CN111363007A - Synthetic method of efficient active targeting near-infrared fluorescent tracer - Google Patents
Synthetic method of efficient active targeting near-infrared fluorescent tracer Download PDFInfo
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- CN111363007A CN111363007A CN201910587417.5A CN201910587417A CN111363007A CN 111363007 A CN111363007 A CN 111363007A CN 201910587417 A CN201910587417 A CN 201910587417A CN 111363007 A CN111363007 A CN 111363007A
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- 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
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Abstract
The invention discloses a synthetic method of an efficient active targeting near-infrared fluorescent tracer, which synthesizes an iRGD modified ZW800 near-infrared micromolecule, namely ZW800-iRGD by using an organic total synthesis method, so that the tracer has a good tumor targeting effect. The near-infrared small molecule linked with the iRGD not only promotes the water solubility but also has no influence on the fluorescence property. The active targeting near-infrared fluorescent molecule has a high-efficiency specific targeting effect, can efficiently enter tumor cells, has the advantages of good water solubility, high fluorescence quantum yield and the like, and has great development potential in the fields of tumor surgical navigation imaging and medical cell marking.
Description
Technical Field
The invention relates to a synthesis method of an efficient active targeting near-infrared fluorescent tracer, which combines a fully water-soluble near-infrared fluorescent micromolecule with high fluorescence quantum yield ZW800 with iRGD (indium-gallium-aspartic acid) die-penetrating peptide by a full synthesis method to form a high-specificity active targeting tracer.
Technical Field
Indocyanine green (ICG) is an FDA approved hydrophilic fluorescent tracer, and is used primarily for the assessment of liver function, cardiac output, and fundus angiography. In the present year, the near infrared light absorbing 780nm emits fluorescence with the wavelength of about 830nm, so that the autofluorescence of human tissues is avoided well, the tissue penetrability is good, and the ICG can be used for fluorescence detection in some deep tissues. After entering blood, ICG can be rapidly combined with plasma protein to form nano particles of about 7nm with protein in body fluid, and the nano particles are enriched in tumor tissues through an EPR effect to participate in tumor development, so that the ICG becomes a mainstream near-infrared small molecule for surgical real-time navigation imaging at present. However, according to the results reported in the literature and observed in a large number of clinical and animal in vivo experiments in recent years, ICG as a tumor fluorescent tracer has the following problems:
1) low fluorescence emission efficiency (quantum yield is less than 1% in aqueous solution), and high equipment sensitivity requirement. According to the regulations of the national drug administration, the maximum injection dosage of the ICG in the human body is less than 2mg/kg, and under the dosage, the concentration of the ICG in the human tumor is 10-1000nM through literature reports and detection data of the ICG per se, while the effective detection range of most current devices is 10-1000 MuM, and the difference between the two is 1000 times.
2) It has been found in clinical practice that ICG has a small difference in the metabolic rate between tumor and normal tissue, and it takes at least 12 hours to generate sufficient fluorescence contrast (tumor: normal tissue), increasing the burden on hospitals and patients.
The research shows that integrin has higher-level expression on the surfaces of various malignant tumor cells or on neovascular endothelial cells of tumor tissues, such as gastric cancer, ovarian cancer, breast cancer and the like, while normal tissue cells or mature vascular endothelial cells express little, so that the hydraulic pressure between tumor tissues is high due to the fact that solid tumor tissues are compact, lymphatic defects and vascular disorders inside tissues cause high infiltration of drug carriers or chemotherapeutic drugs into the deep part of tumor tissues, general RDG targeted receptors only can selectively exist tumor stromal cells and neovascular endothelial cells, but no precise targeting is performed on tumor cells, therefore, the search for suitable tumor cell specific targeted transmembrane polypeptides is a research direction of many researchers from 2010, the research direction of targeted transmembrane fetal RGD can be reported on Science, the targeted transmembrane polypeptides can obviously improve the infiltration of drugs into tumor tissues, and a plurality of tumor cells or tumor cells can be widely combined with a tumor tissue-specific targeting peptide (such as a tumor targeting RGD-RGD receptor-RGD.
