CN113952463B - Nanometer diagnosis and treatment agent and preparation method and application thereof - Google Patents

Nanometer diagnosis and treatment agent and preparation method and application thereof Download PDF

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CN113952463B
CN113952463B CN202111161264.1A CN202111161264A CN113952463B CN 113952463 B CN113952463 B CN 113952463B CN 202111161264 A CN202111161264 A CN 202111161264A CN 113952463 B CN113952463 B CN 113952463B
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CN113952463A (en
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单玲玲
钱玉梅
余伟雄
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Suzhou University
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Abstract

The invention discloses a nano diagnosis and treatment agent, which relates to the technical field of anti-tumor medicines, wherein the inner core of the nano diagnosis and treatment agent is formed by covalently coupled small-molecule anti-tumor medicines, small-molecule ligands and metal ions with coordination capability, and the periphery of the nano diagnosis and treatment agent is formed by covalently coupled polyphenol-fluorescent dye. The invention also discloses a preparation method and application of the nano diagnosis and treatment agent. The invention has the beneficial effects that: the nano diagnosis and treatment agent can overcome the defects of low drug encapsulation efficiency, poor stability and the like of the traditional liposome formulation, and simultaneously avoid the problems of strong drug resistance and the like of the targeting small molecule prodrug.

Description

Nanometer diagnosis and treatment agent and preparation method and application thereof
Technical Field
The invention relates to the technical field of antitumor drugs, in particular to a nano diagnosis and treatment agent and a preparation method and application thereof.
Background
The mortality rate of malignant tumors has been high for the past decades, and one of the main reasons for this high mortality rate is the inability to deliver drugs to tumor sites effectively. At present, chemotherapy occupies a very important position in malignant tumor treatment, such as Paclitaxel (PTX), and the discovery of the action mechanism and the clinical application of tumor treatment are praised as a significant progress of global tumor chemotherapy in the recent 20 years by the field of global anti-tumor medicines. However, due to the lack of selectivity of paclitaxel therapy drugs in vivo and multiple drug resistance of tumor cells, the paclitaxel therapy drugs have obvious toxic and side effects, so that patients are difficult to tolerate, the administration dosage of the paclitaxel therapy drugs in treatment is limited, and the effect of chemotherapy is poor. With the continuous intensive research on malignant tumors, the single treatment method is not enough to control the occurrence and the development of the malignant tumors, and a better treatment effect can be obtained by combining a plurality of treatment methods together with the synergistic effect of the treatment methods. Recent researches show that the nano diagnosis and treatment agent can improve the targeting property of the medicine while realizing the integration mode of various treatment methods of malignant tumors, so that the medicine is effectively released at tumor positions, thereby improving the treatment effect.
Early studies of paclitaxel targeted drug modification have focused mainly on:
(1) Prodrugs: the research and development of the taxol prodrug can mainly solve the problems of poor water solubility, high cytotoxicity, improved antitumor activity and the like of taxol. If the taxol prodrug is prepared by modifying taxol with a targeted small molecule ligand or a small molecule inhibitor, the problems of kidney accumulation, shorter internal circulation, larger dosage and the like can be caused although the solubility of the taxol prodrug is improved and the purpose of active targeting is improved.
(2) Clinically used paclitaxel nano dosage form: a. the paclitaxel liposome is spherical vesicle, can encapsulate hydrophobic drugs in lipid bilayer membrane, the liposome antitumor drugs are nano-preparation for treating cancer, which is approved by the U.S. food and drug administration 1 st, and the first paclitaxel liposome injection in China, linaive, is put into clinical application and is used for treating malignant tumors such as breast cancer, non-small cell lung cancer and the like. Although the liposome can be used to deliver cytotoxic compounds to selected tissues, it can be rapidly cleared by the mononuclear phagocytes of the liver and spleen, thus reducing the efficacy of paclitaxel, and in addition, the liposome as a conventional dosage form has the problems of low encapsulation efficiency, instability, larger nanoparticles, etc.
b. Albumin-bound paclitaxel: albumin-bound paclitaxel is lyophilized granule with average diameter of 130nm prepared from human serum albumin and paclitaxel by high pressure vibration technique. Albumin-bound paclitaxel passes through a special transport path of gp 60-cellar protein-SPARC, so that the paclitaxel enters into a cell membrane cave-like depression to complete transmembrane transport and promote the paclitaxel to enter into tumor cells. Compared with the traditional PTX preparation, the preparation can obviously improve the drug concentration in tumor tissues, does not need polyoxyethylene castor oil solvent as a carrier, and is marketed in China in 2005. However, albumin paclitaxel enters tumor cells through gp60 protein, is easy to generate drug resistance and is expensive.
