CN113912649B - Amphiphilic nano metal complex and preparation method and application thereof - Google Patents
Amphiphilic nano metal complex and preparation method and application thereof Download PDFInfo
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- CN113912649B CN113912649B CN202111165511.5A CN202111165511A CN113912649B CN 113912649 B CN113912649 B CN 113912649B CN 202111165511 A CN202111165511 A CN 202111165511A CN 113912649 B CN113912649 B CN 113912649B
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0033—Iridium compounds
- C07F15/004—Iridium compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0036—Porphyrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an amphiphilic nano metal complex and a preparation method and application thereof, belonging to the technical field of nano materials. The invention discloses a cationic diagnosis and treatment integrated nano-drug carrier material, which synthesizes a novel positively-charged amphiphilic polymer chain-shaped nano-material with metal linking points as a drug carrier and is applied to the preparation of antitumor drugs. The novel linear amphiphilic polymer nano-carrier based on the metal coordination nucleus is a cationic material, so that the assembled micelle has positive charges, and is beneficial to interacting with cell membranes with negative charges, thereby increasing the intake of cells and enhancing the damage effect of tumor cells.
Description
Technical Field
The invention belongs to the technical field of nano materials, and particularly relates to an amphiphilic nano metal complex and a preparation method and application thereof.
Background
Chemotherapy, which is the most commonly used treatment method except for the relay surgery in the course of tumor treatment. Commonly used broad-spectrum chemotherapeutic drugs include Doxorubicin (Doxorubicin; DOX), paclitaxel (Paclitaxel), and platinum drugs (Cisplatin cisclin; carboplatin; oxaliplatin oxaplatin; lobaplatin), and the like. However, these small molecule chemotherapeutic agents are generally small in size and have a short residence time in the body after intravenous injection. Therefore, higher drug concentrations at the tumor site require higher drug doses. In addition, these small molecule drugs often tend to produce multidrug Resistance (MDR) due to their strong lipophilicity, which pumps the Drug out of tumor cells and reduces the therapeutic effect. Finally, the solubility of the drugs is low, thereby reducing the enrichment of most small molecular drugs in tumor parts, causing the drugs not to effectively cause tumor tissue damage, and increasing the toxic and side effects of the drugs.
The nano-micelle can be formed by self-assembly of amphiphilic molecules in water (figure 1), and can form a micelle with hydrophilic outside and hydrophobic inside or a double-layer vesicle structure with hydrophilic inside and outside. The nanomicelle can effectively encapsulate the drug by self-assembling with the lipophilic drug to increase the water solubility thereof. The drug-loaded nano-micelle can realize passive targeting of a tumor part through a high Permeability and long Retention (EPR) effect.
Most of the nano-drugs reported at present face a plurality of obstacles to clinical transformation, such as low drug loading, poor particle stability, poor active targeting, difficult tracking, less tumor site enrichment, low cancer cell uptake, poor single treatment mode effect, and the like. The subject group of professor Shang Guping of Zhejiang university designs and synthesizes a pH/reduction double-sensitive and size-variable multifunctional nano-micelle PSPD/P123-Dex (adv.Funct.Mater.2017, 27,1700339). The micelle has negative charge under normal physiological acid-base environment, the particle size is about 120nm, but the Zeta potential on the surface of a weakly acidic tumor part can be changed into positive charge to interact with a cell membrane with the negative charge, so that the micelle is more favorable for entering the interior of a tumor cell, and meanwhile, the particle size of the micelle is reduced to 90nm, so that the micelle can be better taken up by the cell. After entering cells, the micelle-loaded Dexamethasone (Dexamethasone, dex) has a targeting effect on cell nuclei and can enlarge nuclear pores, and finally, the drug-loaded micelle enters the cell nuclei through the nuclear pores to release drugs (fig. 2).
In 2018, the Luan Yuxia topic group of Shandong university reported that the nano-micelle carrier TPGS-IR820/Ce6 (Small 2018,14,1802994) combines Photothermal Therapy (PTT) and photodynamic Therapy (PDT). The micelle can trigger PTT and PDT by single near infrared light, and can realize the function of drug tracking by the fluorescence effect generated by the material. Depending on the IR820 group, the micelle shows excellent photothermal conversion efficiency in vitro and in vivo. While the micelles have a higher singlet oxygen production capacity in tumor cells depending on the Ce6 photosensitizer (fig. 3).
Firstly, the existing nano drug delivery system is generally formed by self-assembly of multi-component materials, the obtained particles have poor stability, drug leakage is easy to occur, and potential or unknown toxic and side effects of the drug are increased. Secondly, the electroneutrality of most nano-drug particles is not easy to interact with negatively charged cell membranes and thus are taken up by tumor cells, which results in poor therapeutic effect. Thirdly, most nano-drug carriers need to be loaded with an imaging module (fluorescence or contrast imaging) for evaluating the enrichment and metabolism conditions of tumor and normal organ tissues (such as heart, liver, spleen, lung, kidney, etc.), which greatly increases the complexity, production difficulty and cost of nano-drugs. Finally, a single treatment modality is not sufficient to achieve a higher level of cancer treatment, and the combination of multiple treatment modalities can increase the efficiency of the treatment, but a combination modality based on multicomponent assembly increases the cost of materials and clinical applicability.