Disclosure of Invention
The purpose of the invention is as follows: based on the problems found above, the invention discloses a preparation method of an active targeting near-infrared fluorescent molecule, which is a high-efficiency near-infrared fluorescent tracer based on an iRGD active targeting group, and the tracer has the advantages of high active targeting property, strong specificity, good water solubility, high fluorescence quantum yield and the like.
The technical scheme is as follows: the invention comprises the following contents:
1. a preparation method of an active targeting near-infrared fluorescent molecule is characterized by comprising the following main steps: step A: the ZW800 near infrared micromolecules are completely synthesized, a unilateral sulfate radical intermediate is synthesized by utilizing a cycloaddition reaction, and then the unilateral sulfonate radical intermediate is connected with a sulfonate radical by a nucleophilic substitution mode. The chloro-fully water soluble ICG derivative precursors were synthesized by linking the mono-bis-sulfonate intermediates together via Vilsmeier-Haack reagent. Methods of determination and Experimental procedure (A1) the parent structures of ZW800-C1 were first synthesized by varying reaction times and dosages, and were the basis for the next halogen substitution reaction.
(A2) Preparing ZW800-COOH by means of nucleophilic substitution based on the existing chloro ZW800 precursor, and then separating and purifying.
And B: further linking iRGD on the basis of ZW800-COOH to synthesize ZW800-iRGD, and further separating and purifying.
(B1) The ZW800-iRGD is synthesized by a one-step solid phase method.
(B2) Separating and purifying the totally synthesized totally water-soluble ZW800-iRGD micromolecules.
2. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (A1) comprise:
(A1.1)1eq 4-hydrazinobenzenesulfonic acid (1g, 19.9mmol), 3eq 3-methyl-2-butane (1.5ml, 60mmol) was mixed with glacial acetic acid (40ml) and heated to 90 ℃ for 15h under a nitrogen atmosphere.
(A1.2) after precipitation in ethyl acetate, the crude product was filtered and collected as a pink solid and the resulting product was dissolved in methanol (40 mL).
(A1.3) to a solution of 1eq of potassium hydroxide (1.12g, 19.9mmol) and isopropanol (30ml) was added dropwise at room temperature, and the mixture was filtered through a filter paper to obtain a crude product.
(A1.4) the crude product was washed three times with isopropanol to clarity without further purification to give a brown solid. (97%)
(A1.5) 1eq of 2(1g, 3.6mmol) and 1.5eq of (3-bromopropyl) trimethylammonium bromide (2g, 7.68mmol) were added to a toluene solution under a nitrogen atmosphere and heated at 80 ℃ for 30 h.
(A1.6) the mixture was cooled to room temperature, and the solvent precipitated. Adding methanol (10ml) into the crude mixture, stirring for 20-40min, filtering the crude mixture, collecting, and dissolving in a mixed solvent of 1: 2(v/v) methanol (10ml) and water (20 ml).
(A1.7) the mixed solution was then slowly added to acetonitrile (120ml) using a dropping funnel. The precipitate was filtered and collected as a pink solid. (40%)
(A1.8) 2eq of 3(1g, 1.86mmol), 1eq of Vilsmeier-Haack reagent (0.33g, 0.93mmol) and 3eq of anhydrous sodium acetate (0.22g, 2.79mmol) were heated at reflux in 10mL of anhydrous ethanol under a nitrogen atmosphere for 4 h.
(A1.9) the reaction mixture was cooled to room temperature, then filtered, washed with excess ethanol and methanol and collected as a brown-green solid 4. (90%)
3. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (A2) comprise:
(A2.1)1eq 3- (4-hydroxyphenyl) propionic acid (1g, 6.0mmol) was dissolved in 10mL of 2eq aqueous sodium hydroxide (0.48g, 12mmol), reacted at room temperature for 24h and rotary evaporated to give 5 as a white solid. (95%)
(A2.2) 2eq of 5(1g, 4.7mmol) were mixed with 1eq of 4(1.9g, 2.35mmol) and added to a solution of DMSO and water (40mL, 1: 1v/v) under reflux for 6h and allowed to settle out with a mixture of ethyl acetate and ethanol (400mL, 1: 1 v/v). The precipitate was filtered, washed with ethanol and acetone and collected as a dark green solid (10.4g, 80%) as 6.
