CN111196896B - Water-soluble heptamethine cyanine near-infrared dye with tumor targeting property and application thereof - Google Patents
Water-soluble heptamethine cyanine near-infrared dye with tumor targeting property and application thereof Download PDFInfo
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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
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/10—The polymethine chain containing an even number of >CH- groups
- C09B23/105—The polymethine chain containing an even number of >CH- groups two >CH- groups
-
- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
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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
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
Abstract
The invention discloses a water-soluble heptamethine cyanine near-infrared dye with tumor targeting and application thereof. After the near infrared dye of the structural formula I is widely distributed in the tissues of the whole body along with the hemoglobin, the dye is metabolized faster in normal tissues than in tumor tissues, so that the dye can be used for treating tumors and tumorsCan be retained in a large amount in tumor tissues, thereby achieving the function of in vivo diagnosis. Therefore, the near-infrared fluorescent dye can be applied to the preparation of tumor diagnosis reagents.
Description
Technical Field
The invention belongs to the technical field of nonspecific molecular targeting diagnostic reagents, and relates to a water-soluble heptamethine cyanine near-infrared dye with tumor targeting and application thereof.
Background
With the increase of the average life span of residents and the change of living environment and dietary habits, malignant tumors become one of the most common high-mortality diseases in the world. In recent years, the incidence and mortality of Chinese malignant tumors have also increased year by year. In the current clinical treatment, surgery is the more effective method for treating early stage tumors. Direct resection of the non-metastatic tumor may provide the patient with more chances for survival.
Currently, clinicians often determine the size, location, and surrounding environment of a tumor by preoperative medical imaging techniques. Common preoperative imaging methods include ultrasound US, CT, MRI, etc., by which a physician has access to a clear image. However, stretching of the tissue during surgery, resection of a solid tumor, and the like often cause the tissue to shift. At this time, the preoperative conventional imaging cannot provide intraoperative real-time image data, and the navigation deviation cannot be corrected in time. Compared with preoperative imaging examination, the in-vivo fluorescence imaging technology has the advantages of timeliness, high resolution, high specificity and the like, and provides a better application prospect for accurate surgical navigation.
In the living body fluorescence imaging technology, a near infrared probe plays a key role. Because the light wave in the near infrared band avoids the optimal absorption wavelength of tissues such as water, hemoglobin and the like in vivo, the biological tissue penetration capability is better, and the biological tissue is not damaged. Indocyanine green (ICG) is a commonly used near-infrared fluorescent dye. The method has the advantages of high molar extinction coefficient, high fluorescence quantum yield and the like, and more importantly, the method has nonspecific passive targeting on tumor tissues. Currently, the U.S. Food and Drug Administration (FDA) approves it as an infrared contrast agent for clinical use. However, the poor water solubility of ICG, its instability in aqueous solution and its rapid clearance in plasma have limited its use to some extent.
In order to overcome the defects of ICG, the parent nucleus and a substituent group of the ICG are modified, and a novel structure ICG-03 is provided in ZL 201710290191.3. ICG-03 has greater stability and targeting than ICG, but its imaging efficacy at low dose administration remains to be improved.
Disclosure of Invention
The invention discloses a near-infrared dye capable of effectively targeting tumor tissues.
Another object of the present invention is to provide the use of the near-infrared dye.
The object of the present invention is to provide an optical imaging diagnostic reagent containing a compound of formula I as an active ingredient.
The invention synthesizes a compound of formula I
After the near infrared dye with the structural formula I is widely distributed in tissues of the whole body along with hemoglobin, the dye is metabolized faster than tumor tissues in normal tissues, and therefore, the dye can be greatly retained in the tumor tissues, and the function of in vivo diagnosis is achieved.
The dye is a derivative of indocyanine green, so that the near-infrared dye with the structural formula I has obvious advantages in biocompatibility compared with other near-infrared probes in vivo safety.