Disclosure of Invention
The invention provides a novel amphiphilic nano-sized metal complex and a preparation method and application thereof, aiming at solving various problems of biological materials in anticancer, mainly comprising the water solubility of hydrophobic drugs, the compatibility in organisms, the tracking of the drugs entering the organisms, the toxic and side effects of chemical drugs in the organisms and the like.
An amphiphilic nano metal complex, the structure of which is shown as formula (1) to formula (3):
wherein m = an integer of 0-16;
n = an integer from 5 to 45;
m is selected from Co, rh, ir, fe, ru, os, mn.
The preparation method of the metal complex comprises the following steps:
s1: the N-based ligand,
And carbonate is mixed in an organic solvent and reacts for 12h-24h at 65-85 ℃ to obtain a compound (1), wherein X is F, cl, br and I; m = an integer of 0-16;
s2: reacting the compound (1) with metal salt in an organic solvent at 140-200 ℃ for 1-10h to obtain a compound (2);
s3: the N-based ligand,
And reacting carbonate in an organic solvent at 50-100 ℃ for 1-24 h to prepare a compound (3), wherein n = 5-45;
s4: mixing the compound (2) and the compound (3) in an organic solvent, heating to react at 120-200 ℃ for 1-12 hours, carrying out solid-liquid separation, taking supernatant, adding hexafluorophosphate for flocculation precipitation, carrying out solid-liquid separation, taking solid phase, and obtaining the metal complex.
In one embodiment of the invention, in S1 and S3, the N-based ligand is selected from
In one embodiment of the invention, the metal salt in S2 is selected from CoCl 2 、RhCl 3 、IrCl 3 、FeCl 3 、RuCl 3 、OsCl 3 Or MnCl 2 。
In one embodiment of the invention, the N-based ligand of S3 is a ligand of the formula
In a molar ratio of 1:1-1:3.
In one embodiment of the invention, the molar ratio of compound (2) to compound (3) in S4 is 1:3-3:1.
In one embodiment of the invention, the hexafluorophosphate salt in S4 is selected from NH 4 PF 6 、KPF 6 、NaPF 6 、LiPF 6 。
In one embodiment of the present invention, the carbonate described in S1 and S3 is sodium carbonate or potassium carbonate.
Dissolving the metal complex in an organic solvent to obtain a metal complex solution, adding the metal complex solution into water at the speed of 5-10 mu L/s, stirring for reaction, removing the organic solvent after the reaction is finished, and dialyzing and filtering to obtain the micelle.
The synthesis method is used for preparing the micelle.
The micelle is applied to the preparation of antitumor drugs, and the tumors are breast cancer and melanoma.
The invention provides a cationic diagnosis and treatment integrated nano-drug carrier material, and synthesizes a novel amphiphilic polymer chain-shaped nano-material with positive charges and taking metal Ir (III) as a linking point as a drug carrier. The drug carrier is formed by chelating two 4'- (4-hydroxyphenyl) -2,2',6', 2' -tripyridine (Terpy) macromolecule derivatives with Ir3+ (R) to form a linear polymer (named as C) with an alkane chain with hydrophobicity at one end and hydrophilic PEG at the other end 18 -Ir-PEG)。C 18 the-Ir-PEG can be self-assembled into nano spherical micelles in water, and the size of the nano spherical micelles is 130 +/-50 nm. C 18 the-Ir-PEG can also be further loaded with model drug molecule Chlorin E6 (Chlorin E6, ce 6), and the encapsulation rate is 35.18 +/-0.65%.
