CN115212314A - Albumin-bound antitumor drug and nano-composite thereof, and preparation method and application thereof - Google Patents
Albumin-bound antitumor drug and nano-composite thereof, and preparation method and application thereof Download PDFInfo
- Publication number
- CN115212314A CN115212314A CN202210664403.0A CN202210664403A CN115212314A CN 115212314 A CN115212314 A CN 115212314A CN 202210664403 A CN202210664403 A CN 202210664403A CN 115212314 A CN115212314 A CN 115212314A
- Authority
- CN
- China
- Prior art keywords
- albumin
- acid
- polyphenol derivative
- antitumor drug
- polyphenol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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- 108010088751 Albumins Proteins 0.000 title claims abstract description 110
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 66
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 54
- 239000002114 nanocomposite Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 235000013824 polyphenols Nutrition 0.000 claims abstract description 118
- 150000008442 polyphenolic compounds Chemical class 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 29
- 229940079593 drug Drugs 0.000 claims abstract description 25
- 238000012377 drug delivery Methods 0.000 claims abstract description 6
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- 150000001875 compounds Chemical class 0.000 claims description 29
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- 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
- A61K47/62—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 a protein, peptide or polyamino acid
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
An albumin-bound antitumor drug and a nano-composite thereof, a preparation method and application belong to the technical field of medicines, and particularly relate to synthesis of a series of albumin-bound antitumor drug polyphenol derivatives, construction of an antitumor drug polyphenol derivative albumin nano-composite and application of the antitumor drug polyphenol derivative albumin nano-composite in drug delivery. The invention improves the affinity of the antitumor drug to the albumin by carrying out polyphenol derivatization modification on the antitumor drug, converts some drugs which cannot be originally prepared into albumin nanoparticles by a simple microfluid mixing mode into polyphenol derivatives which can be prepared into albumin-bound nanoparticles by simple mixing, provides new ideas and opportunities for developing the albumin nanoparticles of some drugs with poor protein binding rate, and also provides new strategies and selections for enriching and developing albumin-bound nano preparations of different types of drugs so as to meet the urgent needs of different types of high-end chemotherapy preparations clinically.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to synthesis of an albumin-bound antitumor drug polyphenol derivative, construction of an antitumor drug polyphenol derivative albumin nano-composite and application of the antitumor drug polyphenol derivative albumin nano-composite in a drug delivery system.
Background
Cancer is a serious disease threatening human health, the number of people suffering from cancer increases year by year, and the death rate is high. Chemotherapy remains the mainstay of cancer therapy, particularly for cancers that cannot be surgically removed and metastasized. However, most chemotherapy drugs are cytotoxic drugs, and have the disadvantages of low solubility, poor stability, narrow therapeutic window, poor pharmacokinetic properties, and the like. For example, the anticancer drug of star-paclitaxel has a wide anti-tumor spectrum, and is widely applied to the treatment of various cancers clinically as a first-line chemotherapeutic drug, including ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer and the like. However, the currently used Taxol injection (Taxol) in clinical use uses polyoxyethylene castor oil and ethanol as organic solvents, and these allergens can stimulate the body to release histamine, resulting in severe allergic reaction and peripheral neuropathy, and before use, the Taxol injection must be pretreated with glucocorticoid and antihistamine drugs, which is very inconvenient for clinical use. Of course, the clinical deficiencies of this formulation also leave a wide room for improvement in paclitaxel formulations. Albumin-binding paclitaxel nanoparticles with great attentionThe paclitaxel has a brilliant effect by virtue of wide adaptation diseases and low adverse reaction, is approved by FDA for treating breast cancer in 2005, and the adaptation diseases are expanded to non-small cell lung cancer, pancreatic cancer and the like. At present, the number of the current day,the annual global sales of which exceeds 10 billion dollars. Although it is a matter of courseGreat success is achieved, but the technical platform for preparing the nanoparticles also has certain limitations: (1) Has strict requirements on the physicochemical properties of the medicine, and the technology is mainly suitable for whiteningHydrophobic drugs with high protein binding rate, while some drugs with low albumin binding rate cannot realize high-efficiency entrapment; (2) The method needs to mix oil and water phases to prepare the primary emulsion, and has multiple operation steps and complex time consumption; (3) The method has higher requirements on instruments and equipment, generally needs high-pressure homogenizing equipment, and needs to work for hours under a high-pressure state, and the homogenizing process is easy to cause larger equipment loss, such as abrasion of pipelines and cavities, and the like, so that the production cost is increased; (4) During homogenization, the problem that the freeze-dried product is difficult to disperse due to albumin aggregation can be caused, and the product yield is adversely affected. Based on the above problems, how to find and develop a technical platform with wide applicability, mild preparation conditions, simple and easy operation, high throughput and high repeatability to realize the preparation of albumin nanoparticles of different drugs is a difficult problem and challenge faced by the next generation of drug delivery technology.
The polyphenol is widely existed in nature, is a secondary metabolite of plants, and has multiple biological activities of resisting oxidation, inflammation, bacteria, viruses and tumors, preventing cardiovascular and cerebrovascular diseases and the like. Dividing the polyphenol compounds into three classes according to the molecular structure characteristics: phenolic acids, flavonoids and non-flavonoids. The molecular structure of the phenolic acid compound comprises a carboxyl and a benzene ring, and each benzene ring is provided with one or more hydroxyl and/or methoxyl. The polyphenol structure of natural plants contains a large amount of catechol or pyrogallol groups, and the polyphenol hydroxyl groups endow the natural plant polyphenol structure with unique physicochemical properties, such as the ability of being combined with proteins through hydrogen bonds, hydrophobic interaction or electrostatic interaction and the like, and in addition, the natural plant polyphenol structure can also be complexed with metal ions. The naturally evolving biological phenomenon of polyphenol-protein interaction also exists widely in life, for example, when people eat fruits and beverages, the oral cavity can generate astringency feeling, and the astringency is the embodiment of the interaction of polyphenol substances and saliva protein in the oral cavity. Therefore, the natural interaction between polyphenol and protein also provides a new idea for the design of albumin-bound preparations. With the development of nanotechnology and materials science, several studies have demonstrated the great potential of polyphenols for their application in the field of drug delivery. However, no studies have been reported on the preparation of albumin-bound nano-formulations by polyphenol derivatization of chemically active drugs.
Disclosure of Invention
In order to overcome the existing Nab TM The invention designs and synthesizes the polyphenol derivative of the anti-tumor medicament with high protein affinity, and mixes the polyphenol derivative with human serum albumin through simple microfluid to prepare the albumin-bound anti-tumor polyphenol derivative nano compound with high drug loading and good stability, and provides the application of the albumin-bound anti-tumor polyphenol derivative nano compound in a medicament delivery system.
The invention is realized by the following technical scheme:
the invention provides an albumin-bound antitumor drug which is an antitumor drug polyphenol derivative with affinity with albumin, and the structural general formula is as follows:
wherein Drug is antitumor Drug containing hydroxyl, carboxyl, carbonyl, thiol or amino and selected from taxane, anthracycline, nucleoside, camptothecin, platinum, vinblastine, peneoside, artemisinin compound, macrolide, and terpenoid; the antitumor drug is connected with the Spacer through a Linker; wherein the Linker is ester, amide, imine, oxime, hydrazone, carbonate, carbamate, borate, oxalate oxide, monothioether bond, disulfide bond, diselenide bond, trithioether bond or thioketal bond; the Spacer is an alkyl chain containing or not containing heteroatoms, double bonds or not, and the heteroatoms are O, S or N; n is an integer of 1 to 3.
Furthermore, the antitumor drugs are paclitaxel, docetaxel, cabazitaxel, podophyllotoxin, triptolide, larotaxel, rapamycin, SN-38, ursolic acid, oleanolic acid and glycyrrhetinic acid, in the antitumor drug polyphenol derivative, hydroxyl of the antitumor drugs is connected with phenolic acid compounds through ester bonds, the ester bonds are broken under the action of in vivo esterase to release antitumor drugs, and the molecular structure of the phenolic acid compounds comprises carboxyl and hydroxyl substituted benzene rings, including caffeic acid, p-coumaric acid, ferulic acid, sinapic acid, rosmarinic acid, 4-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, 3, 4-dihydroxybenzoic acid, 3,4, 5-trihydroxybenzoic acid and 3, 4-dihydroxyphenylacetic acid.
