Medical device containing fluorescent tracer agent and fluorescent tracing method thereof

Abstract

The invention discloses a medical instrument containing a fluorescent tracer agent and a fluorescent tracing method of the medical instrument, and particularly discloses application of a compound shown in a formula (1) as the fluorescent tracer agent in the medical instrument: # imgabs0 #. The fluorescent tracer agent disclosed by the invention has stable fluorescent characteristics and no biological toxic or side effect, and can be applied to the medical instrument.

Description

Technical Field

[0001] The invention belongs to the technical field of fluorescent tracing, and particularly relates to a medical device containing a fluorescent tracer and a fluorescent tracing method thereof. Background Art

[0002] Optical imaging has very wide applications in research and clinical practice. Currently, materials that can emit longer wavelength fluorescence in a solid state can hardly be translated and applied in clinical research due to their inherent toxicity or nanostructures with unknown toxicity and metabolic characteristics.

[0003] Arteriovenous malformations often occur in the brain. The current treatment method is to first inject the liquid embolic agent n-butyl cyanoacrylate (such as n-BCA) into the abnormal blood vessel mass through arterial intervention surgery, and then perform a craniotomy to remove the lesion at a later date. However, during the process of removing the lesion in the brain, the boundary range of the lesion is often unclear, resulting in incomplete removal of the lesion or excessive removal of the lesion, which damages the surrounding normal brain tissue.

[0004] Surgeries such as ventriculoperitoneal shunts require the passage of very long medical catheters through the subcutaneous fat layer of the chest and abdomen. The chance of the catheter breaking or breaking is very high. Currently, there is no effective imaging technology for diagnosing this type of medical catheter that is implanted superficially in the body for a long time. Summary of the invention

[0005] The purpose of the present invention is to provide a medical device containing a fluorescent tracer and a fluorescent tracer method thereof. The fluorescent tracer of the present invention has stable fluorescent properties and has no biological toxicity or side effects, and can be applied to medical devices.

[0006] To achieve the above object, the present invention provides a compound represented by formula (1) for use as a fluorescent tracer in medical devices:

[0007]

[0008] Among them, R 1 , R 2 are the same or different, each independently selected from: hydrogen, -C 0-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 、-OC 1-10 Alkyl-R 16 , -SC 1-10 Alkyl-R 16 、-C(O)-NH-C 1-10 Alkyl-R 16 or

[0009] R 3 , R 4 , R 5 , R 6 are the same or different, each independently selected from: hydrogen, -C 1-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 or -C(O)-C 1-10 Alkyl-R 16 ; R 7 Not present or -(CH2) 1-10 -;

[0010] is selected from: cycloalkenyl, aryl, N-containing aromatic or non-aromatic monocyclic or polycyclic heterocyclic ring, wherein the heterocyclic ring optionally contains 1-3 heteroatoms selected from O, S, Se and N; when R 7 When absent or attached to a benzene ring, X is a carbon atom;

[0011] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 the same or different, each independently selected from: hydrogen, -C 0-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 、-OC 1-10 Alkyl-R 16 , -SC 1-10 Alkyl-R 16 、-C(O)-NH-C 1-10 Alkyl-R 16 or -NH-C(O)-C 1-10 Alkyl-R 16 ;

[0012] R 16 Selected from: hydrogen, amino or the corresponding salt, nitro, carboxyl or the corresponding salt, hydroxyl, sulfonic acid or the corresponding salt, cyano, halogen, phosphate or the corresponding salt, aldehyde, thiol or -SO2NH2.

[0013] The application of the present invention, R 1 , R 2are the same or different, each independently selected from: hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -(CH2)3CH3, -(CH2)4CH3,

[0014] -C 0-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 、-OC 1-10 Alkyl-R 16 , -SC 1-10 Alkyl-R 16 、-C(O)-NH-C 1-10 Alkyl-R 16 or

[0015] R 3 , R 4 are the same or different, each independently selected from: hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -(CH2)3CH3, -(CH2)4CH3,

[0016] R 10 , R 11 , R 12 , R 13 , R 14 , R 15 are the same or different, each independently selected from: hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -(CH2)3CH3, -(CH2)4CH3,

[0017] In the application of the present invention, the compound represented by formula (1) is:

[0018] Compound 1:

[0019]

[0020] Compound 2:

[0021]

[0022] Compound 3:

[0023]

[0024] The present invention also provides a medical device, which comprises a fluorescent tracer, wherein the fluorescent tracer comprises the compound represented by the formula (1).