C 18 The encapsulation of Ce6 by-Ir-PEG effectively increases the water solubility of Ce6 and the final cytotoxicity of bioavailability system, thereby achieving better effectThe in vitro tumor treatment effect of (1). At the same time, [ Ir (Terpy) 2 ] 3+ The chelating structural unit has stronger fluorescence emission at 570nm and better photosensitivity, and can generate active oxygen with cytotoxicity under proper illumination conditions. Therefore, the amphiphilic nano-drug carrier also has the potential of imaging and Photodynamic Therapy (PDT). Furthermore, C 18 The micelle of the Ir-PEG has positive charge and can interact with a cell membrane with negative charge, so that the drug-loaded micelle penetrates through the cell membrane to enter cells, and the internalization speed and degree of cancer cells are improved to exert the best treatment effect. This may be by C 18 The main reason why the efficacy of the-Ir-PEG-coated Ce6 is better than that of Ce6 per se.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the novel linear amphiphilic polymer nano-carrier based on the Ir (III) -Terpy coordination nucleus is a cationic material, so that the assembled micelle has positive charges, and is beneficial to interacting with cell membranes with negative charges, thereby increasing the intake of cells and enhancing the damage effect of tumor cells. Chelate Ir 3+ Of (A) is [ Ir (Terpy) 2 ] 3+ Due to the blocking of the high-molecular long chain, the unit effectively inhibits the triplet state-triplet state energy annihilation between the nucleus and the nucleus in an excited state, so that the nano-carrier has stronger fluorescence property, can be used as an imaging module to observe the distribution condition of the drug in cells and in vivo, and is convenient for real-time tracing and positioning of the drug-loaded micelle. Meanwhile, ir has good photosensitive properties and can generate singlet oxygen with cytotoxicity under the excitation of a light source with specific wavelength. PDT and chemotherapy can be combined through the single material, on one hand, the use of chemical drugs is saved, on the other hand, other photosensitizers do not need to be added into micelles, the complexity of a drug loading system is greatly reduced, and the possibility of clinical transformation of the drug loading system is further enhanced.
Drawings
In order that the present disclosure may be more readily and clearly understood, reference is now made to the following detailed description of the embodiments of the present disclosure taken in conjunction with the accompanying drawings, in which
Fig. 1 is a schematic diagram of two common nanoparticle assembly formats.
FIG. 2 is a schematic diagram of hybrid micelle PSPD/P123-Dex mediated anticancer drug co-delivery strategy.
FIG. 3 is a schematic representation of T820/Ce6 micelles for use in cancer therapy.
FIG. 4 shows a polymer complex C 18 Schematic diagram of Ir-PEG synthesis.
FIG. 5 is 4'- (4-hydroxyphenyl) -2,2' of example 1 of the present invention; 6',2 "-Tripyridines in DMSO-d 6 In (1) 1 H NMR spectrum.
FIG. 6 shows the CDCl of the product (2) in example 1 of the present invention 3 In 1 H NMR spectrum.
FIG. 7 shows the presence of PEG-OTs in CDCl in example 1 of the present invention 3 In (1) 1 H NMR spectrum.
FIG. 8 shows the CDCl of the product (3) in example 1 of the present invention 3 In (1) 1 H NMR spectrum.
FIG. 9 shows the CDCl of the product (4) in example 1 of the present invention 3 In (1) 1 H NMR spectrum.
FIG. 10 shows a graph C in example 1 of the present invention 18 -Ir-PEG in CD 3 In CN 1 H NMR spectrum.
FIG. 11 shows a graph C in example 1 of the present invention 18 Transmission electron microscopy of Ir-PEG micelles.
FIG. 12 shows a graph C in example 1 of the present invention 18 UV absorption profile of Ir-PEG micellar solution.
FIG. 13 shows different concentrations of C in example 1 of the present invention 18 Conductivity of Ir-PEG solution.
FIG. 14 shows a graph C in example 1 of the present invention 18 Fluorescence spectrogram and fluorescence emission photograph of-Ir-PEG (ethylene glycol) -micelle solution
FIG. 15 shows a graph C in example 1 of the present invention 18 Transmission electron microscopy of Ir-PEG @ Ce6 micelles.
FIG. 16 shows 4T1 cells with different concentrations of C in example 1 of the present invention 18 -Ir-PEG (A) and C at different concentrations 18 After incubation with or without light-Ir-PEG @ Ce6Cytotoxicity (B).
Detailed Description
The present invention is further described below in conjunction with the following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit the present invention.
Example 1 (m =16 and n =45 for the metal complex synthesized in this example)
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1). 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine characterization results: 1 H NMR(400MHz,DMSO-d 6 ) δ 10.03 (s, 1H), 9.00 (d, J =5.7hz, 4h), 8.78 (d, J =5.7hz, 4h), 8.67 (s, 2H), 8.07 (d, J =8.2hz, 2h), 6.98 (d, J =8.2hz, 2h) (see fig. 5).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromooctadecane (0.6 mmol, 198mg) (m = 16) were added to a reaction flask, followed by the addition of excess potassium carbonate and finally the addition of 20mL acetonitrile, warmed to 85 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder. The characterization chart is shown in FIG. 6, and it can be seen from the nuclear magnetic data that 14H exists between the shift value of 7.0-9.0ppm in the aromatic ring region, which satisfies 4'- (4-hydroxyphenyl) -2,2'; characteristic peaks of 6',2 "-tripyridine. 2H appears at a displacement value of 4.0ppm, due to the methylene groups on the alkane chains being affected by oxygen atoms and being displaced towards low fields. In addition, a very high peak occurs around a displacement value of 1.5ppm, which satisfies the characteristic peak of the octadecane chain, indicating 4'- (4-hydroxyphenyl) -2,2'; the 6', 2' -tripyridine is successfully grafted with the octadecane chain with hydrophobicity, so that the product (2) is successfully synthesized.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs). Characterization figure see fig. 6, characterization results: as can be seen from the nuclear magnetic data, there is a single peak at a displacement value of 3.3ppm and 4H between 7.0 and 8.0ppm, which satisfy the characteristic peaks for p-toluenesulfonyl. At the same time, a higher and broader peak around a displacement value of 3.6ppm was present, which satisfied the characteristic peak of polyethylene glycol, and these data indicate that one end of polyethylene glycol was successfully grafted with p-toluenesulfonyl group. Thus, the product PEG-OTs were also successfully synthesized.