(A2.3) separation and purification in preparative liquid chromatography using 0.1% formic acid water and 10% methanol as mobile phases.
4. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (B1) comprise:
(B1.1) Fmoc solid phase peptide chemical synthesis using standard automated continuous flow precursor peptide synthesizer using HCys (Trt) -2Cl resin (0.4mmol/g substitution) as solid support.
(B1.2) before use the resin was soaked in N, N-Dimethylformamide (DMF) for 15 minutes.
(B1.3) after DMF filtration, a mixture of Fmoc-Asp (Otbu) -OH (2equiv), HBTU (2equiv) and N, N-diisopropylethylamine (DIEA, 2 equiv); the solution was added to the resin and stirred with nitrogen.
(B1.4) after one hour, the solvent was removed and the resin was washed three times with Dimethylformamide (DMF).
(B1.5) then, the Fmoc group was deprotected with 20% piperidine, shaken for 20 min, and washed 9 times by draining.
(B1.6) Each acylation and deprotection cycle was monitored in real time. After repeated deprotection and acylation reactions, the protected precursor of ZW800-iRGD is cleaved from the resin.
(B1.7) the peptide fragment is cleaved with trifluoroacetic acid (TFA)/Triisopropylsilane (TIS)/water in a ratio of 95: 2.5 for 2-2.5h to obtain crude ZW 800-iRGD. (30%)
5. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (B2) comprise:
(B2.1) then washed several times with cold diethyl ether and then dried in vacuo.
(B2.2) the precipitate was dissolved in water and the residual TFA was neutralized with trimethylamine.
(B2.3) finally concentrating by rotary evaporation and freezing, and determining the purity of the polypeptide by adopting an Agilent 100 series high performance liquid chromatography system.
The efficient active targeting near-infrared fluorescent tracer is characterized in that a full-synthesis method is adopted to combine near-infrared fluorescent micromolecules with high fluorescent quantum yield of fully water-soluble ZW800 with iRGD (indium-gallium-aspartic acid) die-penetrating peptides to form a high-specificity active targeting tracer, and the tracer has the advantages of better active targeting property, stronger specificity, super-good water solubility, higher fluorescent quantum yield and the like compared with the traditional ICG.
Description of the drawings:
FIG. 1 is a flow chart of the synthesis of an actively targeted near-infrared fluorescent tracer.
FIG. 2 is a water solution fluorescence test chart of the active targeting near infrared fluorescent tracer.
FIG. 3 is a high performance liquid phase analysis of the actively targeted near-infrared fluorescent tracer.
FIG. 4 is a mass spectrum of the active targeting near infrared fluorescent tracer.
Figure 5 is a graph of the active targeting near infrared fluorescent tracer for in vivo imaging of different tumor sizes.
Table 1 is a table of high performance liquid analytical purities for the active targeted near infrared fluorescent tracers.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention is further described in detail below with reference to specific embodiments, as shown in the flowchart of fig. 1.
The implementation of the invention comprises the following steps:
1. a method for synthesizing a high-efficiency active targeting near-infrared fluorescent tracer is characterized by mainly comprising the following steps:
step A: the ZW800 near infrared micromolecules are completely synthesized, a unilateral sulfate radical intermediate is synthesized by utilizing a cycloaddition reaction, and then the unilateral sulfonate radical intermediate is connected with a sulfonate radical by a nucleophilic substitution mode. The chloro-fully water soluble ICG derivative precursors were synthesized by linking the mono-bis-sulfonate intermediates together via Vilsmeier-Haack reagent. Methods of determination and Experimental procedures
(A1) Firstly, synthesizing a parent structure of ZW800-Cl through different reaction time and dosage, and making the base for the next halogen substitution reaction.
(A2) Preparing ZW800-COOH by means of nucleophilic substitution based on the existing chloro ZW800 precursor, and then separating and purifying.
And B: further linking iRGD on the basis of ZW800-COOH to synthesize ZW800-iRGD, and further separating and purifying.
(B1) The ZW800-iRGD is synthesized by a one-step solid phase method.
(B2) Separating and purifying the totally synthesized totally water-soluble ZW800-iRGD micromolecules.
2. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (A1) comprise:
(A1.1)1eq 4-hydrazinobenzenesulfonic acid (1g, 19.9mmol), 3eq 3-methyl-2-butane (1.5ml, 60mmol) and glacial acetic acid (40ml) were mixed and added to a 100 ml round bottom reaction flask and heated to 90 ℃ for 15h under nitrogen.
(A1.2) the product obtained in A1.1 was precipitated slowly dropwise in ethyl acetate, the crude product was filtered and collected as a pink solid, washed with excess ethyl acetate and dried to give a pink powder.
(A1.3) the product obtained in A1.2 was dissolved in methanol (40mL) at room temperature, and 1eq of a solution of potassium hydroxide (1.12g, 19.9mmol) and isopropanol (30mL) was added dropwise to the solution and filtered through filter paper to obtain a crude product.
(A1.4) the crude product from A1.3 was washed three times with isopropanol to clarify without further purification to give 2 as a brown solid. (97%)
(A1.5) 1eq of 2(1g, 3.6mmol) and 1.5eq of (3-bromopropyl) trimethylammonium bromide (2g, 7.68mmol) were added to a toluene solution under a nitrogen atmosphere and heated at 80 ℃ for 30 h.
(A1.6) the mixture was cooled to room temperature, and the solvent precipitated. Adding methanol (10ml) into the crude mixture, stirring for 20-40min, filtering the crude mixture, collecting, and dissolving in a mixed solvent of 1: 2(v/v) methanol (10ml) and water (20 ml).
(A1.7) the mixed solution was then slowly added to acetonitrile (120ml) using a dropping funnel. The precipitate was filtered and collected as a pink solid. (40%)
(A1.8) 2eq of 3(1g, 1.86mmol), 1eq of Vilsmeier-Haack reagent (0.33g, 0.93mmol) and 3eq of anhydrous sodium acetate (0.22g, 2.79mmol) were heated at reflux in 10mL of anhydrous ethanol under a nitrogen atmosphere for 4 h.
(A1.9) the reaction mixture was cooled to room temperature, then filtered, washed with excess ethanol and methanol and collected as a brown-green solid 4. (90%)
3. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (A2) comprise:
(A2.1)1eq 3- (4-hydroxyphenyl) propionic acid (1g, 6.0mmol) was dissolved in 10mL of 2eq aqueous sodium hydroxide (0.48g, 12mmol), reacted at room temperature for 24h and rotary evaporated to give 5 as a white solid. (95%)
(A2.2) 2eq of 5(1g, 4.7mmol) were mixed with 1eq of 4(1.9g, 2.35mmol) and added to a solution of DMSO and water (40mL, 1: 1v/v) under reflux for 6h and allowed to settle out with a mixture of ethyl acetate and ethanol (400mL, 1: 1 v/v). The precipitate was filtered, washed with ethanol and acetone and collected as a dark green solid (10.4g, 80%) as 6.
(A2.3) separation and purification in preparative liquid chromatography using 0.1% formic acid water and 10% methanol as mobile phases.
4. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (B1) comprise:
(B1.1) Fmoc solid phase peptide chemical synthesis using standard automated continuous flow precursor peptide synthesizer using HCys (Trt) -2Cl resin (0.4mmol/g substitution) as solid support.
(B1.2) before use the resin was soaked in N, N-Dimethylformamide (DMF) for 15 minutes.
(B1.3) after DMF filtration, a mixture of Fmoc-Asp (Otbu) -OH (2equiv), HBTU (2equiv) and N, N-diisopropylethylamine (DIEA, 2 equiv); the solution was added to the resin and stirred with nitrogen.
(B1.4) after one hour, the solvent was removed and the resin was washed three times with Dimethylformamide (DMF).
(B1.5) then, the Fmoc group was deprotected with 20% piperidine, shaken for 20 min, and washed 9 times by draining.
(B1.6) Each acylation and deprotection cycle was monitored in real time. After repeated deprotection and acylation reactions, the protected precursor of ZW800-iRGD is cleaved from the resin.