Still further, the paclitaxel polyphenol derivative with affinity to albumin according to the present invention is any one of the following structures:
the docetaxel polyphenol derivative with affinity with albumin has any one of the following structures:
the cabazitaxel polyphenol derivative with affinity to albumin has any one of the following structures:
the podophyllotoxin polyphenol derivative with affinity with albumin has the following structure:
the triptolide polyphenol derivative with affinity with albumin has the following structure:
the invention also provides a pharmaceutical composition which comprises the albumin-bound antitumor drug or the pharmaceutically acceptable salt and excipient thereof.
The invention also provides a synthesis method of the antineoplastic drug polyphenol derivative, which comprises the following steps:
reacting 4-hydroxybenzoic acid, or 3, 4-dihydroxybenzoic acid, or 3,4, 5-trihydroxybenzoic acid, or 3, 4-dihydroxybenzoic acid with benzyl bromide under the catalysis of anhydrous potassium carbonate to obtain 4-benzyloxybenzoic acid, or 3, 4-bis (benzyloxy) benzoic acid, or 3,4, 5-tris (benzyloxy) benzoic acid, or 3, 4-bis (benzyloxy) phenylacetic acid; under the catalysis of DMAP, EDCI and HOBT, 4-benzyloxy benzoic acid, 3, 4-bis (benzyloxy) benzoic acid, 3,4, 5-tris (benzyloxy) benzoic acid, or 3, 4-bis (benzyloxy) phenylacetic acid reacts with antitumor drugs containing hydroxyl, and an intermediate compound is obtained by separation and purification; the intermediate compound is subjected to hydrogenation catalysis by palladium carbon, protecting groups are removed, and the antitumor drug polyphenol derivative is obtained through separation and purification.
For amino group-containing antitumor drugs: dissolving 4-benzyloxy benzoic acid, or 3, 4-bis (benzyloxy) benzoic acid, or 3,4, 5-tris (benzyloxy) benzoic acid, or 3, 4-bis (benzyloxy) phenylacetic acid in an organic solvent, adding O-benzotriazole-tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, performing ice bath, adding an antitumor drug containing amino, stirring for 24-48 h at room temperature to obtain an intermediate product, performing palladium-carbon hydrogenation catalysis, removing a protecting group, and performing liquid phase separation and purification to obtain the antitumor drug polyphenol derivative.
Furthermore, the invention also provides an antitumor drug polyphenol derivative albumin nano compound, which comprises the antitumor drug polyphenol derivative and albumin; the weight ratio of the polyphenol derivative of the antitumor drug to albumin is (1. The albumin is human serum albumin, bovine serum albumin or mouse serum albumin, preferably human serum albumin and bovine serum albumin.
The preparation method of the antitumor drug polyphenol derivative albumin nano compound comprises the following steps: dissolving the antitumor drug polyphenol derivative into an organic solvent to serve as an organic phase, dissolving albumin into deionized water to serve as a water phase, and mixing the organic phase and the water phase by rapid microflow to form a uniform nano compound with the antitumor drug polyphenol derivative and the albumin. The organic solvent is one or a mixture of acetone, ethanol, methanol, acetonitrile or tetrahydrofuran. The weight ratio of the antitumor drug polyphenol derivative to albumin is (1.
The invention also provides the application of the albumin-bound antitumor drug and the nano-composite thereof, or the pharmaceutical composition thereof in the preparation of a drug delivery system.
The invention also provides the application of the albumin-bound antitumor drug and the nano-composite thereof, or the pharmaceutical composition thereof in preparing antitumor drugs.
The invention also provides application of the albumin-bound antitumor drug and the nano-composite thereof or the pharmaceutical composition thereof in preparation of injection administration, oral administration or local administration systems.
The antitumor drug polyphenol derivative albumin nano compound has the advantages that: (1) By adopting the micro-fluidic technology, the proportion of an organic phase and a water phase and the total flow rate can be accurately controlled, the preparation process is simple, and the large-scale production is easy to realize; (2) The particle size is small and uniform (110 nm), and the accumulation in tumor tissues is facilitated through an EPR effect; (3) the drug loading is high and the stability is good; (4) The freeze-drying is easy, the redispersibility is good after redissolution, and the long-term storage is convenient; (5) The pharmacokinetic property is better, and particularly, the pharmacokinetic property of the taxol-gallic acid derivative is optimal; (6) Compared with the commercial preparation, the tolerance dose of the prepared taxol polyphenol derivative albumin nano compound is obviously improved; (7) The tumor inhibition effect is improved, the toxic and side effects are obviously reduced, and the clinical application potential is greater.
The Drug in the invention is not limited to anti-tumor drugs, but also can be anti-metabolism drugs, anti-inflammatory drugs, antibacterial drugs, hormone drugs, antimalarial drugs or other insoluble drugs. The antimetabolite is selected from pyrimidine, purine and capecitabine; the anti-inflammatory drug is selected from non-steroids, diterpenes, triterpenes and glycosides and tetraterpenoids thereof; the antibacterial drugs are selected from beta lactams, macrolides, sulfonamides, aminoglycosides, quinolones, polypeptidyl, phosphorus-containing polysaccharides and polyethers; the hormone medicine is selected from adrenal cortex hormone, sex hormone and thyroid hormone; the antimalarial drugs are selected from artemisinin, aminoquinoline, quinolones or other insoluble drugs and derivatives thereof.
The invention has the beneficial effects that:
the invention improves the affinity of the antitumor drug to albumin by carrying out polyphenol derivatization modification on the antitumor drug, converts some drugs which cannot be prepared into albumin nanoparticles by simple microfluid mixing into polyphenol derivatives which can be prepared into albumin-bound nanoparticles by simple mixing, provides new ideas and opportunities for developing albumin nanoparticles of some drugs with poor protein binding rate, and also provides new strategies and selections for enriching and developing albumin-bound nano preparations of different types of drugs so as to meet the urgent needs of different types of high-end chemotherapy preparations clinically.
Drawings
FIG. 1 is a high resolution mass spectrum and analysis of the phenyl derivative of paclitaxel (PTX-PH) with benzoic acid as the phenolic moiety in example 1 of the present invention 1 H-NMR spectrum.
FIG. 2 is a high resolution mass spectrum and sum of the spectrum of paclitaxel polyphenol derivative (PTX-PA) with 4-hydroxybenzoic acid as the phenolic acid moiety in example 2 of the present invention 1 H-NMR spectrum.
FIG. 3 is a high-resolution mass spectrum and sum of spectra of paclitaxel polyphenol derivative (PTX-CA) with 3, 4-dihydroxybenzoic acid as phenolic acid moiety in example 3 of the present invention 1 H-NMR spectrum.
FIG. 4 is a high-resolution mass spectrum and sum of spectra of paclitaxel polyphenol derivative (PTX-GA) having 3,4, 5-trihydroxybenzoic acid as a phenolic acid moiety in example 4 of the present invention 1 H-NMR spectrum.
FIG. 5 is a high resolution mass spectrum of a paclitaxel polyphenol derivative (PTX-EA) with a phenolic acid moiety of 3, 4-dihydroxybenzeneacetic acid according to example 5 of the present invention.
FIG. 6 is a high resolution mass spectrum of docetaxel polyphenol derivative having 3, 4-dihydroxybenzoic acid as the phenolic acid moiety (DTX-CA) of example 6 of the present invention and 1 H-NMR spectrum.
FIG. 7 is a high-resolution mass spectrum and sum of spectra of docetaxel polyphenol derivative (DTX-GA) having 3,4, 5-trihydroxybenzoic acid as a phenolic acid moiety obtained in example 7 of the present invention 1 H-NMR spectrum.
FIG. 8 is a high resolution mass spectrum and sum of spectrum of Cabazitaxel polyphenol derivative (CTX-CA) with 3, 4-dihydroxybenzoic acid as phenolic acid moiety in example 8 of the present invention 1 H-NMR spectrum.
FIG. 9 is a high-resolution mass spectrum and sum of spectra of cabazitaxel polyphenol derivative (CTX-GA) in which the phenolic acid moiety is 3,4, 5-trihydroxybenzoic acid according to example 9 of the present invention 1 H-NMR spectrum.
FIG. 10 is a high-resolution mass spectrum and sum of spectra of podophyllotoxin polyphenol derivative (POD-CA) having 3, 4-dihydroxybenzoic acid as the phenolic acid moiety in example 10 of the present invention 1 H-NMR spectrum.