Weighing (0.3mmol, 98mg) of 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine and (0.3 mmol,660 mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 85 ℃ in acetonitrile and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), finally a white waxy product (3) is obtained. The characterization chart is shown in FIG. 8, and it can be seen from the nuclear magnetic data that 14H exists between the shift value of 7.0-9.0ppm in the aromatic ring region, which satisfies 4'- (4-hydroxyphenyl) -2,2'; the characteristic peak of 6', 2' -tripyridine, and a broader and higher peak around a displacement value of 3.7ppm, which satisfies the characteristic peak of polyethylene glycol. It is noted that the peak at a displacement value of 5.3ppm is due to the shift of H on polyethylene glycol to a low field due to the influence of oxygen atom, which indicates that the product (3) has been synthesized successfully.
Product (2) (0.1mmol, 58mg) and iridium chloride (0.1mmol, 30mg) were weighed, 5mL of ethylene glycol was added, mixed well by sonication, stirred and warmed to 160 ℃ under nitrogen and held for 1 hour, cooled to room temperature, producing a large amount of red precipitate, followed by washing with water and ethanol and drying to give the final product (4) in red. The characterization is shown in FIG. 9, and it can be seen from the nuclear magnetic data that product (4) is affected by the coordinated iridium chloride, 4'- (4-hydroxyphenyl) -2,2', compared to product (1); the 6',2 "-tripyridine displacements move overall towards the high field. It can thus be seen that iridium chloride has been successfully sequestered into product (1) and thus product (4) has been successfully synthesized.
Weighing (0.04mmol, 38mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by ultrasound, stirring under nitrogen and heating to 180 ℃ for 4 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess NH 4 PF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG. The characterization is shown in FIG. 10, from which it can be seen that 4'- (4-hydroxyphenyl) -2,2' remains at displacement values of 7.0-9.5 ppm; the characteristic peak of 6',2 "-tripyridine, and the broader, higher peak appearing at a displacement value of 3.6ppm is clearly characteristic of PEG. At the same time, the peak appearing at a displacement value of 1.3ppm is clearly characteristic of the hydrophobic octadecane, summarizing the target product C with amphiphilicity 18 -Ir-PEG has also been successfully synthesized.
Weighing 15mg of C 18 -Ir-PEG was dissolved in 1.5mL (10 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution. The results of micelle preparation are shown in fig. 11: with products C 18 -Ir-PThe micelle prepared by EG has uniform particle size which is about 130 +/-50 nm, and the micelle has good dispersibility and no obvious agglomeration phenomenon.
Example 2
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were added to the reaction flask, followed by excess potassium carbonate and finally 20mL acetonitrile, warmed to 70 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
4'- (4-hydroxyphenyl) -2,2' was weighed (0.3mmol, 98mg); 6',2 "-Tripyridine and (0.6mmol, 1320 mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 70 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Product (2) (0.1mmol, 55mg) and iridium chloride (0.05mmol, 15mg) were weighed, 5mL of ethylene glycol was added, mixed well by sonication, stirred and warmed to 160 ℃ under nitrogen and held for 3 hours, cooled to room temperature, producing a large amount of red precipitate, followed by washing with water and ethanol and drying to finally obtain red product (4).
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by sonication, stirring under nitrogen and heating to 170 ℃ for 3 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 -Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Example 3
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromooctadecane (1.8mmol, 600mg) (m = 16) were added to a reaction flask, followed by the addition of excess potassium carbonate and finally 20mL acetonitrile, warmed to 75 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 1500 (n = 34) (2mmol, 3g) was weighed out in 100mL of dichloromethane, and 1.4mL of triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
4'- (4-hydroxyphenyl) -2,2' was weighed (0.3mmol, 98mg); 6',2 "-Tripyridine and (0.9mmol, 1485mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 75 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying with silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Product (2) (0.12mmol, 69mg) and iridium chloride (0.042mg) were weighed, 5mL of ethylene glycol was added, mixed well by sonication, stirred under nitrogen and warmed to 160 ℃ for 2 hours, cooled to room temperature to produce a large amount of red precipitate, which was then washed with water and ethanol and dried to give the final red product (4).