(B1.7) the peptide fragment is cleaved with trifluoroacetic acid (TFA)/Triisopropylsilane (TIS)/water in a ratio of 95: 2.5 for 2-2.5h to obtain crude ZW 800-iRGD. (30%)
5. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (B2) comprise:
(B2.1) then washed several times with cold diethyl ether and then dried in vacuo.
(B2.2) the precipitate was dissolved in water and the residual TFA was neutralized with trimethylamine.
(B2.3) finally concentrating by rotary evaporation and freezing, and determining the purity of the polypeptide by adopting an Agilent 100 series high performance liquid chromatography system.
6. The structure and performance characterization of the active targeting near-infrared small molecule comprises the following specific operations:
(1) characterization of optical properties: as shown in FIG. 2, the fluorescence properties of the obtained fluorescent small molecules are tested by a fluorescence gradiometer, and fluorescence spectra are obtained under different excitation wavelengths. After the iRGD is linked, the fluorescence peak at 800nm is not obviously changed, and the good fluorescence property is kept.
(2) High performance liquid chromatography and mass spectrometry: as shown in fig. 3, 4 and table 1, the fluorescent small molecules obtained by linking iRGD have higher purity (98%) in hplc analysis, and mass spectrometry and molecular weight match.
(3) Characterization of in vivo animal imaging: as shown in figure 5, tumors of different diameters of the mouse are imaged by injecting ZW800-iRGD near-infrared active targeting small molecules into the tail vein, and the small molecules can be enriched on the tumors after 1h observed by near-infrared surgical navigation equipment, so that the boundaries and the sizes of the tumors can be clearly observed. The imaging effect of the tumor is not greatly influenced after the enrichment for a long time.
Claims (5)
1. A synthetic method of an active targeting near-infrared fluorescent molecule is characterized by comprising the following main steps:
step A: the ZW800 near infrared micromolecules are completely synthesized, a unilateral sulfate radical intermediate is synthesized by utilizing a cycloaddition reaction, and then the unilateral sulfonate radical intermediate is connected with a sulfonate radical by a nucleophilic substitution mode. The chloro-fully water soluble ICG derivative precursors were synthesized by linking the mono-bis-sulfonate intermediates together via Vilsmeier-Haack reagent. Methods of determination and Experimental procedures
(A1) Firstly, synthesizing a parent structure of ZW800-Cl through different reaction time and dosage, and making the base for the next halogen substitution reaction.
(A2) Preparing ZW800-COOH by means of nucleophilic substitution based on the existing chloro ZW800 precursor, and then separating and purifying.
And B: further linking iRGD on the basis of ZW800-COOH to synthesize ZW800-iRGD, and further separating and purifying.
(B1) The ZW800-iRGD is synthesized by a one-step solid phase method.
(B2) Separating and purifying the totally synthesized totally water-soluble ZW800-iRGD micromolecules.
2. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (A1) comprise:
(A1.1)1eq 4-hydrazinobenzenesulfonic acid (1-2g, 19.9-39.8mmol), 3eq 3-methyl-2-butane (1.5-3ml, 60-120mmol) and glacial acetic acid (40-60ml) were mixed and heated to 90-120 ℃ for 15-20h under nitrogen atmosphere.
(A1.2) after precipitation in ethyl acetate, the crude product was filtered and collected as a pink solid and the resulting product was dissolved in methanol (40mL-60 mL).
(A1.3) at room temperature, 1eq of a solution of potassium hydroxide (1.12-2.24g, 19.9-39.8mmol) and isopropanol (30-40ml) was added dropwise to the solution, and the mixture was filtered through a filter paper to obtain a crude product.
(A1.4) the crude product was washed three times with isopropanol to clarity without further purification to give a brown solid. (97%)
(A1.5) 1eq of 2(1-2g, 3.6-7.2mmol) and 1.5eq of (3-bromopropyl) trimethylammonium bromide (2-3g, 7.68-11.52mmol) are added to a toluene solution under a nitrogen atmosphere and heated at 80-110 ℃ for 30-48 h.
(A1.6) the mixture was cooled to room temperature, and the solvent precipitated. Adding methanol (10-20ml) into the crude mixture, stirring for 20-40min, filtering the crude mixture, collecting, and dissolving in a mixed solvent of 1: 2(v/v) methanol (10-20ml) and water (20-40 ml).