FIG. 11 is a high-resolution mass spectrum and sum of spectra of triptolide polyphenol derivative (TPL-GA) with 3,4, 5-trihydroxybenzoic acid as the phenolic acid moiety in example 11 of the present invention 1 H-NMR spectrum.
FIG. 12 is a graph showing the affinity values and kinetic fits of the paclitaxel polyphenol derivative of example 12 of the present invention to human serum albumin.
Fig. 13 is a graph of a particle size distribution and an appearance of docetaxel polyphenol derivative, cabazitaxel polyphenol derivative, podophyllotoxin polyphenol derivative, and triptolide polyphenol derivative albumin nanocomposite according to example 13 of the present invention.
Fig. 14 is an appearance morphology diagram of a lyophilized powder and a reconstituted paclitaxel polyphenol derivative albumin nanocomposite obtained in example 14 of the present invention.
Fig. 15 is a graph of the change in body weight of mice subjected to tolerance experiments using the paclitaxel solution, the commercially available albumin-bound paclitaxel nanoparticles, and the paclitaxel polyphenol derivative albumin nanocomposite of example 16 of the present invention.
FIG. 16 is a graph of in vivo efficacy experiment of paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention showing the growth curve of tumor volume versus time in 4T1 tumor-bearing mice.
FIG. 17 is a graph showing the change of body weight with time in 4T1 tumor-bearing mice in the in vivo efficacy experiment of paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention.
FIG. 18 is a graph showing the change of blood index of 4T1 tumor-bearing mice in the in vivo efficacy experiment of paclitaxel polyphenol derivative albumin nanocomposite according to example 17 of the present invention.
FIG. 19 is a graph of the in vivo efficacy of paclitaxel polyphenol derivative albumin nanocomposite in MCF-7 tumor volume-time growth in mice bearing tumors according to example 17 of the present invention.
FIG. 20 is a graph showing the change of weight with time of MCF-7 tumor-bearing mice in the in vivo efficacy experiment of paclitaxel polyphenol derivative albumin nanocomposite of example 17 of the present invention.
Fig. 21 is a graph of in vivo efficacy experiment of docetaxel polyphenol derivative albumin nanocomposite of example 18 of the present invention showing tumor volume-time growth in 4T1 tumor-bearing mice.
Fig. 22 is a graph of the change of the in vivo efficacy of the docetaxel polyphenol derivative albumin nanocomposite of example 18 in 4T1 tumor-bearing mice in weight versus time.
Detailed Description
The following examples are intended to further illustrate the invention, but are not intended to limit the invention in any way.
Example 1
Synthesis of paclitaxel-phenyl derivatives (PTX-PH)
Benzoic acid (91.5mg, 0.75mmol), DMAP (91.62mg, 0.75mmol), EDCI (143.75mg, 0.75mmol) and HOBT (101.3mg, 0.75mmol) were weighed out accurately, added to a 100mL eggplant-type bottle, dissolved with 25mL of anhydrous dichloromethane, and stirred for 2h in an ice-water bath. Then, PTX (426.8 mg,0.5 mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in an ice bath, heated to 25 ℃ to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. And after the reaction is finished, spin-drying the reaction liquid to obtain a crude product. The crude product was isolated and purified from the preparation (white powder, yield 35.3%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 1, and the results of NMR spectroscopy were as follows: δ 9.31 (d, J =8.9Hz,1H,3 '-NH), 8.03 (d, J =7.4Hz,2H,2' -o-OBz), 7.95 (d, J =7.5Hz,2H, 2-o-OBz), 7.84 (d, J =7.3Hz,2H,3 '-o-NHBz), 7.72 (t, J =7.4Hz,2H,2-p-OBz,2' -p-OBz), 7.61 (t, J =7.7Hz,2H,2 '-m-OBz), 7.58-7.52 (m, 5H,3' -p-NHBz,3'-m-NHBz, 2-m-OBz), 7.48 (t, J =7.1Hz,4H,3' -o-Ph,3 '-m-Ph), 7.24 (t, J =7.4hz,1h,3' -p-Ph), 6.31 (s, 1H, 10-H), 5.88 (t, J =9.0hz,1h, 13-H), 5.80 (t, J =8.7hz,1h,3 '-H), 5.55 (d, J =8.6hz,1h,2' -H), 5.43 (d, J =7.2hz,1h, 2-H), 4.96-4.91 (m, 2h,5-H, 7-OH), 4.68 (s, 1h, 1-OH), 4.14 (dt, J =11.0,6.9hz,1h, 7-H), 4.05-3.98 (m, 2h,20-CH 2 ),3.62(d,J=7.2Hz,1H,3-H),2.37–2.30(m,1H,6α-H),2.28(s,3H,4-OAc),2.10(s,3H,10-OAc),1.90(dd,J=15.3,9.4Hz,1H,14α-H),1.84(s,3H,18-CH 3 ),1.68–1.59(m,2H,14β-H,6β-H),1.51(s,3H,19-CH 3 ),1.03(s,3H,17-CH 3 ),1.01(s,3H,16-CH 3 ).
Example 2
Synthesis of paclitaxel-4-hydroxybenzoic acid derivative (PTX-PA)
4-hydroxybenzoic acid (304.3mg, 2.0 mmol), benzyl bromide (342.6mg, 2.0 mmol) and anhydrous potassium carbonate (828.2mg, 6.0 mmol) were weighed out precisely, added to a 100mL eggplant-type bottle, dissolved in 30mL DMF, stirred at 70 ℃ for 48h, the progress of the reaction was monitored by thin layer chromatography, and after the reaction was completed, 4-benzyloxybenzoic acid was obtained by column chromatography. 4-Benzyloxybenzoic acid (171.6 mg, 0.75mmol), DMAP (91.62mg, 0.75mmol), EDCI (143.75mg, 0.75mmol) and HOBT (101.3mg, 0.75mmol) were weighed out precisely, charged into a 100mL eggplant-shaped bottle, dissolved with 25mL of anhydrous dichloromethane, and stirred for 2 hours in an ice-water bath. Then, PTX (426.8mg, 0.5mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in an ice bath, heated to 25 ℃ to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. And after the reaction is finished, spin-drying the reaction liquid to obtain a crude product. The crude product was isolated and purified from the preparation to give an intermediate product (white powder, yield 15.3%). The intermediate (130.1 mg) was added to a 100mL eggplant-shaped flask and dissolved with 15mL absolute ethanol. Then adding the intermediate product by mass10% of Pd/C (13mg, 10% w/w) in H 2 The reaction was carried out for 8 hours at room temperature under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, pd/C is removed by filtration through a microporous membrane, and the filtrate is separated and purified through a preparative liquid phase to obtain the target product PTX-PA (white powder, yield 90.5%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 2, and the results of NMR spectroscopy were as follows: δ 10.51 (s, 1h,2 '-OBzOH), 9.27 (d, J =8.9hz,1h,3' -NH), 7.94 (d, J =7.5hz,2h, 2-o-OBz), 7.87 (d, J =8.6hz,2h,2 '-o-OBz), 7.84 (d, J =7.4hz,2h,3' -o-NHBz), 7.72 (t, J =7.4hz,1h, 2-p-OBz), 7.60 (t, J =7.7hz,2H, 2-m-OBz), 7.58-7.44 (m, 7h,3'-p-NHBz,3' -m-NHBz,3'-o-Ph,3' -m-Ph), 7.23 (t, J =7.3hz,1h,3 '-p-Ph), 6.86 (d, J =8.6hz,2h,2' -m-OBz), 6.30 (s, 1h, 10-H), 5.85 (t, J =8.9hz,1h, 13-H), 5.75 (t, J =8.4hz,1h,3 '-H), 5.47 (d, J =8.7Hz,1H,2' -H), 5.42 (d, J =7.2Hz,1H, 2-H), 4.95-4.90 (m, 2H,5-H, 7-OH), 4.66 (s, 1H, 1-OH), 4.13 (dt, J =11.0,6.9Hz,1H, 7-H), 4.05-3.96 (m, 2H, 20-CH) 2 ),3.61(d,J=7.1Hz,1H,3-H),2.33(td,J=8.1,3.1Hz,1H,6α-H),2.28(s,3H,4-OAc),2.10(s,3H,10-OAc),1.89(dd,J=15.2,9.6Hz,1H,14α-H),1.82(s,3H,18-CH 3 ),1.68–1.56(m,2H,14β-H,6β-H),1.50(s,3H,19-CH 3 ),1.02(s,3H,17-CH 3 ),1.00(s,3H,16-CH 3 ).