Product (4) (0.02mmol, 18mg) and product (3) (0.04mmol, 72mg) were weighed, 5mL of ethylene glycol was added, mixed well by sonication, stirred and warmed to 175 ℃ under nitrogen and held for 4 hours,cooling to room temperature and diluting with 30mL of water, centrifuging the precipitate to give a brown-yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
22.5mg of C are weighed out 18 -Ir-PEG was dissolved in 1.5mL (15 mg/mL) of DMF and added dropwise to 3mL of water, 100. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Example 4
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were added to the reaction flask, followed by excess potassium carbonate and finally 20mL acetonitrile, warmed to 85 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 1000 (n = 23) (2mmol, 2g) was weighed out in 100mL of dichloromethane, and 1.4mL of triethylamine was added and stirred well in an ice bath. At the same time, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solutionAfter addition was complete, stir at room temperature overnight. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into a large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
Weighing (0.3mmol, 98mg) of 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine and (0.3 mmol, 330mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 85 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Product (2) (0.1mmol, 55mg) and iridium chloride (0.1mmol, 30mg) were weighed, 5mL of ethylene glycol was added, mixed well by sonication, stirred and warmed to 170 ℃ under nitrogen and held for 1 hour, cooled to room temperature, producing a large amount of red precipitate, which was then washed with water and ethanol and dried to finally give product (4) in red.
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 48mg) product (3), adding 5mL of ethylene glycol, mixing well by ultrasound, stirring under nitrogen and heating to 180 ℃ for 4 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess NH 4 PF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 18mg of C 18 -Ir-PEG was dissolved in 1.5mL (12 mg/mL) of DMF and added dropwise to 3mL of water, 80. Mu.L of solution each time being added to 3mL of water every 10s until the addition was complete. Stirring for 3h, dialyzing with dialysis bag with cut-off molecular weight of 1000 for 24 hr to remove DMSO, taking out after dialysis, and filtering with 450nm water system filter head to obtain final productMicellar solutions.
Example 5
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were added to the reaction flask, followed by excess potassium carbonate and finally 20mL acetonitrile, warmed to 70 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
Weighing (0.3mmol, 98mg) of 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine and (0.6mmol, 1320 mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 70 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Product (2) (0.1mmol, 55mg) was weighed out with RhCl 3 (0.05mmol, 13mg), adding 5mL of ethylene glycol, mixing uniformly by ultrasound, stirring under the protection of nitrogen, heating to 160 ℃ and keeping for 3 hours, cooling to room temperature to generate a large amount of red precipitate, then washing with water and ethanol and drying to finally obtain a red product (4).
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by ultrasound, stirring under nitrogen and warming to 170 ℃ for 3 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 -Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Example 6
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were added to the reaction flask, followed by excess potassium carbonate and finally 20mL acetonitrile, warmed to 70 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
Weighing (0.3mmol, 98mg) of 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine and (0.6mmol, 1320 mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 70 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Weighing (0.1mmol, 55mg) of product (2) with RuCl 3 (0.05mmol, 10mg), 5mL of ethylene glycol is added, the mixture is subjected to uniform mixing by ultrasound, the mixture is stirred under the protection of nitrogen, the temperature is raised to 160 ℃ and kept for 3 hours, the mixture is cooled to room temperature, a large amount of red precipitate is generated, and then the red precipitate is washed by water and ethanol and dried to finally obtain a red product (4).
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by ultrasound, stirring under nitrogen and heating to 170 ℃ for 3 hours, cooling to room temperature and adding 30mL of water to dilute, centrifuging to obtain a brown yellow clear solution, addingExcess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 -Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Example 7
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were added to the reaction flask, followed by excess potassium carbonate and finally 20mL acetonitrile, warmed to 70 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, and carrying out chromatography separation and purification by using silica gel, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Hydrochloric acidWashing the solution, evaporating and concentrating the reaction solution, dissolving the residue with a trace amount of methanol, adding into a large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
Weighing (0.3mmol, 98mg) of 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine and (0.6 mmol,1320 mg) PEG-OTs, and excess potassium carbonate was added, and the mixture was heated to 70 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying with silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Weighing (0.1mmol, 55mg) product (2) and FeCl 3 (0.05mmol, 8 mg), adding 5mL of ethylene glycol, uniformly mixing by ultrasound, stirring under the protection of nitrogen, heating to 160 ℃ and keeping for 3 hours, cooling to room temperature to generate a large amount of red precipitate, then washing with water and ethanol, and drying to finally obtain a red product (4).
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by sonication, stirring under nitrogen and heating to 170 ℃ for 3 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 -Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Example 8
P-hydroxybenzaldehyde (2mmol, 244mg) was weighed out and dissolved in 10mL of 95% ethanol, 2-acetylpyridine (4mmol, 484mg) and 420mg of KOH were added thereto, and after stirring well, 5mL of ammonia water was added and the mixture was heated to 50 ℃ overnight. After the reaction is finished, 1mol L of the catalyst is used -1 Adjusting the pH of the reaction solution to 3-4 by hydrochloric acid solution, filtering out precipitate, washing the precipitate by ethanol, and finally recrystallizing the precipitate by methanol to obtain a yellow crystalline product 4'- (4-hydroxyphenyl) -2,2';6', 2' -Tripyridine (1).