The compound of the structural formula I is abbreviated as NIR-04 hereinafter, and the maximum absorption peak of the compound is about 779nm, and the corresponding maximum fluorescence emission peak is about 800 nm. The ultraviolet absorption spectrum is shown in FIG. 1A, and the fluorescence spectrum is shown in FIG. 1B.
NIR-04 is insoluble in nonpolar solvents such as diethyl ether, and soluble in polar solvents such as water, methanol, acetonitrile, etc. The NIR-04 with tumor targeting can be used as a probe for in vivo tissue imaging because the NIR-04 has strong near infrared fluorescence emission between 700-900nm and the near infrared light in the band can penetrate deep tissues. The method fully shows that the NIR-04 has a potential wide application prospect in the research fields of living tissue imaging, in-situ living body detection and the like.
A near-infrared fluorescent molecular probe comprises the near-infrared fluorescent dye NIR-04.
The near-infrared fluorescent dye is applied to the preparation of tumor diagnosis reagents.
The near-infrared fluorescent dye is preferably applied to the preparation of a tumor precise diagnostic reagent, and further preferably applied to the preparation of a tumor living body fluorescence imaging diagnostic reagent.
The tumors include but are not limited to liver cancer, pancreatic cancer, breast cancer, lung cancer and brain glioma.
The near-infrared fluorescent dye is applied to the preparation of a live body fluorescence imaging reagent for precise tumor surgical navigation.
The dye NIR-04 can accumulate non-specifically at the tumor site. Thereby achieving the purpose of living body tumor fluorescence imaging. In tumor-bearing mouse imaging experiments of various human tumors, the targeted imaging effect of the dye is superior to ICG. Therefore, the dye can be used for clinical tumor detection and intraoperative navigation.
The compound is a non-specific tumor-targeted near-infrared dye and can be used for fluorescence imaging of various tumor models. The applicable tumors include but are not limited to liver cancer, pancreatic cancer, breast cancer, lung cancer and brain glioma.
The invention also encompasses pharmaceutical formulations comprising compound I or other prodrug forms thereof as an active ingredient, together with a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier refers to a pharmaceutical carrier that is conventional in the pharmaceutical art, and refers to one or more inert, non-toxic solid or liquid fillers, diluents, adjuvants and the like that do not interact with the active compound or the patient.
The dosage form of the pharmaceutical preparation can be common pharmaceutical dosage forms such as tablets, capsules, pills, suppositories, soft capsules, oral liquid, suspensions, injections and the like. Tablets and capsules for oral use contain conventional excipients such as fillers, lubricants, binders, disintegrating agents.
The pharmaceutical formulations of the present invention may be prepared by methods well known in the pharmaceutical arts.
Compared with the prior art, the invention has the following beneficial technical achievements
The invention provides a near infrared fluorescent dye NIR-04 with nonspecific tumor targeting. The dye is a heptamethine dye, and compared with indocyanine green which is a targeting dye on the market at present, the dye shows better targeting property and stability when being used for detecting various humanized tumor-bearing mouse models. In addition, the NIR-04-based near-infrared in vivo imaging technology provided by the invention overcomes the heterogeneity of tumor cells. The currently internationally developed near-infrared tumor imaging research mainly adopts a method that a tumor-specific targeting fragment is covalently combined with a near-infrared dye to form a targeted probe with pertinence. However, such probes have limitations. Because only tumor cells with specific markers can be detected by the targeting fragment, these cells with well-defined surface molecular properties are a small fraction of the diverse tumor cells. And NIR-04 has broad-spectrum tumor targeting, and can realize fluorescence imaging of more tumor tissues. The dye of the invention still can show better imaging effect when being administrated at low dose compared with ICG-03 disclosed in ZL 201710290191.3.