(3) Other paclitaxel nanoparticles: a. polymer nanoparticles commonly used are polylactic acid (PLA), PLA-glycolic acid copolymer (PLGA) and Polycaprolactone (PCL), such as the paclitaxel-polylactic acid-paclitaxel copolymer prepared in the patent publication No. CN106967211 a. Compared with PTX monomer, the medicine effect can be improved, the cytotoxicity can be reduced, but the problems of large molecular weight, nanoparticle aggregation and the like exist.
Currently, the paclitaxel nano drug-loading system is clinically used: the drug delivery system of the paclitaxel wrapped by the liposome dosage form in China has the defects that the drug delivery system is unstable, small molecular drugs cannot be accurately delivered to focus positions to exert drug effects, and meanwhile, the drug carrier has less drug wrapping amount, the drug effects are reduced, and the like. Foreign countries: albumin-taxol nano medicine has the defects of easy drug resistance, high price and the like. In the research stage, the paclitaxel prodrug and the nano micelle drug-carrying system of the amphiphilic macromolecule wrapped PTX are decomposed into macromolecular amphiphilic block polymers in vivo, so that free PTX is difficult to release, and the drug effect of PTX is reduced. Although compounds with polyphenol structures such as MYR have better functions of resisting oxidation, resisting cancer and the like, the compounds have the problems of poor water solubility, unstable structure and the like, and the purposes of synergistic medication of MYR+PTX and improvement of the drug effect of PTX cannot be realized.
Dihydromyricetin (dihydromyricetin), also known as ampelopsin, is a class of flavonoid compounds that are widely found in fruits, vegetables and herbs. Dihydromyricetin has antibacterial, antiinflammatory, antioxidant, liver protecting, and heart blood protecting effectsPharmacological activity such as pipe system. In recent years, the research shows that dihydromyricetin has inhibition effect on various tumors and lower toxicity on normal cells, and can improve the chemosensitivity of PTX drug-resistant tumor cell strains to PTX/DOX. The focus of the current research is to explore the combined anti-tumor mechanism. A plurality of researches show that the combined application of the dihydromyricetin and the multidrug has stronger anti-tumor effect than the single-drug application. However, because the dihydromyricetin has poor water solubility, unstable structure and low in vivo bioavailability, the single use of MYR as an antioxidant, anti-inflammatory and anticancer drug has the defects of large dosage, low efficiency and the like. Tannic Acid (TA), also known as Tannic acid, belongs to the class of tannins, which hydrolyzes to gallic acid and glucose, chemical formula C 76 H 52 O 46 . Tannic acid is a polyphenol compound having a series of chemical and physiological properties such as binding or complexing with polysaccharides, proteins, alkaloids, metal ions, etc., and having an activity of capturing free radicals, because it contains a plurality of phenolic hydroxyl groups, and thus has an antioxidant function. In recent years, biological action and mechanism of tannic acid are increasingly focused, and besides antioxidation in organisms, the biological action and mechanism of tannic acid have also found effects of resisting tumor, losing weight, inhibiting bacteria and the like. Recent researches show that tannic acid can play an anti-tumor role in cooperation with other medicines, such as bile duct cancer resistance by combining with mitomycin C and 5-fluorouracil, human leukemia resistance by combining with arsenic trioxide, ovarian cancer resistance by combining with cisplatin CDDP, and the like. In addition, the research shows that the oral administration of TA is safer and can be used as a food additive, so that the TA can be used as a low-toxicity chemotherapy drug sensitization drug to assist in preventing and treating tumors.
Studies have shown that one of the effective methods of malignancy treatment is to deliver drugs to the target site effectively and to achieve controlled release of the drug and minimize toxicity, but this goal is difficult to achieve due to the differences between individual patients and malignancy. The nanometer diagnosis and treatment agent integrates diagnosis and treatment of malignant tumor, has diagnosis and treatment functions, can realize targeted drug delivery, can slowly release drugs, reduce toxic and side effects, realizes 'molecular image-chemotherapy' cooperative treatment in the tumor treatment process, and has good application prospect for personalized treatment.