Example 3
Synthesis of paclitaxel-3, 4-dihydroxybenzoic acid derivative (PTX-CA)
3, 4-dihydroxy benzoic acid (308.2mg, 2.0 mmol), benzyl bromide (856.5mg, 5.0 mmol) and anhydrous potassium carbonate (1104.1mg, 8.0 mmol) were weighed out precisely, added to a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70 ℃ for 48h, the progress of the reaction was monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3mg, 1.0 mmol), DMAP (122.1mg, 1.0 mmol), EDCI (191.67mg, 1.0 mmol) and HOBT (135.1mg, 1.0 mmol) were weighed out accurately, charged into a 100mL eggplant-type flask, dissolved in 25mL of dichloromethane, and stirred for 2 hours under ice bath. Then, PTX (571.5 mg, 0.67mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution under stirring in an ice bath, and transferred to room temperature to continue the reactionThe progress of the reaction was monitored by thin layer chromatography for 24 h. After the reaction was completed, the reaction solution was spin-dried, and a sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 45.2%). The intermediate (383.8 mg) was added to a 250mL eggplant-shaped flask and dissolved with 50mL of absolute ethanol. Then, 10% by mass of Pd/C (38mg, 10% w/w) of the intermediate product was added thereto in the presence of H 2 The reaction was carried out for 8 hours at room temperature under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by a microporous membrane to remove Pd/C, and separating and purifying the filtrate by a preparative liquid phase to obtain the target product PTX-CA (grey pink solid, yield 91.2%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 3, and the results of NMR spectroscopy were as follows: δ 9.29 (d, J =8.7Hz,1H,3' -NH), 7.94 (d, J =7.5Hz,2H, 2-o-OBz), 7.84 (d, J =7.4Hz,2H,3' -o-NHBz), 7.71 (t, J =7.4Hz,1H, 2-p-OBz), 7.60 (t, J =7.7Hz,2H, 2-m-OBz), 7.54 (t, J =7.3Hz,1H,3' -p-NHBz), 7.53-7.43 (m, 6H,3' -m-NHBz,3' -o-Ph,3' -m-Ph), 7.38 (m, 2H,2' -o-OBz), 7.22 (t, J =7.3hz,1h,3' -p-Ph), 6.81 (d, J =8.1hz,1h,2' -m-OBz), 6.30 (s, 1h, 10-H), 5.83 (t, J =9.2hz,1h, 13-H), 5.70 (t, J =8.9hz,1h,3' -H), 5.46 (d, J =9.1hz,1h,2' -H), 5.41 (d, J =7.3hz,1h, 2-H), 4.92 (d, J =10.3hz,1h, 5-H), 4.13 (dd, J =10.7,6.8hz,1h, 7-H), 4.05-3.96 (m, 2h, 20-CH-OBz 2 ),3.61(d,J=7.2Hz,1H,3-H),2.34(td,J=8.0,3.2Hz,1H,6α-H),2.28(s,3H,4-OAc),2.10(s,3H,10-OAc),1.86(dd,J=15.2,9.5Hz,1H,14α-H),1.81(s,3H,18-CH 3 ),1.64(t,J=12.3Hz,1H,6β-H),1.55(dd,J=15.3,9.0Hz,1H,14β-H),1.50(s,3H,19-CH 3 ),1.02(s,3H,17-CH 3 ),1.00(s,3H,16-CH 3 ).
Example 4
Synthesis of paclitaxel-3, 4, 5-trihydroxybenzoic acid derivative (PTX-GA)
3,4, 5-Trihydroxybenzoic acid (340.2mg, 2.0 mmol), benzyl bromide (1027.8mg, 6.0 mmol) and anhydrous potassium carbonate (1380.3mg, 10.0 mmol) were weighed out precisely, and dissolved in 50mL of DMF in a 250mL eggplant-type flask, followed by stirring at 70 ℃ for 48 hours, monitoring the progress of the reaction by thin layer chromatography, and after completion of the reaction, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25mg, 1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were charged into a 100mL eggplant type bottle, dissolved with 25mL of dichloromethane and stirred for 2h under ice bath. Then, PTX (853.7mg, 1.0 mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in ice bath, transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and the sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 45.2%). The intermediate (383.8 mg) was added to a 250mL eggplant-shaped flask and dissolved with 50mL of absolute ethanol. Then, adding 10% by mass of intermediate Pd/C (38mg, 10% w/w) in H 2 The reaction was carried out at room temperature for 8 hours under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, pd/C is removed by filtration through a microporous membrane, and the target product PTX-GA (gray pink solid, yield 91.2%) is obtained by separating and purifying the filtrate through a preparation liquid phase. Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 4, where the results of NMR spectroscopy were as follows: δ 9.31 (d, J =8.5hz,1h,3 '-NH), 7.93 (d, J =7.5hz,2h, 2-o-OBz), 7.84 (d, J =7.3hz,2h,3' -o-NHBz), 7.71 (t, J =7.4hz,1h, 2-p-OBz), 7.61 (t, J =7.7hz,2h, 2-m-OBz), 7.54 (t, J =7.3hz,1h,3 '-p-NHBz), 7.51-7.43 (m, 6h,3' -m-NHBz,3'-o-Ph,3' -m-Ph), 7.20 (t, J =7.1hz,1h,3 '-p-Ph), 7.01 (s, 2h,2' -o-OBz), 6.29 (s, 1h, 10-H), 5.80 (t, J =9.1hz,1h, 13-H), 5.64 (t, J =9.0hz,1h,3 '-H), 5.46 (d, J =9.6Hz,1H,2' -H), 5.40 (d, J =7.2Hz,1H, 2-H), 4.93 (d, J =10.5Hz,1H, 5-H), 4.13 (dd, J =10.7,6.8Hz,1H, 7-H), 4.05-3.95 (m, 2H, 20-CH) 2 ),3.60(d,J=7.2Hz,1H,3-H),2.34(ddd,J=15.7,9.5,6.9Hz,1H,6α-H),2.29(s,3H,4-OAc),2.10(s,3H,10-OAc),1.83(dd,J=15.4,9.7Hz,1H,14α-H),1.79(s,3H,18-CH 3 ),1.64(t,J=12.3Hz,1H,6β-H),1.50(s,3H,19-CH 3 ),1.48(d,J=9.1Hz,1H,14β-H),1.02(s,3H,17-CH 3 ),0.99(s,3H,16-CH 3 ).
Example 5
Synthesis of paclitaxel-3, 4-dihydroxyphenylacetic acid derivative (PTX-EA)
3, 4-Dihydroxyphenylacetic acid (336.3mg, 2.0 mmol) was weighed out precisely,benzyl bromide (856.5mg, 5.0 mmol), anhydrous potassium carbonate (1104.1mg, 8.0 mmol) were added to a 250mL eggplant-type bottle, dissolved with 50mL DMF, stirred at 70 ℃ for 48h, the progress of the reaction was monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) phenylacetic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) phenylacetic acid (346.1mg, 1.0 mmol), DMAP (122.1mg, 1.0 mmol), EDCI (191.67mg, 1.0 mmol) and HOBT (135.1mg, 1.0 mmol) were weighed out accurately, charged into a 100mL eggplant-type bottle, dissolved in 25mL of dichloromethane, and stirred for 2 hours under ice bath. Then, PTX (571.5mg, 0.67mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in an ice bath, transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and the sample was dissolved in acetonitrile, which was then separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 43.6%). The intermediate (285.8 mg) was added to a 250mL eggplant-shaped bottle and dissolved with 50mL of anhydrous ethanol. Then, pd/C (28.5 mg,10% w/w) was added in an amount of 10% by mass of the intermediate product in H 2 The reaction was carried out at room temperature for 8 hours under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, pd/C is removed by filtration through a microfiltration membrane, and the filtrate is separated and purified by a preparative liquid phase to obtain the target product PTX-EA (light curry solid, yield 92.4%). The structure of the target compound is confirmed by high-resolution mass spectrometry, and the result is shown in fig. 5.