Description of the drawings:
FIG. 1 shows the spectral properties of the dye NIR-04
FIG. 2 is a graph comparing the tumor targeting and targeting effect of dye NIR-04 with ICG
A is SW1990 tumor-bearing mouse imaging experiment, B is bel7404 tumor-bearing mouse imaging experiment, C is A549 tumor-bearing mouse imaging experiment, D is MCF-7 tumor-bearing mouse imaging experiment, and E is U87 tumor-bearing mouse imaging experiment. Wherein ICG represents indocyanine green, 03 represents ICG-03, and 04 represents NIR-04 of the present invention.
FIG. 3 is a scheme of synthesis of the dye NIR-04
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention made by those skilled in the art should be within the scope of the protection claimed in the present patent application
Example 1
Preparation of Compounds I of the invention
1. 10g of phenylhydrazine-4-sulfonic acid, 6g of methyl isopropyl ketone and 70ml of acetic acid are taken, heated and refluxed for 6 hours at 120 ℃ under the condition of continuous stirring, so that the raw materials are continuously dissolved, and the solution turns brick red. After the reaction is finished, spin-drying the solution, adding ether for washing to obtain brick-red solid 2,3, 3-trimethyl-6-sulfonic indole, wherein mass spectrum and hydrogen spectrum data are as follows: the ratio of m/z is 238.1,1H NMR(400MHz,DMSO-d6)δ7.86(d,J＝1.5Hz,1H),7.70(dd,J＝8.1,1.6Hz,1H),7.51(d,J＝8.1Hz,1H),2.55(s,3H),1.43(s,6H)。
2. 15g of 2,3, 3-trimethyl-6-sulfonic indole, 21g of 1, 3-propane sultone and 240ml of o-dichlorobenzene are taken and refluxed for 12 hours under the condition of continuous stirring, and the raw materials and the product are not dissolved in the solvent, but can be uniformly dispersed in a molten state. After the reaction is finished, the solvent is discarded, and the mauve viscous solid N- (3-propanesulfonic group) -2,3, 3-trimethyl-6-sulfonic indole can be obtained, and the mass spectrum and the hydrogen spectrum data are as follows: the m/z is 360.1,1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.97(d,J＝8.4Hz,1H),7.82(s,1H),4.64(s,2H),2.83(s,3H),2.65(s,2H),2.13(s,2H),1.54(s,6H)。
3. taking 10g of 2,3, 3-trimethylindole, 21g of 1, 3-propane sultone and 240ml of toluene, refluxing for 12h under the condition of continuous stirring, and removing the solvent after the reaction is finished to obtain the N- (3-propanesulfonic acid group) -2,3, 3-trimethylindole, wherein mass spectrum data and hydrogen spectrum data of the N- (3-propanesulfonic acid group) -2,3, 3-trimethylindole are as follows: 280.1, m/z is equal to,1H NMR(400MHz,DMSO-d6)δ8.10–7.99(m,1H),7.86–7.77(m,1H),7.68–7.55(m,2H),4.72–4.60(m,2H),2.83(s,3H),2.62(t,J＝6.5Hz,2H),2.20–2.08(m,2H),1.53(s,6H)。
4. 4ml of phosphorus oxychloride is taken, 16.6ml of anhydrous DMF is added into an ice bath under the protection of nitrogen, and after the addition is finished, the solution is stirred for 40min at room temperature and turns into light red. The solution was cooled to 0 ℃ and 2.4ml of cyclohexanone were slowly added dropwise in an ice bath and stirred at 50 ℃ overnight. The solution changed color from light red to dark yellow, followed by orange-red. After the reaction, the reaction solution was slowly dropped into ice water, and a yellow solid was precipitated. After dripping, standing for 1h at room temperature, and filtering after the product is fully separated out. Yellow crystalline solid 1-carboxaldehyde-2-chloro-3- (hydroxymethylene) cyclohexene was obtained with m/z 172.6.