Disclosure of Invention
The invention aims to provide a novel nano diagnosis and treatment agent and a preparation method and application thereof.
The invention solves the technical problems by the following technical means:
a nanometer diagnosis and treatment agent, wherein the inner core of the nanometer diagnosis and treatment agent is formed by covalently coupling a prodrug of a small-molecule anti-tumor drug and a small-molecule ligand with metal ions with coordination capability, and the periphery of the nanometer diagnosis and treatment agent is formed by covalently coupling a compound with a polyphenol structure with fluorescent dye;
the small molecule ligand comprises dopamine, evanskia (EB), folic acid or 5-methyltetrahydrofolate, and the compound with the polyphenol structure comprises one or more of dihydromyricetin, tannic acid, myricetin or myricetin.
The beneficial effects are that: the nano diagnosis and treatment agent can overcome the defects of low drug encapsulation efficiency, poor stability and the like of the traditional liposome formulation, and simultaneously avoid the problems of strong drug resistance and the like of the targeting small molecule prodrug.
The nano diagnosis and treatment agent provided by the invention carries the compound with the polyphenol structure and the small-molecule anti-tumor drug, has high drug loading capacity and good stability, and can realize the purposes of synergistic drug effect, in-vivo and in-vitro diagnosis and improvement of the small-molecule anti-tumor drug.
In tumor treatment, two separate processes of diagnosis and treatment are integrated, so that diagnosis-treatment is synchronously carried out in tumor treatment, and the treatment scheme can be adjusted in time.
The nanometer diagnosis and treatment agent can carry the anti-tumor drugs and simultaneously carry a plurality of anti-tumor drugs or sensitizer and anti-tumor drugs, thereby realizing the synergistic effect of a plurality of drugs and improving the treatment effect.
The nanometer diagnosis and treatment agent has nanometer structure, and can improve the EPR effect of tumor tissue, the circulation time of medicine in vivo and the medicine concentration in tumor part.
Preferably, the small molecule antitumor drug comprises one or more of paclitaxel, docetaxel, doxorubicin, daunorubicin, gemcitabine, pemetrexed, platinum drugs, emtricitabine and tenofovir disoproxil.
Preferably, the metal ions having coordination ability include one or more of ferric ion, divalent zinc ion and platinum ion, monovalent silver ion or gold ion.
Preferably, the fluorescent dye comprises iversal, alexa Fluor 488, indocyanine green (ICG), ce6, methylene blue, sodium fluorescein, 5-aminolevulinic acid (5-ALA), fluorescein Isothiocyanate (FITC) or rhodamine.
Preferably, the small molecule antitumor drug is Paclitaxel (PTX), the compound with the polyphenol structure is dihydromyricetin (MYR) or tannic acid, and the metal ion with coordination ability is ferric ion.
The beneficial effects are that: PTX is used as a first-line small molecule anticancer drug, but has the problems of indissolvable property, no targeting, large toxic and side effects and the like, and limits the clinical application of the PTX. MYR can reduce toxicity generated by PTX by improving the capacity of an organism to resist oxidation system, and enhance the efficacy of PTX.
MYR as strong reducer has the disadvantages of poor solubility, poor stability, poor bioavailability and the like, and Fe is utilized 3+ The MYR is a platform, so that the solubility and stability of MYR can be improved, and the bioavailability in vivo can be improved, thereby enhancing the synergistic anti-tumor function of MYR.
A preparation method of a nanometer diagnosis and treatment agent comprises the following steps:
(1) Covalently coupling the small-molecule antitumor drug with a small-molecule ligand to obtain a small-molecule antitumor drug-small-molecule ligand, namely a small-molecule antitumor drug prodrug;
(2) Mixing a small-molecule antitumor drug prodrug with an excessive amount of metal ions with coordination ability to form a first coordination complex;
(3) The first coordination complex and the compound of the polyphenol structure which is coupled with the covalent coupling are mixed with fluorescent dye to form the nano diagnosis and treatment agent.
The beneficial effects are that: and (3) obtaining a small-molecule antitumor prodrug in the step (1), then under the condition of excessive metal ions with coordination ability, coordinating with the metal ions to form the inner core of the nano diagnosis and treatment agent, and then coordinating and combining the covalently coupled polyphenol-structured compound-fluorescent dye with the metal ions with coordination ability to form the periphery of the nano diagnosis and treatment agent, thereby forming the nano diagnosis and treatment agent.