Weighing 4'- (4-hydroxyphenyl) -2,2';6',2 "-tripyridine (0.6 mmol, 195mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were added to the reaction flask, followed by excess potassium carbonate and finally 20mL acetonitrile, warmed to 70 ℃ under reflux and overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
Weighing (0.3mmol, 98mg) of 4'- (4-hydroxyphenyl) -2,2';6',2 "-Tripyridine and (0.6mmol, 1320 mg) PEG-OTs, and excess potassium carbonate was added and the mixture was warmed to 70 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Weighing (0.1mmol, 55mg) product (2) with OsCl 3 (0.05mmol, 18mg), 5mL of ethylene glycol was added, mixed well by sonication, stirred under nitrogen and warmed to 160 ℃ for 3 hours, cooled to room temperature to produce a large amount of red precipitate, followed by washing with water and ethanol and drying to finally obtain a red product (4).
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by sonication, stirring under nitrogen and heating to 170 ℃ for 3 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing for 24h by using a dialysis bag with the molecular weight cutoff of 1000 to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Example 9
4- (2,6-bis (2H-tetrazol-5-yl) pyridin-4-yl) phenol (0.6 mmol, 184mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were weighed into a reaction flask, followed by the addition of excess potassium carbonate and finally the addition of 20mL acetonitrile to warm to 70 ℃ under reflux overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, separating and purifying by using a silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was dissolved in 100mL dichloromethane, 1.4mL triethylamine was added and stirred well in an ice bath. At the same time, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethaneTo the alkane, tsCl was added dropwise to the initial solution and stirred overnight at room temperature after the addition was complete. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
4- (2,6-bis (2H-tetrazol-5-yl) pyridin-4-yl) phenol (0.3mmol, 92mg) and PEG-OTs (0.6mmol, 1320 mg) were weighed and excess potassium carbonate was added and the mixture was warmed to 70 ℃ in acetonitrile and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), finally a white waxy product (3) is obtained.
Weighing (0.1mmol, 55mg) product (2) with OsCl 3 (0.05mmol, 18mg), 5mL of ethylene glycol was added, mixed well by sonication, stirred under nitrogen and warmed to 160 ℃ for 3 hours, cooled to room temperature to produce a large amount of red precipitate, followed by washing with water and ethanol and drying to finally obtain a red product (4).
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by sonication, stirring under nitrogen and heating to 170 ℃ for 3 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 -Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. Stirring for 3 hr, dialyzing with dialysis bag with cut-off molecular weight of 1000 for 24 hr to remove the residual substancesAnd (3) taking out the DMSO (dimethyl sulfoxide) after the dialysis is finished, and filtering the DMSO by using a water filter head with the wavelength of 450nm to finally obtain a micelle solution.
Example 10
4- (2,6-bis (1H-benzimidazol-2-yl) pyridin-4-yl) phenol (0.6 mmol, 220mg) and bromohexadecane (1.2mmol, 366 mg) (m = 14) were weighed into a reaction flask, followed by the addition of excess potassium carbonate and finally the addition of 20mL acetonitrile and reflux to 70 ℃ overnight. After the reaction is finished, completely evaporating acetonitrile, extracting the water phase by using dichloromethane for three times, drying by using anhydrous sodium sulfate, and carrying out chromatography separation and purification by using silica gel, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and the product (2) is finally obtained as an off-white powder.
Polyethylene glycol monomethyl ether 2000 (n = 45) (2mmol, 4g) was weighed out and dissolved in 100mL dichloromethane, and 1.4mL triethylamine was added and stirred well in an ice bath. Meanwhile, 1.9g of p-toluenesulfonyl chloride (TsCl) was weighed out and dissolved in 50mL of dichloromethane, and TsCl was added dropwise to the initial solution, followed by stirring overnight at room temperature after completion of the dropwise addition. After the reaction, the reaction solution was used in an amount of 1mol L -1 Washing with hydrochloric acid solution, evaporating and concentrating the reaction solution, dissolving the residue with trace amount of methanol, adding into large amount of diethyl ether, cooling to obtain white precipitate, filtering, and drying at room temperature to obtain white product polyethylene glycol-p-toluenesulfonate (PEG-OTs).
4- (2,6-bis (1H-benzimidazol-2-yl) pyridin-4-yl) phenol (0.3mmol, 110mg) and PEG-OTs (0.6mmol, 1320 mg) were weighed and added excess potassium carbonate and warmed to 70 ℃ in acetonitrile solution and refluxed overnight. After the reaction is finished, completely evaporating acetonitrile, extracting with dichloromethane and water for three times, drying with anhydrous sodium sulfate, separating and purifying by silica gel chromatography, wherein a developing agent is dichloromethane: methanol =20 (volume ratio), and finally a white waxy product (3) is obtained.