5. 1.2g of 1-formaldehyde-2-chloro-3- (hydroxymethylene) cyclohexene, 3.2g of N- (3-propanesulfonic acid) -2,3, 3-trimethyl-6-sulfonic indole, 2.5g of N- (3-propanesulfonic acid) -2,3, 3-trimethylindole and 4.8g of sodium acetate are dissolved in 120ml of absolute ethyl alcohol and refluxed for 4 to 5 hours at 75 ℃, after the reaction is finished, the solvent is dried by spinning, and the residual solid residue is subjected to column chromatography. The product was obtained as emerald solid NIR-04, and its mass and hydrogen spectra data were as follows: m/z is 777.1;1H NMR(400MHz,DMSO-d6)δ8.26(dd,J＝18.8,14.1Hz,2H),7.77(s,1H),7.63(d,J＝7.9Hz,2H),7.56(d,J＝8.0Hz,1H),7.46–7.39(m,2H),7.29(t,J＝7.5Hz,1H),6.53(t,J＝14.0Hz,2H),4.37(dt,J＝19.9,7.6Hz,4H),2.80–2.71(m,4H),2.59(t,J＝6.2Hz,4H),2.09–1.95(m,4H),1.84(s,2H),1.68(d,J＝3.0Hz,12H)。
example 2
Comparison of imaging Effect of ICG, ICG-03 and NIR-04 on human tumor-bearing murine models of different cell lines
In order to examine the tumor targeting capability of NIR-04, five mouse tumor models are constructed in the example, tumor cells bel7404 (liver cancer), sw1990 (pancreatic cancer), MCF7 (breast cancer), A549 (lung cancer) and U87 (brain glioma) are inoculated in the armpit, and the dynamic distribution of NIR-04, ICG-03 (preparation method is shown in 201710290191.3) and ICG in bel7404 (liver cancer), sw1990 (pancreatic cancer), MCF7 (breast cancer), A549 (lung cancer) and U87 (brain glioma) tumor-bearing mice (axillary tumor) is detected in real time by a lossless in-situ near infrared fluorescence imaging technology. In the experiment, a 760nm laser is used as a light source, a high-sensitivity near-infrared inductively coupled camera is used for obtaining a fluorescence signal in a mouse body, an 800nm long-pass optical filter is used in the experiment, the administration dosage of the two dyes is 100 mu g/dye, and the administration mode is tail vein injection.
The experimental result shows that the three dyes are distributed systemically and are accumulated in the liver and intestine part more when the medicine is injected for 2 hours; ICG and ICG-03 are weakly accumulated at a tumor part after the injection of the medicine for 12 hours, the fluorescence signal of NIR-04 at the tumor part reaches the maximum value, signals at other parts of a mouse body are obviously weakened, and the fluorescence intensity of NIR-04 is obviously higher than that of ICG and ICG-03; ICG and ICG-03 are basically metabolized after the medicine is injected for 24 hours, and NIR-04 still has more accumulation at the tumor part. It can be seen that NIR-04 has a superior targeting effect on the tumors involved in the experiment than ICG and ICG-03 (FIGS. 2-3).
Claims (8)
1. A near-infrared fluorescent dye with tumor targeting, which has a structure shown in formula I:
2. a near-infrared fluorescent molecular probe comprising the near-infrared fluorescent dye according to claim 1.
3. Use of the near-infrared fluorescent dye according to claim 1 in the preparation of a tumor diagnostic reagent.
4. The use according to claim 3, characterized in that the near-infrared fluorescent dye according to claim 1 is used for preparing a precise diagnostic reagent for tumors.
5. The use according to claim 3, characterized in that the near-infrared fluorescent dye according to claim 1 is used for preparing a diagnostic reagent for fluorescence imaging of tumor living bodies.
6. The use according to any one of claims 3 to 5, wherein the tumor is liver cancer, pancreatic cancer, breast cancer, lung cancer or brain glioma.
7. The use of the near-infrared fluorescent dye of claim 1 in the preparation of a live body fluorescence imaging reagent for precise surgical navigation of tumors.
8. The use of claim 7, wherein the tumor is liver cancer, pancreatic cancer, breast cancer, lung cancer, brain glioma.
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