Preferably, the small molecule antitumor drug comprises one or more of paclitaxel, docetaxel, doxorubicin, daunorubicin, gemcitabine, pemetrexed, platinum drugs, emtricitabine and tenofovir disoproxil.
Preferably, the small molecule antitumor drug is paclitaxel.
The structure of taxol is utilized, and micromolecular ligand (dopamine, evanskian (EB), folic acid and 5-methyl folic acid) which is covalently coupled with Linker is used for covalently coupling taxol to prepare polyphenol-taxol prodrug/fluorescent dye-polyphenol-taxol prodrug. The nanometer diagnosis and treatment agent carries MYR and targeting taxol prodrug together, has high drug loading capacity and good stability, and can realize the purposes of synergistic drug effect, in-vivo and in-vitro diagnosis and PTX drug effect improvement.
The coordination compound formed by coordination of MYR and ferric iron can solve the problems of insoluble MYR, poor stability and the like, and improve the functions of oxidation resistance and tumor resistance of MYR in vivo.
The MYR is utilized to remove oxygen free radicals, and the function of an organism antioxidant system is enhanced, so that the synergistic medication of MYR and taxol is realized, and the efficacy of an antitumor micromolecular chemotherapeutic drug is improved.
The paclitaxel exists in the form of targeting prodrug in the nano diagnosis and treatment agent, the toxicity of PTX is reduced on the premise of improving the active targeting of the paclitaxel, the function of promoting the expression of immune protein of PTX in a low-toxicity state is realized, and the drug effect of PTX is improved.
The PTX-polyphenol-fluorescent dye or the polyphenol-fluorescent dye is utilized to further modify the nano diagnosis and treatment agent, so that the metabolic pathway of the medicine in the body can be monitored while the biocompatibility of the nano diagnosis and treatment agent is increased.
Preferably, the step (1) specifically includes the following steps: dissolving succinic anhydride-taxol in dichloromethane, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS), stirring at room temperature, adding dopamine, stirring at room temperature overnight, and purifying the reaction solution by a silica gel column to obtain dopamine-taxol.
Preferably, the solvent of the small molecule antitumor drug is dichloromethane or dimethylformamide solution, and the concentration is 1-10mg/mL.
Preferably, in the step (2), the small molecule antitumor drug prodrug is mixed with an excess of a metal salt solution of the metal ion having coordination ability, which is an aqueous halide solution.
Preferably, the aqueous halide solution is a chloride solution at a concentration of 1-10mg/mL, preferably 3mg/mL.
Preferably, the metal ion having coordination ability is selected from ferric ion, divalent zinc ion and platinum ion, monovalent silver ion and gold ion or a combination thereof.
Preferably, the preparation steps of the compound-fluorescent dye with a polyphenol structure are as follows: the amino group in the polyphenol structural compound reacts with polyethylene glycol or fluorescent dye with NHS under EDC/NHS or DDC/NHS catalysis to prepare the polyethylene glycol-polyphenol or polyphenol-fluorescent dye.
Wherein/represent the sum.
Preferably, the polyethylene glycol molecule is a carboxyl polyethylene glycol molecule, more preferably, the polyethylene glycol molecule carboxyl is NHS, and the molecular weight of the polyethylene glycol molecule is 5000-100000, preferably 100000-200000, more preferably 200000.
Preferably, the compound of the polyphenol structure is added in the form of an aqueous solution at a concentration of 100-600mg/mL, preferably 200mg/mL.
Preferably, the small-molecule antitumor drug solution is added into the soluble metal salt solution of the metal ions with coordination ability and then is vortexed, optionally for 1-10 minutes, preferably for 3 minutes;
preferably, the polyphenol solution is added and mixed with the small-molecule antitumor drug prodrug and then vortexed, optionally for 1-10 minutes, preferably for 3 minutes;
preferably, the compound of the polyphenol structure-fluorescent dye is mixed with the first coordination complex and then vortexed, optionally for 1-10 minutes, preferably for 3 minutes;
preferably, the ratio of the polyphenol compound solution to the shell molecule solution is: 40 percent to 60 percent.
Preferably, the step of purifying the nano-medical agent is to put the nano-medical agent into a dialysis bag and dialyze in double distilled water solution.
Preferably, the nano diagnosis and treatment agent is placed in a dialysis bag with a molecular weight of 5000-10000 for dialysis overnight, the rotation speed of a rotor is 200-500 rpm/min, more preferably, the molecular weight of the dialysis bag is 8000, and the rotation speed is 300 rpm/min.