Weighing (0.1mmol, 55mg) product (2) with OsCl 3 (0.05mmol, 18mg), adding 5mL of ethylene glycol, mixing uniformly by ultrasound, stirring under nitrogen and heating to 160 ℃ for 3 hours, cooling to room temperature to generate a large amount of red precipitate, washing with water and ethanol, and drying, and finallyThe red product (4) is finally obtained.
Weighing (0.02mmol, 17mg) product (4) and (0.04mmol, 100mg) product (3), adding 5mL of ethylene glycol, mixing well by ultrasound, stirring under nitrogen and warming to 170 ℃ for 3 hours, cooling to room temperature and diluting with 30mL of water, centrifuging to precipitate a brownish yellow clear solution, and adding excess KPF 6 Precipitating to obtain orange floccule, separating solid, dissolving in water, dialyzing in dialysis bag with molecular cut-off of 3000 for 24 hr, and freeze drying to obtain orange waxy solid C 18 -Ir-PEG。
Weighing 7.5mg of C 18 -Ir-PEG was dissolved in 1.5mL (5 mg/mL) of dimethyl sulfoxide and added dropwise to 3mL of water, 50. Mu.L of the solution each time being added to 3mL of water every 10s until the addition was complete. And (3) continuing stirring for 3h after the addition is finished, finally dialyzing by adopting a dialysis bag with the molecular weight cutoff of 1000 for 24h to remove DMSO in the solution, taking out after the dialysis is finished, and filtering by using a water system filter head with the wavelength of 450nm to finally obtain the micelle solution.
Test example
1, micelle Performance test C obtained in example 1 18 Ultraviolet absorption of Ir-PEG micellar solutions.
The experimental results are shown in fig. 12, and it can be seen from the experiment that: c 18 -Ir-PEG micellar solution at 250-Multiple absorption peaks (260 nm, 280nm, 320nm and 380 nm) are formed in the range of 450nm, and the ultraviolet absorption values of the absorption peaks are reduced in sequence.
2 micelle Performance testing of the micelles obtained in example 1-different concentrations of C 18 Conductivity of the-Ir-PEG solution
The experimental results are shown in fig. 13, and it can be found from the experiment that: only when the concentration is higher than the critical micelle concentration, the amphiphilic substance can self-assemble in water to form micelles. As a result, it was found that C 18 The critical micelle concentration of-Ir-PEG is 154.2. Mu.g mL -1 。
3 micelle Performance test obtained in example 1-fluorescence Spectroscopy
The experimental results are shown in fig. 14, and the experiment shows that: c 18 The micelle of the-Ir-PEG emits stronger orange yellow under the excitation of ultraviolet light with the wavelength of 430nmFluorescence (emission wavelength 570 nm)
4, test of drug-carrying Performance of micelle prepared in example 1
(1) Preparation of materials
1mg of Ce6 was dissolved in 0.5mL of dimethyl sulfoxide, and 8mg of C was dissolved 18 -Ir-PEG was added to the above solution and dissolved completely by sonication for 5 min. Then 50. Mu.L of each solution was added to 3mL of water every 10 seconds until the addition was complete. Stirring for 3h, dialyzing with dialysis bag with cut-off molecular weight of 1000 for 24h to remove DMSO in the solution, taking out after dialysis, filtering with 450nm water system filter head to remove insoluble drug, and finally obtaining drug-loaded micelle solution C 18 -Ir-PEG @ Ce6. The transmission electron microscope test of the prepared drug-loaded micelle shows that the micelle is spherical, is distributed uniformly and has no agglomeration phenomenon as shown in figure 15.
(2) Cytotoxicity test
To study C 18 -Ir-PEG and C 18 The magnitude of dark toxicity and phototoxicity of-Ir-PEG @ Ce6, the cytotoxicity experiments on the two materials are carried out, and the specific process is as follows:
paving a plate: plating 96-well plates at a density of 1 ten thousand 4T1 cells per well, and standing at 37 ℃ with 5% CO 2 Culturing in an incubator for 16h.
Preparing materials: prepare 1mg mL first -1 C of (A) 18 -Ir-PEG in PBS, then diluted in serum-free DMEM to obtain a concentration of 1.25. Mu.g mL -1 、2.5μg mL -1 、5μg mL -1 、10μg mL -1 、20μg mL -1 C of (A) 18 -Ir-PEG solution. The Ce6 concentration is 42.5 mug mL -1 C of (A) 18 PBS solution of-Ir-PEG @ Ce6, then diluted with serum-free DMEM to obtain a Ce6 concentration of 0.0625. Mu.g mL -1 、0.125μg mL -1 、0.25μg mL -1 、0.5μg mL -1 、1μg mL -1 C of (A) 18 -Ir-PEG @ Ce6 solution.
