t,J＝12Hz,4H,CH 2 OH),3.61(t,J＝12Hz,4H,CH 2 ),3.00(t,J＝12Hz,2H,SCH 2 ),2.90(t,J＝16Hz,2H,OCH 2 ),2.85(t,J＝16Hz,4H,CH 2 ),2.54(t,J＝16Hz,2H,SCH 2 ),2.31(t,J＝12Hz,2H,CH 2 ),2.08(s,2H,CH 2 ),1.90(q,J＝20Hz,6H,CH 2 ),1.55(s,12H,CCH 3 ),1.06(t,J＝16Hz,6H,CH 3 ).
EXAMPLE 3 preparation of supramolecular nanomaterials
The preparation method of the supramolecular nano prodrug is shown in fig. 3, and comprises the following specific steps:
4.6mg of IR 806-2-hydroxyethyl disulfide-chlorambucil prepared in example 2 was dissolved in 1mL of N, N-dimethylformamide, and after stirring for 12 hours, a reaction solution C was obtained; 5.4mg of the anionic water-soluble biphenyl extended column [6] arene prepared in example 1 was dissolved in 10mL of deionized water and added dropwise to reaction solution C, followed by stirring for 24 hours. After the completion of the dialysis, the solution is placed in a dialysis bag with the molecular weight of 300, and is dialyzed with 500mL of deionized water for 2 days, deionized water is changed every 8 hours in the middle, and after the completion of the dialysis, the Supramolecular Nano Prodrug (SNP) is obtained with the yield of 86.1-89.8%.
The dynamic light scattering spectrum and the transmission electron microscope graph of the supermolecule nano prodrug prepared in the embodiment are shown in figure 4, the hydrodynamic particle size is 157.6+/-6.2 nm, the PDI is 0.26+/-0.03, and the morphology is a uniform spherical vesicle structure.
EXAMPLE 4 Effect of supramolecular nano-prodrugs on cervical cancer cells
The supramolecular nano-prodrug (SNP), chlorambucil and IR806 prepared in example 3 were prepared separately from cell culture solution: the chlorambucil concentrations were 0.05, 0.1, 0.2, 0.5, 1,2 μg/mL, respectively, and the corresponding IR806 concentrations were 0.23, 0.46, 0.92, 2.3, 4.6, 9.2 μg/mL, respectively. Then cultured with HeLa cells (cervical adenocarcinoma) for 48 hours, respectively. The supramolecular nano prodrug needs to be additionally provided with a group, an IR806 experiment group is added, the supramolecular nano prodrug needs to be co-cultured with cells for 4 hours after the drug is added, and then the supramolecular nano prodrug is irradiated by near infrared laser for 5min (806 nm, 1.0W/cm) 2 ) Culturing was continued for 48 hours. Finally, the MTT method was used for cell activity test, and the results are shown in FIG. 5.
In fig. 5, the lower abscissa indicates the concentration of chlorambucil, the upper abscissa indicates the concentration of IR806, CB indicates the experimental group using chlorambucil alone, IR806+ NIR indicates the experimental group using IR806 alone and irradiated with near infrared light, SNP indicates the experimental group using supramolecular nano-pro-drug alone, and SNP + NIR indicates the experimental group using supramolecular nano-pro-drug alone and irradiated with near infrared light.
As can be seen from fig. 5, for the other three control groups, the snp+nir experimental group can generate a photodynamic therapy-photothermal therapy-chemotherapy triple combination therapy effect, and thus shows the highest cytotoxicity, because under the near infrared illumination effect, the component IR806 can raise the temperature, kill cervical cancer cells, generate a photothermal therapy effect, and simultaneously can generate active oxygen to cause apoptosis of cervical cancer cells, generate a photodynamic therapy effect, and the supramolecular nano prodrug can rapidly release the chemotherapeutic drug chlorambucil under the action of the acidic environment and glutathione in tumor cells, so as to generate a chemotherapeutic effect, and the three anticancer therapies generate synergistic antitumor effects.
The above examples are provided for illustrating the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the contents of the present invention and to implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims (5)

1. The supermolecule nanometer prodrug based on the anionic water-soluble biphenyl expansion column is characterized in that the supermolecule nanometer prodrug is prepared from anionic water-soluble biphenyl expansion column [6] arene and IR 806-chlorambucil; the structural formula of the anionic water-soluble biphenyl expansion type column [6] arene is shown as the following formula I:
the structural formula of the IR 806-chlorambucil is shown in the following formula III:
the preparation method of the supramolecular nano prodrug comprises the following steps:
preparing anionic water-soluble biphenyl expansion type column [6] arene; dissolving IR 806-chlorambucil in N, N-dimethylformamide solvent, dripping deionized water solution of anionic water-soluble biphenyl expansion column [6] arene, stirring at room temperature for 12h, and dialyzing with dialysis bag with molecular weight of 300 and deionized water 500mL×1 times/8 h for 24h to obtain the supermolecule nanometer prodrug;
the concentration of the IR 806-chlorambucil is 4.2mg/mL, and the concentration of the anionic water-soluble biphenyl expansion type column [6] arene is 0.58mg/mL;
the volume ratio of the N, N-dimethylformamide solvent to the deionized water is 1:10.
2. The supramolecular nano-prodrug based on anionic water-soluble biphenyl extended column of claim 1, wherein the particle size of the supramolecular nano-prodrug is 157.6±6.2nm.
3. The supramolecular nano-prodrug based on anionic water-soluble biphenyl extended column according to claim 1, wherein the preparation process of anionic water-soluble biphenyl extended column [6] arene is shown in the following formula II:
the method comprises the following steps:
(1) 3g of biphenyl expansion column [6] arene modified with 8 hydroxyl groups, 21g of potassium carbonate and 50mg of potassium iodide are added with 300mL of acetonitrile and 10mL of methyl 2-bromopropionate under the protection of nitrogen, and reacted for 48 hours at 65 ℃; filtering after the reaction is finished, spin-drying filtrate, and purifying by a column chromatography to obtain a product;
(2) 1.4g of the product obtained in the step (1) and 1.5g of sodium hydroxide are dissolved in 200mL of a mixed solvent of deionized water/ethanol with the volume ratio of 1:1, the mixture is stirred at 60 ℃ for reaction overnight, after the reaction is finished, the reaction liquid is cooled and settled, then suction filtration is carried out to obtain a solid, the solid is dissolved in ammonia water, and spin drying is carried out to obtain the product, namely the anionic water-soluble biphenyl extended column [6] arene.
4. Use of a supramolecular nano-prodrug based on anionic water-soluble biphenyl extended column according to any one of claims 1-3 for preparing antitumor drugs.
5. The use according to claim 4, wherein the antineoplastic agent is an anti-cervical cancer agent.
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