The invention also provides a combined drug system which comprises the nano diagnosis and treatment agent.
The invention also provides a kit which comprises the nano diagnosis and treatment agent.
The invention has the advantages that: the nano diagnosis and treatment agent can overcome the defects of low drug encapsulation efficiency, poor stability and the like of the traditional liposome formulation, and simultaneously avoid the problems of strong drug resistance and the like of the targeting small molecule prodrug.
The nano diagnosis and treatment agent provided by the invention carries the compound with the polyphenol structure and the small-molecule anti-tumor drug, has high drug loading capacity and good stability, and can realize the purposes of synergistic drug effect, in-vivo and in-vitro diagnosis and improvement of the small-molecule anti-tumor drug.
In tumor treatment, two separate processes of diagnosis and treatment are integrated, so that diagnosis-treatment is synchronously carried out in tumor treatment, and the treatment scheme can be adjusted in time.
The nanometer diagnosis and treatment agent can carry the anti-tumor drugs and simultaneously carry a plurality of anti-tumor drugs or sensitizer and anti-tumor drugs, thereby realizing the synergistic effect of a plurality of drugs and improving the treatment effect.
The nanometer diagnosis and treatment agent has nanometer structure, and can improve the EPR effect of tumor tissue, the circulation time of medicine in vivo and the medicine concentration in tumor part.
PTX is used as a first-line small molecule anticancer drug, but has the problems of indissolvable property, no targeting, large toxic and side effects and the like, and limits the clinical application of the PTX. MYR can reduce toxicity generated by PTX by improving the capacity of an organism to resist oxidation system, and enhance the efficacy of PTX.
MYR as strong reducer has the disadvantages of poor solubility, poor stability, poor bioavailability and the like, and Fe is utilized 3+ The MYR is a platform, so that the solubility and stability of MYR can be improved, and the bioavailability in vivo can be improved, thereby enhancing the synergistic anti-tumor function of MYR.
Drawings
FIG. 1 is a synthetic route for dopamine-paclitaxel according to example 1 of the present invention;
FIG. 2 is a TEM image of the nano-medical agent of the present invention in examples 4 and 5;
FIG. 3 is a DLS chart of the nano-medical agent of the present invention in example 4 and example 5;
FIG. 4 is a graph showing the expression level of dopamine receptor mRNA of U87MG and 293T cells detected by reverse transcription PCR according to the present invention, wherein a is U87MG and b is 293T; the right bar in b represents U87MG;
FIG. 5 is a graph of the uptake of DA-PTX-FITC and FITC-TDPP NPs by tumor cells U87MG observed under a laser confocal microscope;
FIG. 6 is a graph showing the quantitative determination of uptake rates of DA-PTX-FITC and FITC-TDPP NPs by tumor cells U87MG by flow cytometry of the present invention;
FIG. 7 is a graph showing the results of animal level studies of targeting of TDPP NPs in U87MG tumor tissue in accordance with the present invention;
FIG. 8 is a graph showing the results of the tumor suppression rate measurement of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The test materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Those of skill in the art, without any particular mention of the techniques or conditions, may follow the techniques or conditions described in the literature in this field or follow the product specifications.
Example 1
Preparation of dopamine-paclitaxel (DA-PTX) prodrug the preparation scheme is shown in FIG. 1.
(1) Synthesis of succinic anhydride-paclitaxel (SUC-PTX)
100mg (0.117 mmol) of PTX was weighed into 15mL of DCM, 59.7mg (0.264 mmol,1.2eq v) of succinic anhydride (SUC) and 14.29mg of DMAP (0.117 mmol) were added simultaneously, 44.85mg (0.234 mmol,2eq v) of EDC was dissolved into 10mL of DCM, 10mL of the solution dissolved in EDC was slowly dropped into the PTX reaction system under ice bath conditions, the ice bath was removed after the dropwise addition was completed, stirring was carried out at room temperature for 26 hours, and the reaction was traced by TLC. After the reaction is finished, the mixture is diluted by DCM with the same volume, then washed by distilled water with the same volume for 2 times, added with anhydrous magnesium sulfate for drying, and the crystalline lens product succinic anhydride-taxol (SUC-PTX) is obtained after vacuum rotary evaporation.