Example 6
Synthesis of docetaxel-3, 4-dihydroxybenzoic acid derivative (DTX-CA)
3, 4-dihydroxy benzoic acid (308.2mg, 2.0 mmol), benzyl bromide (856.5mg, 5.0 mmol) and anhydrous potassium carbonate (1104.1mg, 8.0 mmol) were precisely weighed, added to a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70 ℃ for 48 hours, the progress of the reaction was monitored by thin layer chromatography, and after the reaction was completed, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3mg, 1.0 mmol), DMAP (122.1mg, 1.0 mmol), EDCI (191.67mg, 1.0 mmol) and HOBT (135.1mg, 1.0 mmol) were weighed out accurately, added to a 100mL eggplant-type bottle, dissolved with 25mL of dichloromethane, and stirred for 2h under ice bath. Then Docetaxel (DTX) (540.6mg, 0.67mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in ice bath, and transferred to room temperatureThe reaction was continued for 24h and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and a sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 41.2%). The intermediate (300.8 mg) was added to a 250mL eggplant-shaped bottle and dissolved with 50mL of anhydrous ethanol. Then, 10% by mass of Pd/C (30.08mg, 10% w/w) as an intermediate product was added thereto in the presence of H 2 The reaction was carried out for 8 hours at room temperature under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by a microporous membrane to remove Pd/C, and separating and purifying the filtrate by a preparation liquid phase to obtain the target product DTX-CA (grey pink solid, yield 91.2%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 6, and the results of NMR spectroscopy were as follows: δ 8.02-7.91 (m, 3H,3' -NH and 2-o-OBz), 7.72 (t, J =6.9Hz,1H, 2-p-OBz), 7.62 (t, J =7.3Hz,2H, 2-m-OBz), 7.48 (d, J =8.0Hz,1H,2' -o-OBz), 7.43 (s, 5H,2' -o-OBz,3' -o-Ph,3' -m-Ph), 7.18 (s, 1H,3' -p-Ph), 6.81 (d, J =8.1hz,1h,2' -m-OBz), 5.80 (t, J =8.4hz,1h, 13-H), 5.40 (d, J =6.8hz,1h, 2-H), 5.24-5.16 (m, 2h,3' -H,2' -H), 5.09 (s, 1h, 10-OH), 4.92 (d, J =9.2hz,1h, 5-H), 4.43 (s, 1h, 1-OH), 4.07 (t, J =8.8hz,1h, 7-H), 4.01 (q, J =8.2hz,2h, 20-CH), and so forth 2 ),3.66(d,J=6.0Hz,1H,3-H),2.27(s,4H,6α-H,4-OAc),1.89–1.82(m,1H,14α-H),1.74(s,3H,18-CH 3 ),1.66(t,J=12.5Hz,1H,6β-H),1.58–1.48(m,4H,19-CH 3 ,14β-H),1.39(s,9H,3’-NHBoc),0.98(s,6H,17-CH 3 ,16-CH 3 ).
Example 7
Synthesis of docetaxel-3, 4, 5-trihydroxybenzoic acid derivative (DTX-GA)
3,4, 5-trihydroxybenzoic acid (340.2mg, 2.0mmol), benzyl bromide (1027.8mg, 6.0mmol) and anhydrous potassium carbonate (1380.3mg, 10.0mmol) were precisely weighed, and were added to a 250mL eggplant-shaped bottle, dissolved in 50mL of DMF, stirred at 70 ℃ for 48 hours, the progress of the reaction was monitored by thin layer chromatography, and after the reaction was completed, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25mg, 1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed out accurately, charged into a 100mL eggplant type bottle, dissolved in 25mL of dichloromethane, and dissolved in iceStir for 2h under bath. Then, DTX (807.2mg, 1.0 mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in an ice bath, transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and a sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 43.7%). The intermediate (283.8 mg) was added to a 250mL eggplant-shaped flask and dissolved with 50mL of anhydrous ethanol. Then, 10% by mass of Pd/C (28.3mg, 10% w/w) of the intermediate product was added, in H 2 The reaction was carried out at room temperature for 8 hours under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by using a microporous filter membrane to remove Pd/C, and separating and purifying the filtrate by using a preparative liquid phase to obtain a target product DTX-GA (grey pink solid, yield 91.2%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 7, where the results of NMR spectroscopy were as follows: δ 7.98 (d, J =9.3Hz,1H,3' -NH), 7.96 (d, J =7.5Hz,2H, 2-o-OBz), 7.72 (t, J =7.4Hz,1H, 2-p-OBz), 7.63 (t, J =7.7Hz,2H, 2-m-OBz), 7.46-7.39 (m, 4H,3' -o-Ph,3' -m-Ph), 7.20-7.15 (m, 1H,3' -p-Ph), 7.07 (s, 2H,2' -o-OBz), 5.78 (t, J =8.8Hz,1H, 13-H), 5.39 (d, J =7.2Hz,1H, 2-H), 5.23-5.12 (m, 2H,3' -H,2' -H), 5.09 (s, 1H, 10-OH), 4.92 (d, J =10.7Hz,1H, 5-H), 4.41 (s, 1H, 1-OH), 4.06 (dd, J =11.0,6.7Hz,1H, 7-H), 4.05-3.97 (m, 2H,20-CH, 20-H) 2 ),3.65(d,J=7.1Hz,1H,3-H),2.32–2.24(m,4H,6α-H,4-OAc),1.83(dd,J=15.3,9.4Hz,1H,14α-H),1.72(s,3H,18-CH 3 ),1.66(t,J=12.4Hz,1H,6β-H),1.54–1.47(m,4H,19-CH 3 ,14β-H),1.38(s,9H,3’-NHBoc),0.98(s,6H,17-CH 3 ,16-CH 3 ).
Example 8
Synthesis of Cabazitaxel-3, 4-dihydroxybenzoic acid derivatives (CTX-CA)
3, 4-dihydroxy benzoic acid (308.2mg, 2.0 mmol), benzyl bromide (856.5mg, 5.0 mmol) and anhydrous potassium carbonate (1104.1mg, 8.0 mmol) were weighed out precisely, added to a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70 ℃ for 48h, the progress of the reaction was monitored by thin layer chromatography, and after completion of the reaction, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3mg, 1) was weighed out accurately.0 mmol), DMAP (122.1mg, 1.0 mmol), EDCI (191.67mg, 1.0 mmol) and HOBT (135.1mg, 1.0 mmol) were added to a 100mL eggplant type bottle, dissolved in 25mL of dichloromethane, and stirred for 2h under ice bath. Then, CTX (560.0 mg, 0.67mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution under stirring in an ice bath, transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and the sample was dissolved in acetonitrile, which was then separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 41.2%). The intermediate (300.8 mg) was added to a 250mL eggplant-shaped bottle and dissolved with 50mL of anhydrous ethanol. Then, 10% by mass of Pd/C (30.08mg, 10% w/w) as an intermediate product was added thereto in the presence of H 2 The reaction was carried out at room temperature for 8 hours under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by a microporous membrane to remove Pd/C, and separating and purifying the filtrate by a preparative liquid phase to obtain the target product CTX-CA (grey pink solid, yield 90.7%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 8, and the results of NMR spectroscopy were as follows: δ 8.00 (d, J =9.4hz,1h,3' -NH), 7.96 (d, J =7.5hz,2h, 2-o-OBz), 7.73 (t, J =7.4hz,1h, 2-p-OBz), 7.64 (t, J =7.7hz,2h, 2-m-OBz), 7.48 (dd, J =8.3,2.0hz,1h,2' -o-OBz), 7.45-7.41 (m, 5h,3' -o-Ph,3' -m-Ph, 2' -o-OBz), 7.19 (dt, J =8.7,4.9hz,1h,3' -p-Ph), 6.83 (d, J =8.3hz,1h,2' -m-OBz), 5.83 (t, J =8.9hz,1h, 13-H), 5.37 (d, J =7.1hz,1h, 2-H), 5.24-5.15 (m, 2h,3' -H,2' -H), 4.97 (d, J =10.4hz,1h, 5-H), 4.71 (s, 1h, 10-H), 4.50 (s, 1h, 1-OH), 4.02 (s, 2h, 20-CH) 2 ),3.77(dd,J=10.4,6.8Hz,1H,7-H),3.61(d,J=7.1Hz,1H,3-H),3.28(s,3H,10-OCH 3 ),3.23(s,3H,7-OCH 3 ),2.68(ddd,J=14.1,9.7,6.4Hz,1H,6α-H),2.28(s,3H,4-OAc),1.86–1.78(m,4H,18-CH 3 ,14α-H),1.53–1.49(m,5H,19-CH 3 ,14β-H,6β-H),1.39(s,9H,3’-NHBoc),0.98(s,3H,17-CH 3 ),0.96(s,3H,16-CH 3 ).