(A1.7) the mixed solution was then slowly charged into acetonitrile (120-180ml) using a dropping funnel. The precipitate was filtered and collected as a pink solid. (40%)
(A1.8) 2eq of 3(1-2g, 1.86-3.72mmol), 1eq of Vilsmeier-Haack reagent (0.33-0.67g, 0.93-1.86mmol) and 3eq of anhydrous sodium acetate (0.22g-0.45g, 2.79mmol-5.58mmol) were heated under reflux in 10mL-30mL of anhydrous ethanol under a nitrogen atmosphere for 4h-8 h.
(A1.9) the reaction mixture was cooled to room temperature, then filtered, washed with excess ethanol and methanol and collected as a brown-green solid 4. (90%)
3. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (A2) comprise:
(A2.1)1eq 3- (4-hydroxyphenyl) propionic acid (1-2g, 6.0-12.0mmol) was dissolved in 10-30mL of 2eq aqueous sodium hydroxide (0.48-0.96g, 12-24mmol), reacted at room temperature for 24-48h, and rotary evaporated to give white solid 5. (95%)
(A2.2) 2eq of 5(1-1.5g, 4.7-7.05mmol) and 1eq of 4(1.9-2.88g, 2.35-3.525mmol) were mixed and added to a solution of DMSO and water (40mL, 1: 1v/v) and heated under reflux for 6h, and the mixture was precipitated by mixing ethyl acetate and ethanol (400mL, 1: 1 v/v). The precipitate was filtered, washed with ethanol and acetone and collected as a dark green solid (10.4g, 80%) as 6.
(A2.3) separation and purification in preparative liquid chromatography using 0.1% formic acid water and 10% methanol as mobile phases.
4. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (B1) comprise:
(B1.1) Fmoc solid phase peptide chemical synthesis using standard automated continuous flow precursor peptide synthesizer using HCys (Trt) -2Cl resin (0.4mmol/g substitution) as solid support.
(B1.2) before use the resin was soaked in N, N-Dimethylformamide (DMF) for 15 minutes.
(B1.3) after DMF filtration, a mixture of Fmoc-Asp (Otbu) -OH (2equiv), HBTU (2equiv) and N, N-diisopropylethylamine (DIEA, 2 equiv); the solution was added to the resin and stirred with nitrogen.
(B1.4) after one hour, the solvent was removed and the resin was washed three times with Dimethylformamide (DMF).
(B1.5) then, the Fmoc group was deprotected with 20% piperidine, shaken for 20 min, and washed 9 times by draining.
(B1.6) Each acylation and deprotection cycle was monitored in real time. After repeated deprotection and acylation reactions, the protected precursor of ZW800-iRGD is cleaved from the resin.
(B1.7) cleavage of the peptide fragment with trifluoroacetic acid (TFA)/Triisopropylsilane (TIS)/water at a ratio of 95: 2.5 for 2-2.5h gave crude ZW800-iRGD (30%).
5. The preparation method of the active targeting near-infrared fluorescent molecule based on the patent claim 1 is characterized in that the specific steps (B2) comprise:
(B2.1) then washed several times with cold diethyl ether and then dried in vacuo.
(B2.2) the precipitate was dissolved in water and the residual TFA was neutralized with trimethylamine.
(B2.3) finally concentrating by rotary evaporation and freezing, and determining the purity of the polypeptide by adopting an Agilent 100 series high performance liquid chromatography system.
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| WO2024051308A1 (en) * | 2022-09-09 | 2024-03-14 | 南京诺源医疗器械有限公司 | PEMETREXED NEAR-INFRARED FLUORESCENT MOLECULE TARGETING α-TYPE FOLATE RECEPTOR, PREPARATION METHOD THEREFOR, AND USE THEREOF |
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| WO2024051308A1 (en) * | 2022-09-09 | 2024-03-14 | 南京诺源医疗器械有限公司 | PEMETREXED NEAR-INFRARED FLUORESCENT MOLECULE TARGETING α-TYPE FOLATE RECEPTOR, PREPARATION METHOD THEREFOR, AND USE THEREOF |
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