[0025] The medical device of the present invention is a surgical suture, a catheter, an embolic material or an implant.

[0026] The present invention further provides a fluorescent tracing method, which uses irradiation light to irradiate a medical device containing a fluorescent tracer, wherein the fluorescent tracer includes the compound represented by formula (1), so that the fluorescent tracer emits red fluorescence under the excitation of the irradiation light;

[0027] The medical device is a surgical suture, a catheter, an embolic material or an implant.

[0028] In the fluorescent tracing method of the present invention, the fluorescent tracer is directly or dissolved in a solvent and then combined with the medical device by dipping, coating or mixing.

[0029] In the fluorescent tracing method of the present invention, the solvent is selected from at least one of tetrahydrofuran, methanol, water, n-butyl cyanoacrylate and medical embolic glue.

[0030] In the fluorescent tracing method of the present invention, the medical embolic glue is composed of ethylene-vinyl alcohol copolymer and tantalum powder, or of dimethyl sulfoxide and tantalum powder.

[0031] In the fluorescent tracing method of the present invention, the wavelength of the irradiation light is 800-900nm, with 808nm being the best. The fluorescent tracer of the present invention can emit strong near-infrared II region fluorescence with a wavelength exceeding 1000nm, and the fluorescent tracer has a unique optical characteristic of emitting near-infrared II region fluorescence in a solid state. The fluorescent tracer of the present invention has stable fluorescence characteristics and no biological toxic side effects. In addition, the fluorescent tracer can still maintain stable fluorescence characteristics after high-temperature treatment. The fluorescent tracing method of the present invention is very conducive to its stable adhesion to various forms of medical devices as a coating material, and can be used for non-invasive diagnosis in surgeries such as ventriculoperitoneal shunts, and can guide the post-embolization fluorescence-guided lesion resection of arteriovenous malformation lesions. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the color observation result of compound 1.

[0033] Figure 2 The optical absorption and emission spectra of compound 1.

[0034] Figure 3 The fluorescence intensity change results of the solid powder of compound 1 within 0-24 hours.

[0035] Figure 4 The thermal stability test results of compound 1.

[0036] Figure 5 This is the fluorescence detection result of Example 1.

[0037] Figure 6 This is the fluorescence detection result of Example 2.

[0038] Figure 7 This is the fluorescence detection result of Example 3. DETAILED DESCRIPTION

[0039] The present invention is described in detail below by way of examples. It is necessary to point out that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Those skilled in the art in this field can make some non-essential improvements and adjustments to the present invention based on the above content of the present invention.

[0040] Colorimetric observation of fluorescent tracers:

[0041] Take an appropriate amount of compound 1 solid powder, irradiate it with 808nm light, and observe it under a fluorescent imaging device. The results are as follows: Figure 1 As shown, the results of the light absorption and light emission spectra of compound 1 are as follows Figure 2 The fluorescence intensity change of the solid powder of compound 1 was observed within 0-24 hours, and the results were as follows Figure 3 As shown. Figure 1 The results show that compound 1 can emit infrared II fluorescence with a wavelength exceeding 1000nm. By adjusting the lens filter of the fluorescence imaging device, it can be seen that as the wavelength of the lens filter fluorescence gradually increases, the infrared II fluorescence passing through gradually weakens. Figure 3 The results show that the fluorescence intensity of the solid powder of compound 1 changes very little within 0-24 hours, which proves that compound 1 has stable fluorescence characteristics.