(2) Preparation of dopamine-paclitaxel (DA-PTX) prodrugs
The product, 0.01mmol SUC-PTX, was dissolved in 8mL DCM, EDC and NHS (molar ratio 1:1.2:2) were added to activate the carboxyl group of SUC-PTX, after stirring for 4 hours at room temperature, 0.01mmol DA was added, stirring overnight at room temperature, the reaction solution was purified by silica gel column to give purified dopamine-taxol (DA-PTX) and its chemical structure was characterized.
Example 2
This embodiment differs from embodiment 1 in that: the DA-PEG was obtained by covalently coupling 500mgPEG with 6 mgDA. Wherein the molecular weight of PEG is 200000.
Example 3
This embodiment differs from embodiment 1 in that: 5mg of Fluorescein Isothiocyanate (FITC) was covalently coupled to 2mg of DA to give DA-FITC.
Example 4
Preparation of self-assembled nano diagnosis and treatment agent
(1) Preparing a ferric trichloride aqueous solution with the concentration of 4mg/mL and a dihydromyricetin (MYR) DMF solution with the concentration of 1 mg/mL;
(2) 30. Mu.L of DA-PTX with concentration of 5mg/mL and dimethylformamide as solvent is taken, 80. Mu.L of ferric trichloride solution with concentration of 3mg/mL is added, and the mixture is vortexed for 2 minutes (2000 times/minute);
(3) Dropwise adding 150 mu L of MYR DMF solution with the concentration of 1mg/mL into the step (2), and swirling for 3 minutes (1500 times/min);
(4) To step (3), 20. Mu.L of DA-FITC obtained in example 3 was slowly added dropwise at a concentration of 150mg/mL, and vortexed for 3 minutes (1500 times/min) to form.
(5) Dialyzing overnight in water solution in a dialysis bag with molecular weight of 8000, rotating at 320 times/min to obtain dialysate, named MDPP NP-a, and storing at-20deg.C.
Example 5
This embodiment differs from embodiment 4 in that: and (3) dropwise adding 150 mu L of MYR DMF solution with the concentration of 1mg/mL into the solution, replacing the solution with 100 mu L of Tannic Acid (TA) aqueous solution with the concentration of 1mg/mL into the solution, obtaining a dialysate which is the nano diagnosis and treatment agent, and then naming the dialysate as TDPP NP-b and storing the dialysate at the temperature of minus 20 ℃ for later use.
Experimental data and characterization:
(1) As can be seen from fig. 2 and 3, the particle sizes of the two nano-medical agents are respectively: MDPP NP-a: 77.3+ -5.3 nm, TDPP NP-b: 52.2.+ -. 4nm.
(2) Uptake of nanomedicine in tumor cells:
materials: human glioma cells U87MG tumor cells were purchased from the national center cell bank.
The test steps are as follows: the expression level of DRs (D2) on 293T and U87MG was detected by PCR. DA-PTX and TDPP NP-b were labeled with FITC fluorescent dye, and tumor cells U87MG were incubated with 0.68. Mu.M (PTX concentration), respectively, and cell uptake was analyzed qualitatively and quantitatively by laser confocal microscopy and flow cytometry.
The experimental results are shown in fig. 4-6, and the expression level of dopamine receptor on normal cell 293T and tumor cell U87MG is detected by reverse transcription PCR method, and fig. 4a-b show that the expression level of dopamine receptor on tumor cell surface is far greater than that of normal cell 293T. As shown in FIG. 6, under a laser confocal microscope, both the DA-PTX prodrug marked by fluorescence and the TDPP NP-b nano-agent (FITC-TDPP NPs in the figure) are increased along with time, and the fluorescence intensity is stronger and stronger, which shows that the uptake of the DA-PTX-FITC and the FITC-TDPP NPs by the tumor cell U87MG is in direct proportion to time. The uptake rate of DA-PTX-FITC and FITC-TDPP NPs in U87MG tumor cells is quantitatively analyzed by a flow cytometer, the uptake rate of the DA-PTX-FITC and FITC-TDPP NPs in the U87MG tumor cells is as high as 87.19%, and the fluorescence intensity of the DA-PTX-FITC and FITC-TDPP NPs has obvious displacement after uptake, so that the TDPP NP-b has better uptake rate in the tumor cells compared with the DA-PTX prodrug.