Example 9
Synthesis of Cabazitaxel-3, 4, 5-trihydroxybenzoic acid derivative (CTX-GA)
3,4, 5-trihydroxybenzoic acid (340.2mg, 2.0mmol) and benzyl bromide (102) were precisely weighed7.8mg, 6.0mmol), anhydrous potassium carbonate (1380.3mg, 10.0mmol) was added to a 250mL eggplant-type bottle, dissolved in 50mL DMF, stirred at 70 ℃ for 48 hours, the progress of the reaction was monitored by thin layer chromatography, and after the completion of the reaction, column chromatography was carried out to give 3,4, 5-tris (benzyloxy) benzoic acid. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25mg, 1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed out accurately, charged into a 100mL eggplant-type bottle, dissolved in 25mL of dichloromethane and stirred for 2h under ice bath. Then, CTX (835.9mg, 1.0 mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in an ice bath, transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and the sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 40.6%). The intermediate (283.8 mg) was added to a 250mL eggplant-shaped flask and dissolved with 50mL of anhydrous ethanol. Then, 10% by mass of Pd/C (28.3mg, 10% w/w) as an intermediate product was added thereto in the presence of H 2 The reaction was carried out for 8 hours at room temperature under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by a microporous membrane to remove Pd/C, and separating and purifying the filtrate by a preparative liquid phase to obtain the target product CTX-GA (grey pink solid, 93.2 percent of yield). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 9, where the results of NMR spectroscopy were as follows: δ 9.25 (s, 3H,2 '-OBzOH), 8.00 (d, J =8.7Hz,1H,3' -NH), 7.96 (d, J =7.6Hz,2H, 2-o-OBz), 7.73 (t, J =7.4Hz,1H, 2-p-OBz), 7.64 (t, J =7.7Hz,2H, 2-m-OBz), 7.47-7.39 (m, 4H,3'-o-Ph,3' -m-Ph), 7.18 (t, J =6.8Hz,1H,3 '-p-Ph), 7.07 (s, 2H,2' -o-OBz), 5.81 (t, J =8.9Hz,1H, 13-H), 5.37 (d, J =7.1Hz,1H, 2-H), 5.22-5.14 (m, 2H,3'-H,2' -H), 4.97 (d, J =10.2Hz,1H, 5-H), 4.70 (s, 1H, 10-H), 4.48 (s, 1H, 1-OH), 4.02 (s, 2H,20-CH 2 ),3.77(dd,J=10.3,6.8Hz,1H,7-H),3.60(d,J=7.1Hz,1H,3-H),3.27(s,3H,10-OCH 3 ),3.23(s,3H,7-OCH 3 ),2.67(td,J=7.9,3.3Hz,1H,6α-H),2.28(s,3H,4-OAc),1.83–1.81(m,4H,18-CH 3 ,14α-H),1.53–1.49(m,5H,19-CH 3 ,14β-H,6β-H),1.38(s,9H,3’-NHBoc),0.98(s,3H,17-CH 3 ),0.96(s,3H,16-CH 3 ).
Example 10
Synthesis of podophyllotoxin-3, 4-dihydroxybenzoic acid derivative (POD-CA)
3, 4-dihydroxy benzoic acid (308.2mg, 2.0mmol), benzyl bromide (856.5mg, 5.0mmol) and anhydrous potassium carbonate (1104.3mg, 8.0mmol) were precisely weighed, added to a 250mL eggplant-type bottle, dissolved in 50mL of DMF, stirred at 70 ℃ for 48 hours, the progress of the reaction was monitored by thin layer chromatography, and after the reaction was completed, 3, 4-bis (benzyloxy) benzoic acid was obtained by column chromatography. 3, 4-bis (benzyloxy) benzoic acid (334.3mg, 1.0 mmol), DMAP (122.1mg, 1.0 mmol), EDCI (191.67mg, 1.0 mmol) and HOBT (135.1mg, 1.0 mmol) were weighed out accurately, charged into a 100mL eggplant-type flask, dissolved in 25mL of dichloromethane, and stirred for 2 hours under ice bath. Then, podophyllotoxin (POD) (277.3mg, 0.67mmol) was precisely weighed, dissolved in 5mL of dichloromethane, slowly dropped into the above reaction solution while stirring in ice bath, transferred to room temperature to continue the reaction for 24 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and a sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 60.2%). The intermediate (100.8 mg) was added to a 100mL eggplant-shaped flask and dissolved with 50mL of anhydrous ethanol. Then, 10% by mass of the intermediate Pd/C (10.08mg, 10% w/w) was added thereto in H 2 The reaction was carried out at room temperature for 8 hours under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by a microporous membrane to remove Pd/C, and separating and purifying the filtrate by a preparative liquid phase to obtain the target product POD-CA (grey pink solid, yield 87.2%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 10, and the results of NMR spectroscopy were as follows: δ 7.40 (d, J =2.0hz,1h,2 ″ -H), 7.36 (dd, J =8.3,2.0hz,1h,6 '-H), 6.92 (s, 1h, 4-H), 6.84 (d, J =8.3hz,1h,5' -H), 6.65 (s, 1h, 10-H), 6.39 (s, 2h,2'-H,6' -H), 6.05 (d, J =9.3hz,1h, 5-H), 6.03 (d, J =3.3hz,2h,2 α -H,2 α -H), 4.60 (d, J =4.6hz,1h, 9-H), 4.39 (t, J =7.8hz,1h,6 α -H), 4.27 (t, J =8.6hz,1h,6 β -H), 3.67 (s, 6H,7 '-H), 3.62 (s, 3h,8' -H), 3.43 (dd, J =14.6,4.6hz,1h, 8a-H), 2.86-2.77 (m, 1h, 5a-H).
Example 11
Synthesis of triptolide-3, 4, 5-trihydroxybenzoic acid derivative (TPL-GA)
3,4, 5-trihydroxybenzoic acid (340.2mg, 2.0mmol), benzyl bromide (1027.8mg, 6.0mmol) and anhydrous potassium carbonate (1380.3mg, 10.0mmol) were precisely weighed, and were added to a 250mL eggplant-shaped bottle, dissolved in 50mL of DMF, stirred at 70 ℃ for 48 hours, the progress of the reaction was monitored by thin layer chromatography, and after the reaction was completed, 3,4, 5-tris (benzyloxy) benzoic acid was obtained by column chromatography. 3,4, 5-tris (benzyloxy) benzoic acid (660.6 mg,1.5 mmol), DMAP (183.25mg, 1.5 mmol), EDCI (287.5 mg,1.5 mmol) and HOBT (202.7 mg,1.5 mmol) were weighed out accurately, charged into a 100mL eggplant type bottle, dissolved in 25mL of dichloromethane, and stirred for 2 hours in an ice bath. Then, triptolide (TPL) (360.5mg, 1.0 mmol) was precisely weighed, dissolved in 5mL dichloromethane, slowly dropped into the above reaction solution under stirring in ice bath, transferred to room temperature to continue the reaction for 24h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction solution was spin-dried, and a sample was dissolved in acetonitrile, and was separated and purified by preparative liquid phase to obtain an intermediate product (white powder, yield 33.7%). The intermediate (93.8 mg) was added to a 250mL eggplant-shaped flask and dissolved with 50mL of anhydrous ethanol. Then, the intermediate product was added with 10% by mass of Pd/C (9.3mg, 10% w/w) in H 2 The reaction was carried out for 8 hours at room temperature under reduced pressure, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering by a microporous membrane to remove Pd/C, and separating and purifying the filtrate by a preparative liquid phase to obtain the target product TPL-GA (grey pink solid, yield 89.2%). Using high resolution mass spectrometry and 1 the structure of the target compound was confirmed by H-NMR spectroscopy, and the results are shown in FIG. 11, and the results of NMR spectroscopy were as follows: δ 7.02 (s, 2H, H-3'), 5.12 (s, 1H, H-14), 4.90-4.71 (m, 2H, H-19), 4.01 (d, J =3.3Hz,1H, H-11), 3.73 (d, J =3.2Hz,1H, H-12), 3.61 (d, J =5.7Hz,1H, H-7), 2.68-2.61 (m, 1H, H-5), 2.16-2.09 (m, 1H, H-2), 2.03-1.90 (m, 2H, H-2, H-6), 1.81 (dd, J =15.0,13.2Hz,1H, H-6), 1.74 (hept, J =6.9Hz,1H, H-15), 1.38-1.28 (m, 2H, H-1), 0.91 (s, 3H, H-20), 0.87 (d, J =7.0Hz,3H, H-16), 0.78 (d, J =6.8Hz,3H, H-17).