[0042] Thermal stability of fluorescent reagents:

[0043] Compound 1 was heated at 50, 75 and 100°C, respectively, and dissolved in water, methanol and dimethyl sulfoxide (DMSO) solvents and then freeze-dried back to powder state. The fluorescence intensity of compound 1 was detected. The results are as follows: Figure 4 shown.

[0044] from Figure 4 It can be seen from the results that compound 1 of the present invention can still maintain the stable characteristic of emitting near-infrared II region fluorescence after being heated at different temperatures and dissolved in different types of solvents.

[0045] Fluorescent tracer:

[0046] Example 1

[0047] The solid powder of compound 1 is added into medical purified water and shaken thoroughly, and then the medical suture thread is immersed in the solution of compound 1 to form a layer of compound 1 evenly attached to the surface, and then passed through a fine aperture to become very thin dyed suture threads, and the dyed suture threads are intertwined into a thread to obtain a surgical suture thread with compound 1 as a stable coating material on the surface.

[0048] The surgical sutures were sutured to the muscle or soft tissue layer deep in the mouse wound, and then the wound was closed by conventional sutures. Since the surgical sutures attached with compound 1 are absorbable materials, the absorption and degradation process of the surgical sutures deep in the wound can be clearly detected through the near-infrared II region fluorescent lens and camera. As time goes by, the surgical sutures gradually degrade, and the compound 1 coating on the surface of the surgical sutures disintegrates, and the fluorescent signal continues to weaken. The results are as follows: Figure 5 shown.

[0049] Example 2

[0050] 20 mg of silicone rubber was mixed with 2 mg of curing agent, and mixed thoroughly until a uniform and transparent solution was formed to obtain polydimethylsiloxane (PDMS). The solid powder of compound 1 was dissolved in methanol, and further diluted with tetrahydrofuran (THF) to a concentration of 1 mmol / L, and the total volume was set to 500 uL to obtain a solution in which compound 1 was dissolved. Polydimethylsiloxane was added to the solution in which compound 1 was dissolved, and the mixture was shaken until completely mixed, and then the tiny bubbles were further removed in a vacuum device to obtain a mixed solution. The silicone catheter was placed in the mixed solution, taken out after soaking for 2 minutes, and then placed at room temperature for 4 days to obtain a medical silicone catheter with compound 1 coated on the surface.

[0051] A medical silicone catheter coated with compound 1 was passed through the subcutaneous soft tissue of mice. When the catheter was broken in the subcutaneous soft tissue of the mice, an 808nm laser was irradiated on the skin. The near-infrared II zone lens and camera could detect the interruption of the near-infrared II zone fluorescence of compound 1. The interrupted fluorescence indicated the catheter break. The results are shown in Figure 2. Figure 6 shown.

[0052] When the near-infrared II zone fluorescence is interrupted, the width of the catheter fracture can be determined by quantitative analysis. The fluorescence tracing method of the present invention can perform non-invasive diagnosis of the depth of the catheter fracture, the size of the crack, etc. according to the interruption of the fluorescence signal.

[0053] Example 3

[0054] Compound 1 was dissolved in n-butyl cyanoacrylate (n-BCA) embolic agent at a concentration of 20 mg / mL, and after micro-oscillation and centrifugation for at least 10-20 minutes, compound 1 was basically completely dispersed in the n-BCA embolic agent before being used for embolization surgery; a rat model of cervical arteriovenous malformation was established, and the n-BCA embolic agent mixed with compound 1 was injected into the abnormal vascular mass through a conventional arterial catheter. X-ray imaging showed that n-BCA was basically completely embolized in the abnormal vascular mass, and the embolic agent gradually changed from liquid phase to solid phase after encountering blood. About 1 week after the interventional surgery, open surgery was performed. Under the condition of 808nm laser excitation, the near-infrared II fluorescence detector and lens were used to observe the very obvious near-infrared II fluorescence emitted by compound 1 in the condensed state in the abnormal vascular mass lesions. The fluorescence clearly and accurately outlined the edge of the lesion. The results are as follows: Figure 7 As shown, more precise and complete resection of the lesion can be achieved according to this margin.