(3) Application test
30U 87MG tumor mice (tumor volume: 95.+ -. 28mm 3) were divided into 3 groups: PTX, DA-PTX and TDPP NP-b, 6mg/kg PTX or DA-PTX and TDPP NP-b equivalent to 6mg/kg PTX, respectively, were injected. Every 3 tumor mice were bled at 0.15,0.25,0.5,1,2,4,6,8,24,and 48h time point post injection. Each 100. Mu.L of plasma was extracted with 3mL of diethyl ether and 30. Mu.L of internal standard diazepam (500 ng/mL) was added and centrifuged at 15000 for 3min, the supernatant was taken and blow dried and redissolved in 200. Mu.L of methanol for HPLC detection. Likewise, the tissue was homogenized at 0.2g to 2mL of a saline solution, extracted 3 times with diethyl ether, centrifuged for 10min, and the solution was blow-dried with nitrogen and redissolved in 300. Mu.L of methanol for HPLC analysis.
Imaging results see fig. 7, and it can be seen that the distribution of paclitaxel in blood and tissues in vivo is studied by using a pharmacokinetic method, which proves that compared with paclitaxel monomers and DA-PTX paclitaxel prodrugs, TDPP NP-b has the advantages of increasing half-life in vivo and retention and time in tumor tissues, and reducing accumulation of paclitaxel in liver, thereby improving targeting of drugs and reducing toxicity.
The distribution of the FITC-labeled DA-PTX and TDPP NP-b nano drug-loading system in tumor tissues is observed under a fluorescence microscope, a small amount of tumor tissues are taken after tail vein injection is carried out for 48 hours and 72 hours to prepare tumor tissue slices, the fluorescence of the FITC-TDPP NPs group is shown in FIG. 7, meanwhile, the fluorescence intensity of the FITC-TDPP NPs group is obviously stronger than that of the DA-PTX-FITC group, and the EPR effect of the TDPP NP-b nano drug-loading system in the tumor tissues can enhance the targeting property of the TDPP NP-b nano drug-loading system.
(4) Experiment of drug efficacy
Average random U87MG tumor mice were divided into five groups: control, PBS pH7.4 solution set; PTX single product with the dosage of 6mg/kg; TA+PTX, 6mg/kg based on the amount of PTX contained; TDPP NP-b, 6mg/kg based on the amount of PTX contained. When tumors all grew to 2cm, the mice were sacrificed, the tumors were removed and weighed by intravenous injection at the tail of every other day for three consecutive days, the mice were terminated in experimental investigation, the weights of the groups of nude mice were weighed daily during this period, and the survival rates were calculated. The tumor mice were observed for body weight, tumor size change, and mortality by three injections of tail vein three times per day using the U87MG tumor model.
As shown in FIG. 8, the experimental result shows that the tumor inhibition rate of the PTX monomer group is 51.06%, the tumor inhibition rate of the TA+PTX group is 58.09%, the tumor inhibition rate of the TDPP NP-b group is as high as 76.8%, the tumor inhibition effect is obviously better than that of the PTX monomer group and the TA+PTX group, and after 16 days of treatment, the tumor necrosis is reduced, which indicates that the PTX is targeted to the tumor part by using the TA as a medicament of the carrier, and the TA carrier can promote the PTX to inhibit the tumor, and the drug effect of the TDPP NP-b is the superposition effect of the PTX and the TA.
The invention selects targeted polyphenol (5-hydroxydopamine) covalent coupling antitumor micromolecule drug taxol and fluorescent dye or other micromolecule drugs to prepare targeted drug prodrug or micromolecule anticancer drug Doxorubicin (DOX) with phenolic hydroxyl structure, polyphenol compound (MYR), polyphenol-fluorescent dye and polyphenol covalent coupling soluble macromolecule PEG (5-hydroxydopamine-PEG). In coordination with metal ion Fe 3+ In excess, the Fe is formed gradually from the nucleus to the outside 3+ -polyphenol-PTX-fluorescent dye @ MYR-PEG/Fe 3+ -the polyphenol-ptx@myr-PEG-Y fluorescent dye forms a stable nanoparticle complex. Wherein Fe is 3+ polyphenol-PTX as core of nanoparticle, fe 3+ MYR is the surface of the nanoparticle, and dopamine-PEG/dopamine-fluorescent dye is the periphery of the nanoparticle.