Example 12
Determination of affinity of taxol polyphenol derivative and human serum albumin
The affinity of the paclitaxel polyphenol derivative with human serum albumin was determined by a surface plasmon resonance method. Human Serum Albumin (HSA)) The protein is fixed on the surface of a CM5 sensor chip through amino coupling, and then a sample to be detected (paclitaxel, paclitaxel phenyl derivatives and paclitaxel polyphenol derivatives) passes through the surface at different concentrations and is combined with albumin. The concentration of the fixed HSA is 80 mug/mL, and the concentration range of the sample to be detected is set between 0.006 and 41.15 muM. And determining the affinity value of the steady state and the kinetic data of the binding by the real-time dynamic analysis of the binding of the sample to be tested and the HSA. Dissociation constant K D The smaller the value, the higher the affinity. The results are shown in fig. 12, and the affinity of paclitaxel and four paclitaxel derivatives is in the following order: PTX-GA (K) D =0.812nM)>PTX-PA(K D =12.5nM)≥PTX-CA(K D =12.7nM)>PTX-PH(K D =24.2nM)>PTX(K D =26.6 nM). The results show that the affinity of the taxol polyphenol derivatives for human serum albumin is significantly improved compared with taxol and taxol phenyl derivatives (PTX-PH).
Example 13
Preparation of paclitaxel polyphenol derivative albumin nano-composite
Paclitaxel and the paclitaxel derivatives (including paclitaxel phenyl derivative and paclitaxel polyphenol derivative) prepared in examples 1 to 5 were precisely weighed, each 5mg and human serum albumin 100mg were dissolved in 0.5mL of acetone, paclitaxel and the paclitaxel derivatives were dissolved in 10mL of deionized water, the acetone solution of paclitaxel and the paclitaxel derivatives was used as an organic phase, and the aqueous solution of human serum albumin was used as an aqueous phase. Controlling the flow rate ratio of organic phase and water phase to be 1/4, the total flow rate to be 12mL/min, and removing the organic solvent in the nano preparation by rotary evaporation at 25 deg.C to obtain paclitaxel albumin nano complex (PTX @ HSA NCs), paclitaxel derivative albumin nano complex (PTX-PH @ HSA NCs, PTX-PA @ HSA NCs, PTX-CA @ HSA NCs, PTX-GA @ HSA NCs and PTX-EA @ HSA NCs). The particle size and particle size distribution are shown in Table 1.
TABLE 1 particle size and PDI of different paclitaxel and paclitaxel derivative albumin nanocomposites
In addition, docetaxel (DTX), docetaxel polyphenol derivatives (DTX-CA, DTX-GA), cabazitaxel (CTX), cabazitaxel polyphenol derivatives (CTX-CA, CTX-GA), podophyllotoxin (POD), podophyllotoxin polyphenol derivatives (POD-CA), triptolide (TPL), triptolide polyphenol derivatives (TPL-GA) 5.00mg and human serum albumin (hsa) were precisely weighed, and the nanocomposite was prepared according to the above preparation method, wherein the appearance of the nanocomposite was as shown in fig. 13 (particles with multimodal distribution were obtained after mixing bulk drug and albumin, particles with unimodal distribution were obtained after mixing polyphenol derivatives and albumin), and the results of the average particle size and the particle size distribution were shown in table 2. The results show that drug precipitation is observed after docetaxel, cabazitaxel, podophyllotoxin, triptolide and human serum albumin are mixed by microflow, and the nano-composite with uniform particle size cannot be directly obtained; in contrast, under the same experimental conditions, the polyphenol derivative of the albumin can be effectively combined with albumin to form a nano-composite with uniform particle size, PDI is less than 0.2, and the particle size is uniform, which further illustrates that some drugs with weak albumin combination can be successfully prepared into albumin nanoparticles through a polyphenol derivatization strategy.
TABLE 2 particle size and PDI of different nanocomposites
Example 14
Freeze-drying preparation of paclitaxel polyphenol derivative albumin nano compound
Concentrating the paclitaxel polyphenol derivative albumin nano compound to ensure that the concentration of the paclitaxel polyphenol derivative is 10mg/mL, and adding 5% of sucrose as a freeze-drying protective agent for freeze-drying. The states of the paclitaxel polyphenol derivative albumin nanocomposite before and after freeze-drying are shown in fig. 14, and the paclitaxel polyphenol derivative albumin nanocomposite has good freeze-drying appearance, smooth surface and a round cake-shaped structure which is full and loose. Adding physiological saline, shaking gently, and redispersing in short time, compared with the particle size before freeze-drying, the particle size has no obvious change, and the particle size change before and after freeze-drying is shown in Table 3.
TABLE 3 particle size and PDI before and after lyophilization of paclitaxel polyphenol derivative albumin nanocomposites
Example 15
Pharmacokinetics research of paclitaxel polyphenol derivative albumin nano compound
Taking 16 male healthy rats with the weight of 200-250 g, randomly dividing the rats into 4 groups, and respectively injecting a commercial preparation Taxol solution (Taxol), albumin-bound Taxol nanoparticles (Abraxane) and the Taxol polyphenol derivative albumin nano-composite prepared in example 12 into tail veins, wherein the equivalent dose of the Taxol is 5mg/kg. Collecting blood from orbit at a specified time, centrifuging at 13000 rpm for 10min to obtain plasma, measuring the concentrations of paclitaxel and paclitaxel polyphenol derivatives in the plasma by high performance liquid chromatography-mass spectrometer, and processing by DAS software to obtain main pharmacokinetic parameters shown in Table 4. The results show a significant increase in the area under the curve (AUC) of the paclitaxel polyphenol derivative albumin nanocomplexes when compared to the two commercial formulations Taxol, abraxane.
TABLE 4 pharmacokinetic parameters of paclitaxel solution, albumin-bound paclitaxel nanoparticles and paclitaxel polyphenol derivative albumin nanocomposites
A PTX is from PTX-CA @ HSA NCs, b PTX is from PTX-GA @ HSA NCs.
Example 16
Maximum tolerated dose assessment of paclitaxel polyphenol derivative albumin nanocomposites
The safety and tolerance of different preparations (paclitaxel polyphenol derivative albumin nano complex) on healthy BALB/c mice are evaluated and studied by adopting a multi-dose administration scheme, the survival state and the weight change of each group of mice are observed every day during the administration period, when the average weight of the mice is reduced by 15 percent or abnormal behaviors such as humpback posture, hair roughness and the like occur, the mice are defined as causing toxicity, and the highest dose which does not cause the toxicity is defined as the maximum tolerance dose. Mice were randomly divided into 19 groups of 3 animals each, and the saline group served as a control. Paclitaxel (paclitaxel equivalent dose of 10, 20, 30 mg/kg), albumin bound paclitaxel nanoparticles (paclitaxel equivalent dose of 10, 30, 60, 90 and 120 mg/kg), PTX-ca @ hsa NCs (paclitaxel equivalent dose of 10, 30, 60, 90 and 120 mg/kg) and PTX-ga @ hsa NCs (paclitaxel equivalent dose of 10, 30, 60, 90 and 120 mg/kg) were injected into tail vein respectively. Once every 2 days for 5 doses, body weight was monitored, recorded and mouse behavior observed.