Administration: after the cells are cultured for 16h, the culture solution is aspirated, the prepared solutions are sequentially added, and serum-free DMEM and deionized water are added as controls, wherein the volume of each well is 200 muL, five replicates per material. The 96-well plate without illumination is directly placed at 37 ℃ and contains 5% CO 2 Incubating in an incubator for 48h. After incubation in an incubator for 24h in a 96-well plate with light, a laser (0.22W/cm) 2 ) Irradiating for 30s, and placing in an incubator for further incubation for 24h.
Add 3- (4 ',5' -dimethylthiazol-2 ' -yl) -2,5-diphenyltetrazolium bromide (MTT) solution: after 48h incubation of the cells with the material, the drug was aspirated, and 200. Mu.L of serum-free DMEM prepared in advance at a concentration of 0.5mg mL was added to each well -1 The MTT solution was further placed in the oven to incubate for 4h. And (3) turning the plate, adding 100 mu L of DMSO solution into each hole, oscillating for 3min on a shaking table, and testing the absorbance at 570nm by using a microplate reader to obtain the corresponding survival rate.
The experimental results are as follows: as can be seen from FIG. 16, the micelle C was associated with the micelle 18 The concentration of the-Ir-PEG is gradually increased, and the cell activity is kept above 50%, which shows that the material has lower toxicity to the cell 4T1 and can be used for subsequent drug loading experiments. Warp C 18 Cells treated with-Ir-PEG @ Ce6, with higher survival in the absence of light, suggesting C 18 -Ir-peg @ ce6 has lower dark toxicity. With C 18 The phototoxicity of the increased Ce6 concentration in-Ir-PEG @ Ce6 is significantly enhanced, thus C 18 -Ir-PEG @ Ce6 has a high tumor cell killing effect under laser irradiation, its IC 50 0.42. Mu.g mL -1 。
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.
Claims (10)
1. An amphiphilic nano metal complex is characterized in that the structure of the metal complex is shown as a formula (1) to a formula (3):
wherein m = an integer of 14-16;
n = an integer from 23-45;
m is selected from Rh, ir, fe, ru and Os.
2. The method for producing a metal complex according to claim 1, comprising the steps of:
s1: the N-based ligand,
And carbonate is mixed and reacted in an organic solvent to obtain a compound (1), wherein X is F, cl, br or I; m = an integer of 0-16;
s2: reacting the compound (1) with a metal salt in an organic solvent to obtain a compound (2);
s3: the N-based ligand,
And reacting a carbonate in an organic solvent to obtain a compound (3), wherein n = an integer of 5-45;
s4: and (3) mixing the compound (2) and the compound (3) in an organic solvent for heating reaction, performing solid-liquid separation after the reaction is finished, taking supernatant, adding hexafluorophosphate for flocculation precipitation, performing solid-liquid separation, and taking a solid phase to obtain the metal complex.
3. The method according to claim 2, wherein the N-based ligand in S1 and S3 is selected from the group consisting of
、
Or
。
4. The method according to claim 2, wherein the metal salt in S2 is selected from RhCl 3 、IrCl 3 、FeCl 3 、RuCl 3 、OsCl 3 。
5. The method according to claim 2, wherein the N-based ligand in S3 is bonded to
In a molar ratio of 1:1-1:3.
6. The method according to claim 2, wherein the molar ratio of the compound (2) to the compound (3) in S4 is 1:3-3:1.
7. The method according to claim 2, wherein said hexafluorophosphate salt in S4 is selected from NH 4 PF 6 、KPF 6 、NaPF 6 Or LiPF 6 。
8. A method for synthesizing micelles, comprising the steps of dissolving the metal complex of claim 1 in an organic solvent to obtain a metal complex solution, adding the metal complex solution to water at a rate of 5 to 10. Mu.L/s, stirring for reaction, removing the organic solvent after the reaction is completed, and dialyzing and filtering to obtain the micelles.
9. The resulting micelles were prepared by the synthetic method as described in claim 8.
10. The use of the micelle of claim 9 in the preparation of an anti-tumor medicament, wherein the tumor is breast cancer or melanoma.
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| CN108078924A (en) * | 2017-12-07 | 2018-05-29 | 同济大学 | A kind of preparation method of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses |
| CN111662333A (en) * | 2019-03-07 | 2020-09-15 | 天津理工大学 | Bis-terpyridyl iridium (III) complex and synthetic method thereof |
| CN111939124A (en) * | 2020-07-13 | 2020-11-17 | 东南大学 | Metal polymer, metal polymer nano micelle, and preparation method and application thereof |
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| CN108078924A (en) * | 2017-12-07 | 2018-05-29 | 同济大学 | A kind of preparation method of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses |
| CN111662333A (en) * | 2019-03-07 | 2020-09-15 | 天津理工大学 | Bis-terpyridyl iridium (III) complex and synthetic method thereof |
| CN111939124A (en) * | 2020-07-13 | 2020-11-17 | 东南大学 | Metal polymer, metal polymer nano micelle, and preparation method and application thereof |
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