The invention utilizes the technology of combining organic synthesis and metal-polyphenol coordination to form nano particles, and the first step of Fe 3+ Formation of coordination with a binding site on the polyphenol-PTX structure to form Fe 3+ PTX Compound As a first step in FIG. 1, red represents Fe 3+ PTX compound, second step excess Fe 3+ Two binding sites form coordination with MYR to further form Fe 3+ -polyphenol-ptx@myr/TA, in a third step, excess iron coordinates with PEG-polyphenol/fluorochrome-polyphenol to form a self-assembled nano-diagnostic agent.
The invention prepares the inner core containing the taxol prodrug/fluorescent label-taxol prodrug by combining the technology of organic synthesis and nano preparation, fe 3+ -MYR/PEG-fluorescent dye-polyphenol as the periphery of the nano-diagnostic agent, self-assembling a novel nano-diagnostic agent. Use of "fluorescent dye- & gt monitoring drug distribution and metabolism", "polyphenols and Fe 3+ Scavenging oxygen free radical ROS and 'small molecular polyphenol enhancing small molecular medicine/chemotherapeutic medicine curative effect', killing tumor cells, and realizing accurate treatment of molecular images and chemotherapy.
The invention utilizes organic synthesis and chemical coordination method, uses first step small molecular medicine such as taxol, docetaxel and Doxorubicin (DOX) to prepare taxol or docetaxel into polyphenol prodrug such as dopamine-taxol/docetaxel or fluorescent dye labeled-dopamine-taxol/docetaxel or doxorubicin DOX by utilizing organic synthesis, prepares small molecular antitumor prodrug, uses dihydromyricetin with active site and excessive ferric ion to form coordination compound as skeleton of nano diagnosis and treatment agent, uses small molecular polyphenol to covalently couple PEG/PEG-polyphenol-fluorescent dye to further coordinate with excessive ferric ion to prepare peripheral Fe of nano diagnosis and treatment agent 3+ PEG-polyphenol/PEG-fluorescent dye-polyphenol, increasing its biocompatibility/marking function, thus self-assembling into nano diagnosis and treatment agent, utilizing "fluorescent dye- & gt monitoring medicine distribution and tumor position", "Fe 3+ Polyphenol scavenging-oxygen free radical ROS and dihydromyricetin enhancing small molecular medicine/chemotherapeutic medicine curative effect are combined to kill tumor cells, so that accurate treatment of molecular image and chemotherapy is realized。
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (5)

1. A nano diagnosis and treatment agent, which is characterized in that: the inner core of the nano diagnosis and treatment agent is formed by coordination of a prodrug covalently coupled by a small-molecule antitumor drug and a small-molecule ligand and metal ions with coordination capability, and the periphery of the nano diagnosis and treatment agent is formed by covalent coupling of a compound with a polyphenol structure and a fluorescent dye;
the small molecule ligand is dopamine; the small-molecule antitumor drug is paclitaxel, the compound with the polyphenol structure is dihydromyricetin or tannic acid, and the metal ion with coordination ability is ferric ion;
the fluorescent dye comprises Evanskia, alexa Fluor 488, indocyanine green, ce6, methylene blue, sodium fluorescein, 5-aminolevulinic acid, fluorescein isothiocyanate or rhodamine.
2. A method for preparing the nano-therapeutic agent of claim 1, characterized by: the method comprises the following steps:
(1) Covalently coupling the small-molecule antitumor drug with a small-molecule ligand to obtain a small-molecule antitumor drug-small-molecule ligand, namely a small-molecule antitumor drug prodrug;
(2) Mixing a small-molecule antitumor drug prodrug with an excessive amount of metal ions with coordination ability to form a first coordination complex;
(3) The first coordination complex and the compound of the polyphenol structure which is coupled with the covalent coupling are mixed with fluorescent dye to form the nano diagnosis and treatment agent.
3. A method of preparing a nano-therapeutic agent according to claim 2, wherein: the step (1) specifically comprises the following steps: dissolving succinic anhydride-taxol in dichloromethane, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, stirring at room temperature, adding dopamine, stirring at room temperature overnight, and purifying the reaction solution by a silica gel column to obtain dopamine-taxol.
4. A method of preparing a nano-therapeutic agent according to claim 2, wherein: in the step (2), the small-molecule antitumor drug prodrug is mixed with an excessive amount of metal salt solution of metal ions with coordination ability, wherein the metal salt solution of the metal ions with coordination ability is a halide aqueous solution.
5. A kit comprising the nanodiagnostic agent of claim 1.
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