The results are shown in FIG. 15, tail vein injection of 30mg/kg of taxol resulted in severe treatment-related death; when the administration dose is 20mg/kg, abnormal behaviors such as lethargy, rough fur, humpback and the like appear in the mice, although the body weight of the mice slightly decreases by about 10 percent, one mouse dies after the fourth administration, which indicates that the mice are not tolerant and have certain accumulated toxicity at the dose level. Thus, it was determined here that the maximum tolerated dose of healthy BALB/c mice for taxol was 10mg/kg. In contrast, the maximum tolerated dose of the commercial formulation Abraxane was significantly increased. When the dose is more than 60mg/kg, the weight of the mice is reduced by more than 15%, and abnormal behaviors such as rickets, bradykinesia, lethargy and the like occur, so that the maximum tolerated dose of Abraxane is determined to be 30mg/kg here. When the paclitaxel polyphenol derivative albumin nano-composite with paclitaxel equivalent dose of 120mg/kg is administered, the weight of a mouse is slightly reduced, but the weight is still fluctuated within the range of less than 10%, and the health state of the mouse is not obviously abnormal, which indicates that the paclitaxel polyphenol derivative albumin nano-composite provided by the invention has good safety and the maximum tolerated dose is greatly improved.
Example 17
In vivo efficacy experiment of paclitaxel polyphenol derivative albumin nanocomposite
Digesting 4T1 cells in good growth state with 0.05% pancreatin, terminating digestion with fresh RPMI 1640 cell culture solution, centrifuging at 1000rpm for 5min, discarding the culture solution containing pancreatin, collecting cells, adding cold PBS (pH 7.4) to disperse cells uniformly, and counting to obtain cell suspension with final concentration of 1 × 10 7 cells/mL. 100 μ L of the suspension was inoculated subcutaneously into the right posterior lumbar region of female BALB/c mice. The tumor volume is to be grown to about 120-150 mm 3 At this time, they were randomly grouped into 5 animals per group, namely, a saline control group, a taxol solution group (paclitaxel equivalent administration doses were 10 and 30mg/kg, respectively), an albumin-bound paclitaxel nanoparticle group (paclitaxel equivalent administration doses were 10 and 30mg/kg, respectively), a PTX-CA @ HSA NCs group (paclitaxel equivalent administration doses were 10, 30, 90 and 120mg/kg, respectively), and a PTX-GA @ HSA NCs group (paclitaxel equivalent administration doses were 10, 30, 90 and 120mg/kg, respectively). The administration mode is tail vein injection, the administration is carried out once every other day for 5 times, and the weight change and the tumor volume of the mice are measured and recorded every day after the administration. After the last administration, the eyeball of the mouse is picked up and blood is taken out, and the whole blood of the mouse is collected for blood cell level analysis.
The results are shown in fig. 16, where at the maximum tolerated dose of each formulation, the taxol solution (10 mg/kg) only mildly inhibited tumor growth; the albumin-bound paclitaxel nanoparticles (30 mg/kg) have a good effect of inhibiting tumor growth; the tumor of the mice treated by the paclitaxel polyphenol derivative albumin nano compound (120 mg/kg) is shrunk, and the tumor is inhibited to the maximum extent, so that the special treatment advantage is shown.
The safety of the preparation is evaluated by analyzing the weight change and the blood index change of tumor-bearing mice, and the result is shown in figure 17, the mice treated by the albumin-bound paclitaxel nanoparticles (30 mg/kg) show obvious weight reduction, which indicates that the accumulation of drug toxicity occurs and certain toxic and side effects are generated on organisms; the weight of the mice does not obviously reduce under the maximum tolerance dose of 120mg/kg of the paclitaxel polyphenol derivative albumin nano compound, which shows that the paclitaxel polyphenol derivative albumin nano compound has good in-vivo safety.
As shown in fig. 18, compared with the normal saline control group, the mouse treated with Taxol (10 mg/kg) and Abraxane (30 mg/kg) showed a significant decrease in the index of blood leukocytes, lymphocytes, monocytes and neutrophils, while the paclitaxel polyphenol derivative albumin nanocomposite induced a relatively low decrease in the level of leukocytes at the maximum tolerated dose of 120mg/kg, indicating that the paclitaxel polyphenol derivative albumin nanocomposite has a certain advantage in safety. Furthermore, similar pharmacodynamic results were observed in the tumor-bearing MCF-7 nude mouse model (see fig. 19-20) as in the 4T1 tumor model, again demonstrating the superiority of the paclitaxel polyphenol derivative albumin nanocomplexes.
Example 18
In vivo efficacy experiment of docetaxel polyphenol derivative albumin nanocomposite
Claims (10)
1. An albumin-binding antitumor drug characterized by being an antitumor drug polyphenol derivative having affinity with albumin, and having the following structural general formula:
wherein Drug is antitumor Drug containing hydroxyl, carboxyl, carbonyl, thiol or amino and selected from taxane, anthracycline, nucleoside, camptothecin, platinum, vinblastine, peneoside, artemisinin compound, macrolide, and terpenoid; the antitumor drug is connected with the Spacer through a Linker; wherein the Linker is ester, amide, imine, oxime, hydrazone, carbonate, carbamate, borate, oxalate oxide, monothioether bond, disulfide bond, diselenide bond, trithioether bond or thioketal bond; the Spacer is an alkyl chain with or without heteroatoms, a double bond or a double bond, and the heteroatoms are O, S or N; n is an integer of 1 to 3.
2. The albumin-binding antitumor agent as claimed in claim 1, wherein the antitumor agent is paclitaxel, docetaxel, cabazitaxel, podophyllotoxin, triptolide, larotaxel, rapamycin, SN-38, ursolic acid, oleanolic acid, and glycyrrhetinic acid, and the polyphenol derivative of the antitumor agent has a hydroxyl group linked to a phenolic compound through an ester bond, the ester bond is cleaved by an in vivo esterase to release an antitumor agent, and the phenolic compound includes caffeic acid, p-coumaric acid, ferulic acid, sinapic acid, rosmarinic acid, 4-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, 3, 4-dihydroxybenzoic acid, 3,4, 5-trihydroxybenzoic acid, and 3, 4-dihydroxyphenylacetic acid.
4. a pharmaceutical composition comprising the albumin-binding antineoplastic agent of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and an excipient.
5. A method for synthesizing an albumin-bound antitumor agent as defined in claim 3, comprising the steps of:
reacting 4-hydroxybenzoic acid, or 3, 4-dihydroxybenzoic acid, or 3,4, 5-trihydroxybenzoic acid, or 3, 4-dihydroxybenzoic acid with benzyl bromide under the catalysis of anhydrous potassium carbonate to obtain 4-benzyloxybenzoic acid, or 3, 4-bis (benzyloxy) benzoic acid, or 3,4, 5-tris (benzyloxy) benzoic acid, or 3, 4-bis (benzyloxy) phenylacetic acid; under the catalysis of DMAP, EDCI and HOBT, 4-benzyloxy benzoic acid, or 3, 4-bis (benzyloxy) benzoic acid, or 3,4, 5-tris (benzyloxy) benzoic acid, or 3, 4-bis (benzyloxy) phenylacetic acid reacts with an anti-tumor drug, and an intermediate compound is obtained by separation and purification; the intermediate compound is subjected to hydrogenation catalysis by palladium carbon, protecting groups are removed, and the antitumor drug polyphenol derivative is obtained through separation and purification.
6. An antitumor drug polyphenol derivative albumin nanocomposite, comprising the antitumor drug polyphenol derivative according to any one of claims 1 to 3 and albumin; the weight ratio of the antineoplastic polyphenol derivative to albumin is (1; the albumin is human serum albumin, bovine serum albumin or mouse serum albumin.
7. The method for preparing the antitumor drug polyphenol derivative albumin nano-composite as claimed in claim 6, which is characterized by comprising the following steps:
dissolving the antitumor drug polyphenol derivative into an organic solvent to serve as an organic phase, dissolving albumin into deionized water to serve as a water phase, and after the organic phase and the water phase are mixed by rapid microflow, the antitumor drug polyphenol derivative and the albumin spontaneously form a uniform nano compound; the organic solvent is one or a mixture of acetone, ethanol, methanol, acetonitrile or tetrahydrofuran; the weight ratio of the polyphenol derivative of the antitumor drug to albumin is (1.
8. Use of the albumin-bound antineoplastic agent of claim 1, or the pharmaceutical composition of claim 4, or the nanocomplex of claim 6, for the preparation of a drug delivery system.
9. Use of the albumin-bound antineoplastic agent of claim 1, or the pharmaceutical composition of claim 4, or the nanocomposite of claim 6 in the preparation of antineoplastic agents.
10. Use of the albumin-bound antineoplastic agent of claim 1, or the pharmaceutical composition of claim 4, or the nanocomplex of claim 6, for the preparation of an injectable, oral, or topical delivery system.
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