[0055] from Figure 7 It can be seen from the results that the fluorescence tracking method of the present invention can guide the fluorescence-based surgical resection of the lesion after embolization of the arteriovenous malformation vascular mass.

[0056] Of course, the present invention may have many other embodiments and variations thereof. Without departing from the spirit and essence of the present invention, technicians familiar with the field may make various corresponding changes and variations based on the present invention, but these corresponding changes and variations should all fall within the scope of protection of the claims of the present invention.

Claims

1. Application of the compound represented by formula (1) as a fluorescent tracer in medical devices: in, R 1 , R 2 are the same or different and are independently selected from: hydrogen, -C 0-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 、-OC 1-10 Alkyl-R 16 , -SC 1-10 Alkyl-R 16 、-C(O)-NH-C 1-10 Alkyl-R 16 or R 3 , R 4 , R 5 , R 6 are the same or different and are independently selected from: hydrogen, -C 1-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 or -C(O)-C 1-10 Alkyl-R 16 ; R 7 Not present or -(CH2) 1-10 -; is selected from: cycloalkenyl, aryl, N-containing aromatic or non-aromatic monocyclic or polycyclic heterocyclic ring, wherein the heterocyclic ring optionally contains 1-3 heteroatoms selected from O, S, Se and N; when R 7 When absent or attached to a benzene ring, X is a carbon atom; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 The same or different, each independently selected from: hydrogen, -C 0-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 、-OC 1-10 Alkyl-R 16 , -SC 1-10 Alkyl-R 16 、-C(O)-NH-C 1-10 Alkyl-R 16 or -NH-C(O)-C 1-10 Alkyl-R 16 ; R 16 Selected from: hydrogen, amino or the corresponding salt, nitro, carboxyl or the corresponding salt, hydroxyl, sulfonic acid or the corresponding salt, cyano, halogen, phosphate or the corresponding salt, aldehyde, thiol or -SO2NH2.

2. The use according to claim 1, characterized in that: R 1 , R 2 are the same or different, each independently selected from: hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -(CH2)3CH3, -(CH2)4CH3, -C 0-10 Alkyl-R 16 , -C 2-10 Alkenyl-R 16 , -C 2-10 Alkynyl-R 16 、-OC 1-10 Alkyl-R 16 , -SC 1-10 Alkyl-R 16 、-C(O)-NH-C 1-10 Alkyl-R 16 or R 3 , R 4 are the same or different, each independently selected from: hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -(CH2)3CH3, -(CH2)4CH3, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 are the same or different, each independently selected from: hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -(CH2)3CH3, -(CH2)4CH3, 3. The use according to claim 1, characterized in that: The compound represented by formula (1) is: Compound 1: Compound 2: or Compound 3:

4. A medical device comprising a fluorescent tracer, wherein the fluorescent tracer comprises the compound represented by formula (1) according to any one of claims 1 to 3.

5. The medical device according to claim 4, characterized in that: The medical device is a surgical suture, a catheter, an embolic material or an implant.

6. A fluorescent tracing method, characterized in that: Using irradiation light to irradiate a medical device containing a fluorescent tracer, wherein the fluorescent tracer includes a compound of formula (1) according to any one of claims 1 to 3, so that the fluorescent tracer emits red fluorescence under the excitation of the irradiation light; The medical device is a surgical suture, a catheter, an embolic material or an implant.

7. The fluorescent tracing method according to claim 6, characterized in that: The fluorescent tracer is directly or dissolved in a solvent and then combined with the medical device by dipping, coating or mixing.

8. The fluorescent tracing method according to claim 7, characterized in that: The solvent is selected from at least one of tetrahydrofuran, methanol, water, n-butyl cyanoacrylate and medical embolic glue.

9. The fluorescent tracing method according to claim 8, characterized in that: The medical embolic glue is composed of ethylene-vinyl alcohol copolymer and tantalum powder, or of dimethyl sulfoxide and tantalum powder.

10. The fluorescent tracing method according to any one of claims 6 to 9, characterized in that: The wavelength of the irradiation light is 800-900nm.

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